Assessment of VEGF and VEGF R1 serum levels in patients with neuroendocrine neoplasms before and after treatment with first-generation somatostatin analogues.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a known promoter of angiogenesis that can support neuroendocrine neoplasm (NEN) development. The aim of the study was to evaluate the serum VEGF and vascular endothelial growth factor receptor 1 (VEGF R1) concentration changes in patients with NEN treated with first-generation long-acting somatostatin analogues (SSA). MATERIAL AND METHODS: The study comprised 55 controls and 56 NEN patients before and after SSA treatment in various periods of time (months): 1-12 (n = 54), 13-24 (n = 46), 25-36 (n = 35), 37-60 (n = 26), and over 60 months (n = 22). An analysis of medical records and serum VEGF and VEGF R1 concentration measurements of NEN patients, by enzyme-linked immunosorbent assay (ELISA) were made. RESULTS: During SSA treatment time, a decrease of the VEGF and an increase of VEGF R1 concentrations was observed. We confirmed significant VEGF differences between 2 pairs of SSA-treated NEN patient subgroups: Group 1-12 vs. Group 37-60 (p = 0.039) and Group 1-12 vs. Group > 60 (p = 0.026). We did not note significant differences of VEGF R1 levels between SSA-treated NEN patient subgroups. Among the studied biomarkers, VEGF R1 exhibited the best performance in distinguishing between NEN patients with controls; area under the curve (AUC) = 1 (p < 0.001). CONCLUSIONS: The examined angiogenesis factors (VEGF and VEGF R1) seem to have limited usage in the assessment of SSA treatment effectiveness in NEN. However, the assessment of serum levels of these factors may help in the differentiation of NEN patients and healthy controls; in particular, VEGF R1 seems to be a good diagnostic biomarker for NEN patients.

Treatment of Neovascular Age-Related Macular Degeneration: An Economic Cost-Risk Analysis of Anti-Vascular Endothelial Growth Factor Agents.

PURPOSE: To find the best cost-effective neovascular age-related macular degeneration (nAMD) treatment to improve vision while avoiding complications. The model is based on a cost-risk tradeoff analysis from policymakers' perspective. DESIGN: A powerful and flexible simulation modeled outcomes of 2 years of treatment with the 4 commonly used anti-vascular endothelial growth factor drugs (bevacizumab, ranibizumab, aflibercept, and brolucizumab) across 3 injection protocols, building on prior findings that these drugs are noninferior. The model incorporates blinding complications, their management, and associated costs to society. Each option and several what-if scenarios were simulated 1,000 times with 100,000 hypothetical patients. PARTICIPANTS: One hundred thousand simulated patients using data from published clinical trials. METHOD: Case- and eye-specific cost-risk economic analysis. MAIN OUTCOME MEASURES: Costs of nAMD treatment per patient and number of eyes that become blind as a result of treatment over 2 years. RESULTS: Using published prices and fees, the injection protocol that follows published clinical studies, results showed that the mean±standard deviation cost per patient were $16,859 ± $3.65, $32,949 ± $3.27, $39,831 ± $3.80, and $53,056 ± $2.99 for bevacizumab, brolucizumab, aflibercept, and ranibizumab, respectively. The numbers±standard deviations of treated eyes that became blind were 108 ± 10.18, 694 ± 26.66, 168 ± 12.83, and 108 ± 10.52, respectively. We further provide a lower bound (when all patients are maximally extended) and upper bound (when no patient is extended) to these numbers. For brolucizumab, the upper bound is the 2-month interval injection protocol. CONCLUSIONS: Taking a policymaking perspective, this study suggested that bevacizumab is the preferred first-line therapy. Recommendation for second-line therapy depends on the extent of the policymaker's risk aversion because of the tradeoff between cost and risk of blindness as a result of treatment. If risk neutral, the least expensive option (brolucizumab) is preferred. But if policymakers are moderately to highly risk averse, then aflibercept or ranibizumab are preferred. Because medical advances and different costs may change our findings, we provide a free application (https://eye-inj.shinyapps.io/calc/) for readers who wish to use different cost structures. Simulating outcomes is an innovative approach, unique in ophthalmology, and presents a significant opportunity because it can be adapted easily to different settings (using different costs, risks, and protocols) and to other diseases (e.g., diabetic macular edema), to ultimately improve wide-scale decision-making and use of funds.

Comprehensive Preclinical Assessment of ADVM-022, an Intravitreal Anti-VEGF Gene Therapy for the Treatment of Neovascular AMD and Diabetic Macular Edema.

Inhibition of vascular endothelial growth factor is the mode of action for several approved therapies, including aflibercept, for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Lack of compliance due to the frequent intravitreal dosing requirements may result in inadequately treated disease, leading to irreversible vision impairment. To date, the majority of gene therapy clinical trials providing sustained anti-VEGF levels in the retina have been limited to subretinal injections requiring a vitrectomy. A single intravitreal injection of a gene therapy product could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, has been optimized for intravitreal delivery and strong protein expression. Long-term expression and efficacy of ADVM-022-derived aflibercept were evaluated in a laser-induced choroidal neovascularization (CNV) model in non-human primates. Ocular safety was evaluated following long-term suppression of VEGF by clinical scoring (inflammatory parameters) as well as optical coherence tomography (OCT) and electroretinography (ERG). Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels in ocular tissues. In addition, ADVM-022 administration 13 months before laser-induced CNV prevented the occurrence of clinically relevant CNV lesions, to the same degree as a bolus of aflibercept delivered at the time of laser. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for nAMD and DME, and may ultimately improve patients' visual outcomes. Clinical trials are currently underway, evaluating safety and efficacy following a single intravitreal injection of ADVM-022.

Cost-Utility of Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.

PURPOSE: To evaluate the cost-utility of treatment for macular edema in central retinal vein occlusion (CRVO) using intravitreal injections of the anti-vascular endothelial growth factor (VEGF) agents bevacizumab, ranibizumab, and aflibercept. DESIGN: Decision analysis model of cost-utility. PARTICIPANTS: Data from study participants in the Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) study. METHODS: A decision analysis of a disease simulation model was used to calculate comparative cost-utility of intravitreal bevacizumab (IVB), intravitreal ranibizumab (IVR), and intravitreal aflibercept (IVA) for the treatment of macular edema associated with CRVO based on data from the LEAVO study. Center for Medicare and Medicaid Services data were used to calculate associated modeled costs in a hospital- or facility-based and nonfacility setting from a third-party payer perspective, and societal costs also were calculated. Cost utility was calculated based on the preserved visual utility during the 2 years of the study and also by estimating utility for the expected lifetime. MAIN OUTCOME MEASURES: Cost of treatment, cost per quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER). RESULTS: From the third-party payer perspective, the estimated lifetime costs per QALY in the facility and nonfacility settings were $39 325 and $17 944, respectively, for IVB; $114 095 and $92 653, respectively, for IVR; and $78 935 and $63 270, respectively, for IVA. From the societal perspective, the estimated lifetime costs per QALY in the facility setting were $52 754 for IVB, $128 242 for IVR, and $86 262 for IVA. The ICER of IVA compared with that of IVB was $153 633/QALY from the third-party facility setting and $152 992/QALY from the societal perspective. The use of IVB compared with IVR and IVA compared with IVR were cost-saving interventions (ICER, <0) regardless of the perspective or setting. CONCLUSIONS: In the treatment of macular edema in CRVO, IVB yields the best cost utility among the 3 anti-VEGF agents modeled. Intravitreal aflibercept maintains acceptable lifetime cost per QALY while having a favorable cost utility compared with IVR.

Preliminary safety assessment of oridonin in zebrafish.

Context: Oridonin, isolated from the leaves of Isodon rubescens (Hemsl.) H.Hara (Lamiaceae), has good antitumor activity. However, its safety in vivo is still unclear. Objective: To investigate the preliminary safety of oridonin in zebrafish. Materials and methods: Embryo, larvae and adult zebrafish (n = 40) were used. Low, medium and high oridonin concentrations (100, 200 and 400 mg/L for embryo; 150, 300 and 600 mg/L for larvae; 200, 400 and 800 mg/L for adult zebrafish) and blank samples were administered. At specific stages of zebrafish development, spontaneous movement, heartbeat, hatching rate, etc., were recorded to assess the developmental effects of oridonin. VEGFA, VEGFR2 and VEGFR3 gene expression were also examined. Results: Low-dose oridonin increased spontaneous movement and hatching rate with median effective doses (ED50) of 115.17 mg/L at 24 h post-fertilization (hpf) and 188.59 mg/L at 54 hpf, but these values decreased at high doses with half maximal inhibitory concentrations (IC50) of 209.11 and 607.84 mg/L. Oridonin decreased heartbeat with IC50 of 285.76 mg/L at 48 hpf, and induced malformation at 120 hpf with half maximal effective concentration (EC50) of 411.94 mg/L. Oridonin also decreased body length with IC50 of 324.78 mg/L at 144 hpf, and increased swimming speed with ED50 of 190.98 mg/L at 120 hpf. The effects of oridonin on zebrafish embryo development may be attributed to the downregulation of VEGFR3 gene expression. Discussions and conclusions: Oridonin showed adverse effects at early stages of zebrafish development. We will perform additional studies on mechanism of oridonin based on VEGFR3.

A Multinational Comparison of Anti-Vascular Endothelial Growth Factor Use: The United States, the United Kingdom, and Asia-Pacific.

PURPOSE: A comparison of anti-vascular endothelial growth factor (anti-VEGF) medication use across multiple countries. CLINICAL RELEVANCE: Anti-VEGF medication use is now considered first-line treatment for numerous retinal diseases globally. Exploring medication choices, costs within each healthcare system, policy challenges, emerging treatments, and patient access all provide insight into a newly recognized and major public health issue. METHODS: All data presented in this review are available through the published English literature in PubMed, non-peer-reviewed trade publications, and reported surveys. The following search terms were used: anti-VEGF OR bevacizumab OR ranibizumab OR aflibercept OR pegaptanib OR conbercept AND trends OR survey OR cost OR patterns OR preference. Countries with large populations and available data included the United States, United Kingdom, China, India, Korea, Singapore, and Australia. Population and economic statistics were obtained from published reports from the World Bank, World Health Organization, and Commonwealth Fund. RESULTS: Anti-VEGF medication use and costs are significant aspects of patient and healthcare system expenditures in each nation and may have an especially large potential economic burden in India and China. Bevacizumab use comprises the majority of anti-VEGF medication use in the United States and Singapore, although aflibercept use is growing rapidly. Paradoxically, data demonstrate that there is a significant trend in medication choice toward ranibizumab and aflibercept among practice settings outside of the United States, such as the United Kingdom, China, South Korea, and Australia. The price of anti-VEGF medications ranged from US $30 (ziv-aflibercept) to US $1950 (ranibizumab and aflibercept). Ranibizumab's price ranged from US $240 in India to US $1950 in the United States. Conbercept in China costs approximately US $1150 per dose. CONCLUSIONS: Outside of the United States, many nations are using a majority of more expensive anti-VEGF medications, which may lead to increased costs and decreased access. Increasing the availability of safely compounded anti-VEGF medications will likely improve access, create patient/provider choice, and decrease relative healthcare costs for the growing burden of retinal diseases globally.

Burden of Wet Age-Related Macular Degeneration and Its Economic Implications in Singapore in the Year 2030.

PURPOSE: To estimate the prevalence of wet age-related macular degeneration (AMD) in Singapore in the year 2030. This projection will help in planning appropriate care provision and build health services capacity to cater to the increasing healthcare demand in 2030. METHODS: The number of AMD patients aged 40-79 years from all Singaporeans was estimated using prevalence rates from a local study and using the United Nations population projections for Singapore to 2030. Age-specific mortality was accounted for. Additionally, two main scenarios were presented: (1) Projected number of wet AMD cases if patients were not taking preventive antioxidant vitamins; (2) projected number of wet AMD cases if patients were taking preventive antioxidant vitamins. Based on these scenarios, the economic burden was calculated. The number of quality-adjusted life years (QALYs) gained as a result of improvement in visual acuity (VA) due to anti-vascular endothelial growth factor (VEGF) treatment was also calculated. RESULTS: An estimated growth of 42% in the number of wet AMD cases is expected by 2030. The estimated economic burden of wet AMD in 2030 for scenarios 1 and 2 is Singapore $203.1 million and $162.9 million, respectively. The QALYs gained as a result of improved VA from wet AMD treatment ranged from 10,114.4 to 14,058.8 over a 5-year period for the 2030 cohort. CONCLUSION: The burden of wet AMD is set to increase over the next 15 years. Appropriate measures to build healthcare capacity and plan for this expected surge in patients should be a priority in Singapore.

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).

BACKGROUND: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. DESIGN: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. SETTING: Twenty-three ophthalmology departments in NHS hospitals. PARTICIPANTS: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. INTERVENTIONS: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. MAIN OUTCOME MEASURES: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. RESULTS: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. CONCLUSIONS: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92166560. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.

Emancipatory practices of nurses in primary health care: the home visit as an instrument of health needs assessment / Prácticas emancipadoras del enfermero en la atención primaria de salud: la visita domiciliaria como instrumento de reconocimiento de necesidades de la salud / Práticas emancipatórias de enfermeiros na Atenção Básica à Saúde: a visita domiciliar como instrumento de reconhecimento de necessidades de saúde

Objective Identify nurses’ emancipatory practices in primary care, to contribute to the improvement of health care. Method A case study type social research of qualitative nature, in which nurses of a primary health care service unit in São Paulo were interviewed. Results The home visit was identified as a nursing practice possible to be expanded in order to identify social determinants of health, triggering emancipatory practices in the service. This expansion occurred because the design of health care labour intended by the service team changed its focus from the traditional object of health services, the disease. Conclusion First, it is advocated that social policies lead projects with the purpose of improving health needs. On the other hand, the daily labour needs to provide opportunities for reflection and discussion of healthcare projects, leading workers to propose labour-processes targeted to both the social determinants of health and people’s illness. .

Objetivo Identificar las prácticas emancipadoras de enfermeras en Unidad de Salud Familiar fueron el objeto de este estudio. Método La investigación social cualitativa tipo estúdio de caso. Fueron entrevistados enfermeros de una Unidad de Salud Familiar en Sao Paulo. Resultados Se identificó que la Visita Domiciliaria ha ampliado su alcance y identificado determinantes del proceso salud-enfermedad, lo que provocó en la Unidad de Salud Familiar prácticas emancipadoras. Esta expansión se produjo debido a que el diseño de la atención en propósito por la USF amplió el tradicional objeto de los servicios de salud. Conclusión Se aboga que las directrices de las políticas sociales basen proyectos que tengan como fin el mejoramiento de las necesidades de salud y que el trabajo diario proporcione la reflexión y discusión de los proyectos de atención, para proponer prácticas que enfoquen en los determinantes del proceso salud-enfermedad, tanto cuanto en sus resultados - la enfermedad en el cuerpo individual. .

Objetivo Identificar as práticas emancipatórias de enfermeiros da Atenção Primária, com a finalidade de contribuir para o aprimoramento do cuidado em saúde. Método Pesquisa social de natureza qualitativa, do tipo estudo de caso. Foram entrevistados os enfermeiros de uma Unidade de Saúde da Família em São Paulo. Resultados Identificou-se que a visita domiciliária, prática protocolar, ampliou seu escopo e identificou determinantes do processo saúde-doença, desencadeando na Unidade de Saúde da Família práticas emancipatórias. Essa ampliação ocorreu porque o projeto de cuidado intencionalizado ampliou o objeto tradicional dos serviços de saúde. Conclusão Advoga-se que as diretrizes das políticas sociais ancorem projetos que tomem como finalidade o aprimoramento das necessidades de saúde e que o cotidiano do trabalho proporcione reflexão e discussão dos projetos de cuidado, para intencionalizar práticas que incidam nos determinantes do processo saúde-doença, tanto quanto nos resultados - a doença expressa no corpo individual. .

Current anti-vascular endothelial growth factor dosing regimens: benefits and burden.

TOPIC: To examine the outcomes of clinical trials and case studies that investigated the different dosing regimens used for the 3 intravitreal anti-vascular endothelial growth factor (VEGF) inhibitors that are available currently. The Comparisons of Age-Related Macular Degeneration (AMD) Treatments Trial (CATT) data are discussed briefly here and are reviewed in greater detail in a separate accompanying article. CLINICAL RELEVANCE: Sustained improvement with the 2 most widely used anti-VEGF drugs, bevacizumab and ranibizumab, requires monthly visits, posing a difficulty for patients. Thus, there is a need to evaluate whether individualized treatment regimens may reduce patient burden and improve patient outcomes. METHODS: Review of clinical trials and case studies presented at recent medical conferences and published in peer-reviewed literature. RESULTS: Numerous trials, including the Efficacy and Safety of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization (CNV) Secondary to AMD, Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab, Study of Ranibizumab in Patients with Subfoveal CNV Secondary to AMD, Extension Study to Evaluate the Safety and Tolerability of Ranibizumab in Subjects with CNV Secondary to AMD or Macular Edema Secondary to Retinal Vein Occlusion, Safety Assessment of Intravitreal Lucentis for AMD, and CATT, have evaluated alternatives to monthly dosing. Evidence suggests that either a treat-as-needed or, possibly, a treat-and-extend regimen provides a reasonable approach to monthly injections recommended for bevacizumab and ranibizumab, with the caveat that as yet, careful and ongoing surveillance remains a key feature of optical management. CONCLUSIONS: Individualization of antiangiogenic treatment using data from clinical trials evaluating various dosing regimens against the patient's disease, lifestyle, and economic restrictions continues to evolve.

Cost analysis comparing adjuvant epimacular brachytherapy with anti-VEGF monotherapy for the management of neovascular age-related macular degeneration.

AIMS: To consider the cost implication of adopting epimacular brachytherapy (EMB) for the treatment of neovascular (wet) age-related macular degeneration (wAMD), compared with ranibizumab or bevacizumab monotherapy. METHODS: This analysis compared the cumulative 3-year costs of anti-VEGF (vascular endothelial growth factor) monotherapy to EMB combined with anti-VEGF therapy. Two patient groups were considered: newly diagnosed (treatment-naïve) patients; and patients already receiving chronic anti-VEGF therapy. RESULTS: In the treatment-naïve patients, the highest cumulative treatment costs were associated with ranibizumab monotherapy (£25,658), followed by bevacizumab monotherapy (£16,177), EMB with ranibizumab (£14,002), then EMB with bevacizumab (£10,289). In previously treated patients, the highest treatment costs were ranibizumab monotherapy (£18,355), followed by EMB with ranibizumab (£17,428), bevacizumab monotherapy (£16,177), then EMB with bevacizumab (£12,129). CONCLUSION: EMB combined with anti-VEGF treatment has the potential to yield considerable cost savings, compared with anti-VEGF monotherapy. If the ongoing large studies of EMB confirm the published feasibility data, then adjuvant EMB may represent a cost-effective alternative to anti-VEGF monotherapy.

[Angiogenesis targeting in breast cancer]. / Le ciblage de l'angiogenèse dans les cancers du sein.

Several anti-angiogenic agents are under evaluation in breast cancer. Currently, only bevacizumab has shown its efficacy, in combination with paclitaxel, on relapse-free survival in the metastatic setting. The combination of targeted therapies (for instance, trastuzumab plus bevacizumab, lapatinib plus pazopanib, etc.) is certainly of utmost interest. However, the anti-angiogenic agents not always bring in phase III the expected effects on patient survival, and an increased toxicity of combinations versus chemotherapy only has been observed. Outside the privileged neo-adjuvant setting, it appears difficult, for technical and ethical reasons, to obtain tissue samples before and after treatment to study predictive factors of drug response and to establish surrogate makers.

Pegaptanib: new drug. In macular degeneration: too many risks for too little benefit.

(1) Age-related macular degeneration with vascular proliferation can markedly hamper vision. In patients with subfoveolar involvement, verteporfin photodynamic therapy slows the loss of visual acuity on the EDTRS scale in about 15% of patients after 2 years of follow-up. (2) Pegaptanib, a vascular endothelial growth factor (VEGF) inhibitor, has been approved for the treatment of the neovascular form of age-related macular degeneration. (3) Two double-blind placebo-controlled trials involved a total of 1208 patients. When pegaptanib was injected into the eye every 6 weeks, at a dose of 0.3 mg, visual loss measured one year after beginning treatment was slowed in about 15% more patients on pegaptanib than on placebo. Efficacy during the second year is uncertain. Pegaptanib has not been compared with other treatments, nor has it been assessed in combination with verteporfin. (4) A variety of ocular adverse events were reported during clinical trials, three of which were serious and each affected about 1% of patients: endophthalmia, retinal detachment, and cataracts. Transient ocular hypertension occurred in about 15% of patients. A few cases of retinal arterial and venous thrombosis have been described. No long-term adverse effects were reported after clinical trials, but hypersensitivity reactions were reported post-approval. (5) Treatment with pegaptanib involves an intraocular injection every 6 weeks under local anaesthesia and under conditions of surgical asepsis. (6) In practice, an indirect comparison suggests that intraocular pegaptanib is no more effective than verteporfin photodynamic therapy. In contrast, adverse events are more numerous and treatment is less convenient.

Pegaptanib: a novel approach to ocular neovascularization.

OBJECTIVE: To review pegaptanib, a novel aptamer for the treatment of age-related macular degeneration (AMD). DATA SOURCES: A literature search using MEDLINE (1980-January 2006) and the Cochrane Database of Systematic Reviews (1978-January 2006) for peer-reviewed, English-language publications was conducted. Abstracts from recent meetings, including the Association for Research in Vision and Ophthalmology and American Society of Retinal Specialists, were reviewed for relevant abstracts and poster presentations. STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic and pharmacology data were extracted from animal and human studies, and double-blind, randomized, controlled trials were included to describe the efficacy and adverse effects of pegaptanib. DATA SYNTHESIS: The efficacy of pegaptanib has been evaluated in 2 concurrent, prospective, randomized, double-blind trials. Patients with AMD were randomly assigned to receive placebo or pegaptanib intravitreous injection into 1 eye every 6 weeks for 48 weeks. The effectiveness of pegaptanib was realized as early as week 6 and continued through week 54. At week 54, 38% of patients receiving pegaptanib 0.3 mg were classified as legally blind versus 56% of those receiving the sham injection. CONCLUSIONS: Pegaptanib, a new inhibitor of ocular neovascularization, provides patients with an alternative to photodynamic therapy with verteporfin and offers a novel approach to future drug developments for AMD. Pegaptanib offers the advantage of not requiring photodynamic therapy in conjunction with drug delivery and may be a viable option for institutions where this service is not easily accessible. Results of clinical trials have shown that pegaptanib is effective in delaying progression of AMD.

Assessment of the clinical significance of serum vascular endothelial growth factor and matrix metalloproteinase-9 in patients with hepatocellular carcinoma.

The pre-therapeutic serum levels of VEGF and MMP-9 were studied in patients with HCC, cirrhotic patients and in healthy subjects by an ELISA assay to elucidate the relationship between serum VEGF, MMP-9 levels and clinicopathological characteristics of HCC. The serum VEGF and MMP-9 were significantly elevated in HCC patients with macroscopic portal vein invasion and with metastasis as compared to HCC patients with neither invasion nor metastasis. Serum VEGF showed a significant difference between HCC patients with tumor size >5cm and <5 cm, however serum MMP-9 did not vary with tumor size. It was concluded that the portal vein invasion and metastasis in HCC is a complex process involving multiple factors including VEGF-mediated angiogenesis and MMP-9 induced degradation of extracellular matrix. The pre-therapeutic serum VEGF & MMP-9 in HCC might be candidate biomarkers reflecting the disease potential for vascular invasion and metastasis, serum VEGF being a superior biomarker as it correlated also with tumor size.

Serum vascular markers and vascular imaging in assessment of rheumatoid arthritis disease activity and response to therapy.

Vascular pathology, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis (RA) and, in the form of endothelial dysfunction, contributes to associated cardiovascular co-morbidity. Emerging evidence suggests that TNFalpha blockade may modify vascular pathology in RA. Serum concentrations of vascular endothelial growth factor (VEGF), a potent endothelial cell-specific growth factor that is up-regulated by pro-inflammatory cytokines and by hypoxia, are elevated in RA and correlate with disease activity. Serum levels of VEGF at first presentation in RA predict radiographic progression of the disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and the vascular signal correlates with histopathological quantification of the vascular density of synovial tissue. Recent data indicate that high-frequency ultrasound and power Doppler are sensitive tools for evaluation of disease activity and assessment of response to therapy. Power Doppler imaging may also have the potential to predict those patients most at risk of accelerated joint destruction. However, much work has yet to be done to standardize the use of these imaging technologies.

Bevacizumab for advanced colorectal cancer.

Bevacizumab is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). It is thought that bevacizumab inhibits the formation of new blood vessels. Two clinical trials show that the addition of bevacizumab to a regimen of either fluorouracil plus leucovorin (FL) or FL combined with irinotecan (IFL), significantly improves response rate and time to tumour progression and increases overall survival for patients with advanced colorectal cancer (ACC). Thromboembolic events are the most clinically significant adverse events, but hypertension, hemorrhage and gastrointestinal perforation are other potential safety concerns. More studies are needed to compare the combination of bevacizumab plus IFL to other chemotherapy regimens used in the treatment of ACC. The addition of bevacizumab to 5-fluorouracil-based chemotherapy regimens will significantly increase the costs of palliation for ACC.

[Assessment of serum levels of some angiogenic factors in healthy children]. / Ocena stezen wybranych czynników angiogennych u zdrowych dzieci.

Angiogenesis is defined as a development of new blood vessels. This process is required for many physiological and pathological conditions. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the most important cytokines stimulating angiogenesis. The purpose of this work was to evaluate serum levels of VEGF and bFGF in healthy children. 39 girls and 31 boys aged 3-18 years were included in the study.