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1.  The Chinese medicine formula HB01 reduces choroidal neovascularization by regulating the expression of vascular endothelial growth factor 
Background
Choroidal neovascularization (CNV) remains the leading cause of newly acquired blindness in the developed world. Currently anti-vascular endothelial growth factor (VEGF) therapies are broadly used to treat neovascular ocular disorders. Here we demonstrate the effect of a traditional Chinese medicine formula, HB01, on CNV.
Methods
A rat model of laser-induced CNV was used to investigate the effect of HB01 in vivo. The CNV lesions in the eye were evaluated using fundus fluorescein angiography and visualized/quantified using confocal microscopy. Expression of VEGF in the choroidal and retinal tissues was measured using quantitative real-time PCR and immunohistochemistry.
Results
We demonstrated that a traditional Chinese Medicine formula, named HB01, significantly reduced neovascularization in a rat CNV model. The effect of HB01 on CNV was comparable to the intravitreal injection of bevacizumab (Avastin). Our results also suggested that HB01 may reduce CNV partially through inhibiting the expression of VEGF.
Conclusions
These data support HB01 as an alternative therapy for ocular neovascular disorders.
doi:10.1186/1479-5876-10-118
PMCID: PMC3479009  PMID: 22676316
Choroidal neovascularization; Traditional Chinese medicine; VEGF
2.  Assessment of Differential Pharmacodynamic Effects Using Optical Coherence Tomography in Neovascular Age-Related Macular Degeneration 
With new treatments for AMD, the capacity of OCT to provide detailed pharmacodynamic information is likely to attain increased importance. Quantification of subretinal tissue may highlight differential effects on vascular proliferation, whereas PED measurement may highlight retinal drug penetration.
Purpose.
To use novel OCT parameters in assessing the differential pharmacodynamic effects of bevacizumab (Avastin; Genentech, South San Francisco, CA), pegaptanib (Macugen; OSI Pharmaceuticals, New York, NY), and verteporfin photodynamic therapy (PDT; Novartis, Basel, Switzerland) in a recently completed phase III/IV clinical trial.
Methods.
Data from 122 patients participating in the Avastin (Bevacizumab) for Choroidal Neovascularization (ABC) trial, were evaluated. OCT scans were analyzed with custom software. Changes in the volume of the neurosensory retina, amount of subretinal fluid (SRF), pigment epithelium detachment (PED), and subretinal tissue (SRT), were calculated over the 54-week trial period.
Results.
Reductions in retinal edema were more than twice as great from bevacizumab as from pegaptanib (−0.82 mm3 vs. −0.31 mm3), whereas SRF reduction was more than three times greater (−0.54 mm3 vs. −0.15 mm3). Both bevacizumab and pegaptanib led to rapid reductions in SRT; however, in those receiving pegaptanib, these improvements were not maintained (at week 54, −0.22 mm3 vs. +0.18 mm3). Acute increases in SRF were seen 1 week after PDT (+0.36 mm3) and, across all treatment groups, PED volume tended to remain unchanged or to regress only slowly.
Conclusions.
In clinical trials, quantitative OCT subanalysis increases the amount of clinically useful information that can be obtained from OCT images. In the emerging era of neovascular AMD therapeutics, the capacity of OCT to provide such detailed pharmacodynamic information in a noninvasive manner is likely to attain increased importance. In future comparative studies, evaluation of SRT may highlight differential effects on vascular proliferation, whereas measurement of PED volume may be useful for the estimation of retinal and subretinal pigment epithelium (RPE) therapeutic penetration. (ClinicalTrials.gov number, ISRCTN83325075.)
doi:10.1167/iovs.11-8130
PMCID: PMC3339900  PMID: 22281826
3.  Intravitreal Bevacizumab for Choroidal Neovascularization Secondary to Non-Age-Related Macular Degeneration 
Purpose
To report the long-term results of intravitreal bevacizumab (Avastin) therapy for choroidal neovascularization (CNV) secondary to non-age-related macular degeneration (non-AMD).
Methods
This prospective interventional case series was conducted on patients with non-AMD CNV. All patients received 1.25 mg intravitreal bevacizumab and were followed for at least 18 weeks. Indications for retreatment were decreased visual acuity or recurrence of subretinal fluid or hemorrhage associated with leakage on fluorescein angiography. Primary outcome measures were changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). Secondary outcome measures consisted of any adverse event related to the therapy.
Results
The study included 31 eyes of 28 patients with non-AMD CNV including idiopathic (n=11), due to myopia (n=7), angioid streaks (n=5), and other disorders (n=8). Mean initial BCVA was 20/100 which improved to 20/60 at 6 weeks; 20/40 at 12, 18, 24, and 36 weeks; and 20/30 at 54 weeks. Serial optical coherence tomography measurements showed mean CMT of 288 μm at baseline, which was decreased to 209 μm at last visit (P=0.95). There was no correlation between the underlying disease and changes in BCVA during the follow-up period.
Conclusion
Intravitreal bevacizumab significantly improved visual acuity in eyes with non-AMD CNV due to various etiologies.
PMCID: PMC3380665  PMID: 22737321
Bevacizumab; Choroidal Neovascularization; Non-Age-Related Macular Degeneration
4.  Modelling Cost Effectiveness in Neovascular Age-Related Macular Degeneration: The Impact of Using Contrast Sensitivity vs. Visual Acuity 
Background
The cost utility of treatments of age-related macular degeneration (AMD) is commonly assessed using health state transition models defined by levels of visual acuity. However, there is evidence that another measure of visual function, contrast sensitivity, may be better associated with utility than visual acuity. This paper investigates the difference in cost effectiveness resulting from models based on visual acuity and contrast sensitivity using the example of bevacizumab (Avastin) for neovascular AMD. The implications of the choice of outcome on structural uncertainty in the model are investigated.
Method
Health state transition Markov models based on levels of visual acuity and contrast sensitivity are used to represent the costs, health utilities and outcomes of the Avastin for choroidal neovascular age-related macular degeneration (ABC) trial. Health states are associated with costs and utilities based on literature values. Treatment outcomes from the ABC trial are used to predict transitions between states in both models. Total costs and quality-adjusted life-years (QALYs) are calculated for a cohort of patients treated over a defined number of model cycles.
Results
Over a 5-year time horizon, a contrast sensitivity model predicts a statistically significant (p < 0.05) 25 % greater QALY gain than the visual acuity model based on 10,000 Monte Carlo simulations. Bevacizumab is more effective and less costly than the comparator in the contrast sensitivity model and the visual acuity model.
Conclusion
There is considerable structural uncertainty associated with the choice of outcome for modelling the cost effectiveness of AMD treatments. Bevacizumab has a higher incremental QALY gain and more favourable incremental cost-effectiveness ratio when cost effectiveness is assessed using contrast sensitivity outcomes compared with using visual acuity outcomes. Previous cost-effectiveness analyses may have underestimated the cost effectiveness of anti-vascular endothelial growth factor (anti-VEGF) therapy.
doi:10.1007/s40258-014-0090-0
PMCID: PMC4026666  PMID: 24610632
5.  A randomised, double-masked phase III/IV study of the efficacy and safety of Avastin® (Bevacizumab) intravitreal injections compared to standard therapy in subjects with choroidal neovascularisation secondary to age-related macular degeneration: clinical trial design 
Trials  2008;9:56.
Background
The management of neovascular age-related macular degeneration (nAMD) has been transformed by the introduction of agents delivered by intravitreal injection which block the action of vascular endothelial growth factor-A (anti-VEGF agents). One such agent in widespread use is bevacizumab which was initially developed for use in oncology. Most of the evidence supporting the use of bevacizumab for nAMD has come from interventional case series and this clinical trial was initiated because of the increasing and widespread use of this agent in the treatment of nAMD (an off-label indication) despite a lack of definitive unbiased safety and efficacy data.
Methods and design
The Avastin® (bevacizumab) for choroidal neovascularisation (ABC) trial is a double-masked randomised controlled trial comparing intravitreal bevacizumab injections to standard therapy in the treatment of nAMD. Patients are randomised to intravitreal bevacizumab or standard therapy available at the time of trial initiation (verteporfin photodynamic therapy, intravitreal pegaptanib or sham treatment). Ranibizumab treatment was not included in the control arm as it had not been licensed for use at the start of recruitment for this trial. The primary outcome is the proportion of patients gaining ≥ 15 letters of visual acuity at 1 year and secondary outcomes include the proportion of patients with stable vision and mean visual acuity change.
Discussion
The ABC Trial is the first double-masked randomised control trial to investigate the efficacy and safety of intravitreal bevacizumab in the treatment of nAMD. This trial fully recruited in November 2007 and results should be available in early 2009. Important design issues for this clinical trial include (a) defining the control group (b) use of gain in vision as primary efficacy end-point and (c) use of pro re nata treatment using intravitreal bevacizumab rather than continuous therapy.
Trial registration
Current controlled trials ISRCTN83325075
doi:10.1186/1745-6215-9-56
PMCID: PMC2576049  PMID: 18854025
6.  Non‐responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions 
The British Journal of Ophthalmology  2007;91(10):1318-1322.
Aims
To determine the characteristics of “non‐responders” to intravitreal bevacizumab treatment in choroidal neovascularisation (CNV).
Methods
Forty‐three patients with visual loss due to neovascular age‐related macular disease (ARMD) (44 eyes) underwent intravitreal injections of 1.25 mg (0.05 ml) bevacizumab and were followed up every 4 weeks for 2, 3 or 6 months. Re‐injection was performed when persistent leakage of the CNV was determined by fluorescein angiography and retinal oedema was assessed by optical coherence tomography (OCT). Non‐responders were defined as those patients having reduced or stable visual acuity at the last follow‐up.
Results
45% of the patients were non‐responders. In this group the initial CNV size was significantly larger than in the responders. Initial reading ability was significantly lower in non‐responders, but the initial foveal oedema was similar in both groups. Gains in mean visual acuity and reading ability were independent of lesion type. The proportion of non‐responders to responders in the different lesion type groups was equally distributed. Only patients with the classic type of CNV seemed to respond better.
Conclusions
In this study initial reasons for non‐responders to intravitreal bevacizumab treatment in CNV are given. The efficiency of bevacizumab depends on initial lesion size and initial reading ability, but is independent of the amount of intraretinal and subretinal fluid. There was no general ineffectiveness of bevacizumab with any particular lesion type.
doi:10.1136/bjo.2006.113902
PMCID: PMC2000982  PMID: 17537784
7.  Anti-vascular endothelial growth factor for neovascular age-related macular degeneration 
Background
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.
Objectives
To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
Search methods
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlledtrials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.
Selection criteria
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.
Data collection and analysis
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.
Main results
We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.
When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.
Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD −13.97 μm; 95% confidence interval (CI) −26.52 to −1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.
Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.
Authors’ conclusions
The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.
doi:10.1002/14651858.CD005139.pub3
PMCID: PMC4270425  PMID: 25170575
Angiogenesis Inhibitors [*therapeutic use]; Antibodies, Monoclonal [therapeutic use]; Antibodies, Monoclonal, Humanized, Aptamers, Nucleotide [therapeutic use]; Choroidal Neovascularization; Macular Degeneration [*drug therapy]; Porphyrins [therapeutic use]; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A [*antagonists & inhibitors]; Aged; Humans; Middle Aged
8.  Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors 
AIM
To document the indications, safety and possible complications of bilateral same-session intravitreal anti-vascular endothelial growth factor (VEGF) injections performed in the ophthalmic operating room.
METHODS
A retrospective case series study. Consecutive records of seventy four patients receiving simultaneous bilateral intravitreal injections of either ranibizumab or bevacizumab, between September 2010 and September 2013, were reviewed and the outcomes were assessed. Data collected included number of injections, indications for injections, pre-injection and post-injection visual acuity (VA), pre-injection and post-injection intraocular pressure and ocular and systemic complications/complaints after each injection.
RESULTS
A total of 342 injections were administered to 74 patients, with a mean of 4.62 injections per patient. Seventy-three patients received bevacizumab (Avastin; Genentech Inc., South San Francisco, California, USA) alone, and only one patient received both bevacizumab and ranibizumab (Lucentis; Genentech Inc.) distributed between the injections. Pre- and post-injection VA follow-up measurements were available for 65 patients. Mean follow up period was 22mo. The indications for initiating therapy were choroidal neovascular membrane from age-related macular degeneration (3 patients) and diabetic macular edema (71 patients). The mean Snellen VA before each injection was 6/22. The next post-injection follow-up mean Snellen VA was 6/20. One patient had a painful, culture-positive endophthalmitis in one eye 3d after bilateral bevacizumab. Another patient had a painless subconjunctival hemorrhage in one eye. No other ocular or systemic adverse side effects/complaints have been registered in this study group.
CONCLUSION
Bilateral same-session intravitreal injections using a separate povidone-iodine preparation, speculum, needle, and syringe for each eye are well-tolerated. None of the subjects in this study requested to switch to alternating unilateral injections. Proper patient counseling as to the risk of complications with this procedure is necessary.
doi:10.3980/j.issn.2222-3959.2014.06.20
PMCID: PMC4270969  PMID: 25540758
anti-vascular endothelial growth factor; diabetic macular edema; age-related macular degeneration; endophthalmitis; visual acuity
9.  Angiographic results of retinal-retinal anastomosis and retinal-choroidal anastomosis after treatments in eyes with retinal angiomatous proliferation 
Background
The purpose of this study was to evaluate the angiographic results of retinal-retinal anastomosis (RRA) and retinal-choroidal anastomosis (RCA) for eyes with retinal angiomatous proliferation (RAP) after treatment with intravitreal bevacizumab injections as monotherapy or intravitreal bevacizumab combined with photodynamic therapy.
Methods
In this interventional, consecutive case series, we retrospectively reviewed five naïve eyes from four patients (mean age 80 years) treated with three consecutive monthly intravitreal bevacizumab (1.25 mg/0.05 mL) injections as initial treatment, and followed up for at least 3 months. In cases with over 3 months of follow-up and having recurrence of RAP or leakage by fluorescein angiography, retreatment was performed with a single intravitreal bevacizumab injection and photodynamic therapy.
Results
Indocyanine green angiography showed RRA in three eyes with subretinal neovascularization and RCA in two eyes with choroidal neovascularization at baseline. At 3 months after baseline (month 3), neither the RRA nor RCA was occluded in any eye on indocyanine green angiography. Retreatment with intravitreal bevacizumab plus photodynamic therapy was performed in three eyes at months 3 (persistent leakage on fluorescein angiography), 6, and 7 (recurrence of RAP lesion), which achieved obvious occlusion of the RRA and RCA. Mean best-corrected visual acuity improved from 0.13 to 0.21 at month 3 (P = 0.066). No complications or systemic adverse events were noted.
Conclusion
Although intravitreal bevacizumab for RAP was effective in improving visual acuity during short-term follow-up, intravitreal bevacizumab could not achieve complete occlusion of RRA and RCA, which could lead to recurrence of a RAP lesion and exudation. Retreatment with intravitreal bevacizumab plus photodynamic therapy ultimately achieved complete occlusion of the RRA and RCA.
doi:10.2147/OPTH.S36333
PMCID: PMC3437956  PMID: 22969283
retinal angiomatous proliferation; retinal-retinal anastomosis; retinal-choroidal anastomosis; bevacizumab; photodynamic therapy; ranibizumab
10.  Histological findings of a choroidal neovascular membrane removed at the time of macular translocation in a patient previously treated with intravitreal bevacizumab treatment (Avastin) 
Aim
To report the findings in a patient treated by repeated intravitreal bevacizumab (Avastin) injections, followed by macular relocation and excision of subfoveal choroidal neovascular membrane (CNV).
Methods
Histopathological evaluation of the CNV specimen, including immunohistochemical assessment.
Results
During surgical excision, the CNV seemed to be avascular and its underlying bed did not bleed. Histopathological examination revealed that the CNV comprised avascular fibrous subretinal tissue containing fibroblastic retinal pigment epithelial (RPE) cells, fragments of irregular thickened Bruch's membrane and fibrotic choroidal tissue containing some medium‐sized vessels but no choriocapillaris.
Conclusions
The development of an RPE tear during the course of Avastin treatment may reflect contraction of the avascular subretinal tissue, whereas the lack of capillaries in both choroidal and subretinal components may be caused by the increased access of Avastin to the choriocapillaris in the presence of the RPE tear.
doi:10.1136/bjo.2006.108795
PMCID: PMC1954763  PMID: 17166893
11.  Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial 
BMJ Open  2014;4(7):e005094.
Objective
To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective.
Design
A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial.
Setting
23 hospital ophthalmology clinics.
Participants
610 patients aged ≥50 years with untreated nAMD in the study eye.
Interventions
0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years.
Main outcome measures
Quality-adjusted life-years (QALYs).
Results
Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI −0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab.
Conclusions
Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective.
Trial registration number
ISRCTN92166560.
doi:10.1136/bmjopen-2014-005094
PMCID: PMC4120317  PMID: 25079928
Neovascular age-related macular degeneration (AMD); vascular endothelial growth factor (VEGF) inhibitors; trial-based economic evaluation; cost-utility analysis; cost-minimisation analysis; cost-effectiveness
12.  Choroidal neovascularization in angioid streaks following microincision vitrectomy surgery: a case report 
BMC Ophthalmology  2013;13:29.
Background
Patients with angioid streaks are prone to developing subretinal hemorrhage after ocular or head injury due to the brittleness of Bruch’s membrane. However, there have been no reports of any angioid streak patients in whom choroidal neovascularization occurred after vitrectomy surgery. We report herein a patient with angioid streaks who developed choroidal neovascularization after vitrectomy surgery for epiretinal membrane.
Case presentation
A 76-year-old man presented with distorted vision in his left eye, with a best corrected visual acuity of 1.2 and 0.6 in his right and left eyes, respectively. Fundus examination showed angioid streaks in both eyes and epiretinal membrane only in the left eye. The patient underwent 23-gauge three-port pars plana vitrectomy with removal of the epiretinal membrane combined with cataract surgery. Internal limiting membrane in addition to the epiretinal membrane were successfully peeled and removed, with indocyanine green dye used to visualize the internal limiting membrane. His left best corrected visual acuity improved to 0.8. An elevated lesion with retinal hemorrhage due to probable choroidal neovascularization was found between the fovea and the optic disc in the left eye at 7 weeks after surgery. Since best corrected visual acuity decreased to 0.15 and the hemorrhage expanded, posterior sub-Tenon injection of triamcinolone acetonide was performed. However, no improvement was observed. Even though intravitreal bevacizumab injection was performed a total of five times, his best corrected visual acuity remained at 0.1. Subsequently, we performed a combination treatment of a standard-fluence photodynamic therapy and intravitreal ranibizumab injection, with additional intravitreal ranibizumab injections performed 3 times after this combination treatment. Best corrected visual acuity improved to 0.5 and the size of the choroidal neovascularization markedly regressed at 4 months after the combined treatment.
Conclusion
Development of choroidal neovascularization could possibly occur in elderly patients with angioid streaks after vitrectomy surgery. In such cases, a combination of photodynamic therapy and intravitreal ranibizumab injection may be considered for initial treatment of the choroidal neovascularization.
doi:10.1186/1471-2415-13-29
PMCID: PMC3704727  PMID: 23829451
Angioid streaks; Choroidal neovascularization; Vitrectomy surgery; Anti-vascular endothelial growth factor treatment; Photodynamic therapy; Pseudoxanthoma elasticum
13.  Effect of systemic bevacizumab therapy on retinal pigment epithelial detachment 
Background
To evaluate the effect of systemic bevacizumab (Avastin®) therapy on pigment epithelial detachment (PED) secondary to age‐related macular degeneration (AMD) and to identify prognostic factors for PED regression and improvement in best corrected visual acuity (BCVA).
Study design
Prospective uncontrolled pilot study.
Methods
Nine patients (nine eyes) received three systemic bevacizumab treatments at 2 week intervals and were examined at baseline, weeks 1, 2, 4, 6 and month 3 by using optical coherence tomography (Stratus OCT™, Carl Zeiss© Meditec, Dublin, California, USA). Changes in maximum PED height and greatest linear diameter (GLD) were planimetrically analysed by using Adobe Photoshop CS and correlated with retinal morphological changes and changes in BCVA.
Results
Systemic bevacizumab therapy was well tolerated. Mean maximum PED height decreased significantly by 21% as early as 1 week (−96 µm (SD 48.8), p<0.01). At 3 months follow‐up, two PEDs resolved completely, mean maximum PED height decreased significantly by 39% (−179 µm (SD 178), p = 0.02) and mean PED GLD by 24% (−714 µm (SD 1010), p = 0.07). Mean BCVA improved significantly by week 2 (+8.7 letters (SD 5.7), p<0.01) and at 3 months with 12.7 letters (SD 6.4) (p<0.01).
Conclusion
In the examined nine patients, systemic bevacizumab therapy showed evidence for an effect on PED secondary to neovascular AMD in terms of a decrease in lesion height and diameter. A high PED at baseline was found to be a negative predictive factor for visual outcome.
doi:10.1136/bjo.2006.102467
PMCID: PMC2266832  PMID: 17050580
AMD; PED; VEGF; bevacizumab; OCT
14.  Neovascularization in Glioblastoma: Current Pitfall in Anti-angiogenic therapy 
Zhong liu za zhi  2013;1(3):16-19.
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. However, the survival of patients with GBM has been dismal after multi-disciplinary treatment with surgery, radiotherapy, and chemotherapy. In the efforts to improve clinical outcome, anti-angiogenic therapy with bevacizumab (Avastin) was introduced to inhibit vascular endothelial growth factor (VEGF) mediated tumor neovascularization. Unfortunately, the results from clinical trials have not lived up to the initial expectations. Patients either fail to respond to anti-angiogenic therapy or develop resistance following an initial response. The failure of anti-angiogenic therapy has led to a frustration among physicians and research community. Recent evidence indicates that the dogma of tumor neovascularization solely dependent on VEGF pathway to be overly simplistic. A realistic model of tumor neovascularization should include alternative pathways that are independent of VEGF signaling. A better understanding of the underlying processes in tumor neovascularization would help in designing successful anti-angiogenic treatment strategies.
PMCID: PMC4073792  PMID: 24976869
GBM; VEGF; neovascularization; angiogenesis; vasculogenesis; vascular mimicry
15.  Avastin and Lucentis: what do patients know? A prospective questionnaire survey 
JRSM Short Reports  2013;4(9):2042533313484146.
Objectives
To assess patients’ knowledge of their drug therapy for neovascular macular degeneration and to identify which aspects of the drug they considered most important if given the option of switching to an alternative drug.
Design
Prospective questionnaire survey.
Setting
Wolverhampton, England.
Participants
A total of 126 patients attending our hospital service for intravitreal ranibizumab therapy for neovascular macular degeneration.
Main outcome measures
Using a questionnaire, patients were asked questions pertaining to aspects of drug therapy in neovascular macular degeneration. Fields covered included drug names, knowledge of alternative drugs, cost of drugs and their views on switching to another drug.
Results
Eighty (63.5%) had heard of Lucentis (ranibizumab) and 31 (24.6%) were aware of Avastin (bevacizumab). Of the latter 31 patients, 20 did not have a preference between Avastin and Lucentis. These patients felt that the factors they would consider important for them to consider switching were effectiveness (10, 50%), specialist recommendation (8, 40%), safety (2, 10%) and cost (0).
Conclusions
Introducing a cheaper, off-label alternative in the therapy of macular degeneration in the presence of a licensed option has been extensively debated. Many patients have no knowledge of this controversial issue but it is likely that efficacy and recommendation by clinicians are more important than cost to patients who may consider switching to the off-label Avastin.
doi:10.1177/2042533313484146
PMCID: PMC3767069  PMID: 24040500
16.  Intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks: A report of two patients 
Saudi Journal of Ophthalmology  2013;28(4):316-318.
The aim of this study is to report clinical course of choroidal neovascularization secondary to angioid streaks (AS) in two patients who underwent intravitreal bevacizumab therapy. Fundus examination, fluorescein angiography (FA) and optical coherence tomography (OCT) revealed the diagnosis of subfoveal classic choroidal neovascularization (CNV) in the right eye in patient 1 and in the left eye in patient 2. After three consecutive bevacizumab injections, visual acuity improved from 20/40 to 20/25 in patient 1 and from 20/80 to 20/50 in patient 2. After 3 months of therapy, additional bevacizumab injection was administered when the lesion showed recurrence. After a follow-up time of 24-months, patient 1 received 14 intravitreal bevacizumab injections; patient 2 received only 4 injections. Visual acuities remained stable at 20/32 and 20/50 in patient 1 and patient 2, respectively. Though, the patients of CNV secondary to AS showed similar clinical appearance at the beginning, this report provides the data for different responses to intravitreal bevacizumab therapy. While fewer injections were required to control the disease in one patient, the other patient needed much more injections for stabilization of the CNV. Further studies are required to understand the cause of varied treatment responses in those patients.
doi:10.1016/j.sjopt.2013.07.012
PMCID: PMC4250500  PMID: 25473350
Angioid streaks; Choroidal neovascularization; Bevacizumab
17.  Surgical management and ultrastructural study of choroidal neovascularization in punctate inner choroidopathy after bevacizumab 
Purpose
This study aims to describe surgical management results and the pathologic features of choroidal neovascularization (CNV) secondary to punctate inner choroidopathy (PIC) following anti-vascular endothelial growth factor treatment.
Design
This study is a case report on the surgical management and ultrastructural study of choroidal neovascularization.
Methods
Clinicopathologic and ultrastructural report of CNV membranes excised from both eyes of one patient was presented.
Results
The right eye responded to bevacizumab, and recurrence 17 months later did not; the left eye never responded. Excision of the active CNVs was performed 3 months after the last injection. In the right eye, there was no recurrence 23 months after surgery. In the left eye, CNV recurred after 6 months, with no response to bevacizumab. Electron microscopy revealed subretinal neovascular tissue and, additionally, Bruch's membrane and inner choroid in the left. In the right eye, lumens of many neovascular channels were occluded by microfibrils and pericytes were infrequent. In the left eye, patent CNV units with pericytes were present. There were scattered macrophages but no lymphocytes in either membrane. An inner focal choroidal lymphocytic infiltrate was discovered.
Conclusions
Submacular surgery did not cause complications following treatment with bevacizumab. Mostly nonfunctional capillaries in the right membrane failed to display pericytes. The left membrane, which was unresponsive to bevacizumab, displayed well-formed neovascular units consistently exhibiting pericytes. A focus of inner choroidal lymphocytic infiltration was found in the left eye despite the absence of overt clinical intraocular inflammation. This is the first pathological study employing human tissue that points to pericytes as a potential critical therapeutic target with the aggravating influence of inner choroidal chronic inflammation in PIC.
doi:10.1007/s12348-011-0050-x
PMCID: PMC3302998  PMID: 22120962
Bevacizumab; Choroidal neovascularization; Electron microscopy; Light microscopy; Punctate inner choroidopathy; Submacular surgery
18.  Surgical management and ultrastructural study of choroidal neovascularization in punctate inner choroidopathy after bevacizumab 
Purpose
This study aims to describe surgical management results and the pathologic features of choroidal neovascularization (CNV) secondary to punctate inner choroidopathy (PIC) following anti-vascular endothelial growth factor treatment.
Design
This study is a case report on the surgical management and ultrastructural study of choroidal neovascularization.
Methods
Clinicopathologic and ultrastructural report of CNV membranes excised from both eyes of one patient was presented.
Results
The right eye responded to bevacizumab, and recurrence 17 months later did not; the left eye never responded. Excision of the active CNVs was performed 3 months after the last injection. In the right eye, there was no recurrence 23 months after surgery. In the left eye, CNV recurred after 6 months, with no response to bevacizumab. Electron microscopy revealed subretinal neovascular tissue and, additionally, Bruch's membrane and inner choroid in the left. In the right eye, lumens of many neovascular channels were occluded by microfibrils and pericytes were infrequent. In the left eye, patent CNV units with pericytes were present. There were scattered macrophages but no lymphocytes in either membrane. An inner focal choroidal lymphocytic infiltrate was discovered.
Conclusions
Submacular surgery did not cause complications following treatment with bevacizumab. Mostly nonfunctional capillaries in the right membrane failed to display pericytes. The left membrane, which was unresponsive to bevacizumab, displayed well-formed neovascular units consistently exhibiting pericytes. A focus of inner choroidal lymphocytic infiltration was found in the left eye despite the absence of overt clinical intraocular inflammation. This is the first pathological study employing human tissue that points to pericytes as a potential critical therapeutic target with the aggravating influence of inner choroidal chronic inflammation in PIC.
doi:10.1007/s12348-011-0050-x
PMCID: PMC3302998  PMID: 22120962
Bevacizumab; Choroidal neovascularization; Electron microscopy; Light microscopy; Punctate inner choroidopathy; Submacular surgery
19.  Pharmacogenetics for Genes Associated with Age-Related Macular Degeneration (AMD) in the Comparison of AMD Treatments Trials (CATT) 
Ophthalmology  2013;120(3):593-599.
Purpose
To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis) or bevacizumab (Avastin) for neovascular AMD.
Design
Clinical trial.
Participants
834 (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
Methods
Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays.
Main Outcomes Measures
Genotypic frequencies were compared to clinical measures of response to therapy at one year including mean visual acuity (VA), mean change in VA, ≥15 letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, p≤0.01 was considered statistically significant.
Results
No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomical response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size) or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; i.e., response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata (PRN) dosing.
Conclusions
Although specific alleles for CFH, ARMS2, HTRA1 and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor (VEGF) therapy.
doi:10.1016/j.ophtha.2012.11.037
PMCID: PMC3633658  PMID: 23337555
20.  Recombinant Human VEGF165b Inhibits Experimental Choroidal Neovascularization 
The alternative splice form of VEGF, VEGF-A165b, inhibits choroidal neovascularization at very low doses in mice, indicating that it may be an effective therapy for age-related macular degeneration, comparable with or better than existing anti-VEGF therapy.
Purpose.
Vascular endothelial growth factor (VEGF-A) is the principal stimulator of angiogenesis in wet age-related macular degeneration (AMD). However, VEGF-A is generated by alternate splicing into two families, the proangiogenic VEGF-Axxx family and the antiangiogenic VEGF-Axxxb family. It is the proangiogenic family that is responsible for the blood vessel growth seen in AMD.
Methods.
To determine the role of antiangiogenic isoforms of VEGF-A as inhibitors of choroidal neovascularization, the authors used a model of laser-induced choroidal neovascularization in the mouse eye and investigated VEGF-A165b effects on endothelial cells and VEGFRs in vitro.
Results.
VEGF-A165b inhibited VEGF-A165–mediated endothelial cell migration with a dose effect similar to that of ranibizumab and bevacizumab and 200-fold more potent than that of pegaptanib. VEGF-A165b bound both VEGFR1 and VEGFR2 with affinity similar to that of VEGF-A165. After laser injury, mice were injected either intraocularly or subcutaneously with recombinant human VEGF-A165b. Intraocular injection of rhVEGF-A165b gave a pronounced dose-dependent inhibition of fluorescein leakage, with an IC50 of 16 pg/eye, neovascularization (IC50, 0.8 pg/eye), and lesion as assessed by histologic staining (IC50, 8 pg/eye). Subcutaneous administration of 100 μg twice a week also inhibited fluorescein leakage and neovascularization and reduced lesion size.
Conclusions.
These results show that VEGF-A165b is a potent antiangiogenic agent in a mouse model of age-related macular degeneration and suggest that increasing the ratio of antiangiogenic-to-proangiogenic isoforms may be therapeutically effective in this condition.
doi:10.1167/iovs.09-4360
PMCID: PMC2910649  PMID: 20237252
21.  Effects of Retinal Morphology on Contrast Sensitivity and Reading Ability in Neovascular Age-Related Macular Degeneration 
Quantitative subanalysis of optical coherence tomography images in neovascular age-related macular degeneration may lead to the detection of novel retinal parameters that are capable of serving as surrogate endpoints in clinical trials of this disorder.
Purpose.
To investigate the effect of changes in retinal morphology on contrast sensitivity and reading ability in patients with neovascular age-related macular degeneration (AMD) in the Avastin (bevacizumab; Genentech, South San Francisco, CA) for choroidal neovascularization (ABC) Trial.
Methods.
Contrast sensitivity obtained with Pelli-Robson charts, reading ability assessed with Minnesota Reading charts, and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) obtained by protocol refraction, were recorded. Raw Stratus optical coherence tomography (OCT; Carl Zeiss Meditec, Inc., Dublin, CA) images were analyzed with the publicly available software OCTOR, which allows precise delineation of any retinal compartment of interest. Thickness and volume were calculated for neurosensory retina, subretinal fluid (SRF), subretinal tissue, and pigment epithelium detachment, and the resulting measurements were correlated with each visual function parameter.
Results.
One hundred twenty-two patients with newly diagnosed neovascular AMD and enrolled in the ABC Trial, were evaluated. Increased subretinal tissue volume correlated with decreased contrast sensitivity (Pearson's correlation coefficient, r = −0.4944, P = 0.001). A modest correlation was detected between SRF volume and contrast sensitivity (r = −0.2562, P = 0.004). Increased retinal thickness at the foveal center also correlated with decreased visual function (ETDRS VA: r = −0.4530, P < 0.001).
Conclusions.
The strongest correlation detected between the functional parameters assessed and any of the OCT-derived morphologic parameters was that between decreased contrast sensitivity and increased subretinal tissue. In the future, assessment of contrast sensitivity and reading ability, in combination with quantitative subanalysis of retinal compartments, may lead to the identification of parameters relevant to functional improvement and ultimate prognosis in patients with newly diagnosed neovascular AMD (www.controlled-trials.com number, ISRCTN83325075).
doi:10.1167/iovs.09-4846
PMCID: PMC3061494  PMID: 20554607
22.  Choroidal osteoma with choroidal neovascular membrane: Successful treatment with intravitreal bevacizumab 
An otherwise healthy 27-year-old woman presented with complaints of sudden painless blurred vision in the right eye for one week. On examination, visual acuity was 20/30 in the right eye and 20/20 in left eye. Fundus examination OS was normal, but OD demonstrated an elevated, opaque, yellowish parapapillary choroidal lesion with grayish membrane associated with minimal subretinal fluid, suggestive of a choroidal neovascular membrane in the center. B-scan ultrasonography revealed findings consistent with a choroidal osteoma. Fundus fluorescein angiography of the right eye revealed a relatively well defined area of hyperfluorescence that increased in size and intensity in the later phases, suggestive of active extrafoveal choroidal neovascular membrane. Optical coherence tomography confirmed the extrafoveal choroidal neovascular membrane with subfoveal fluid. She was treated with intravitreal bevacizumab OD. At the two-week visit, vision OD improved to 20/20. Fluorescein angiography and optical coherence tomography revealed a resolved choroidal neovascular membrane. Intravitreal bevacizumab may be an effective alternative in the management of choroidal neovascular membrane secondary to choroidal osteoma.
doi:10.2147/OPTH.S13730
PMCID: PMC2952608  PMID: 20957052
osteoma; choroidal neovascular membrane; optical coherence tomography; bevacizumab
23.  Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Choroidal Neovascularization Due to Sorsby Macular Dystrophy 
Abstract
Purpose
To report the first case of intravitreal bevacizumab and ranibizumab to treat choroidal neovascularization secondary to Sorsby macular dystrophy.
Case
A 57-year-old male with metamorphopsia, color vision deficits, and ocular family history of Sorsby macular dystrophy was found to have a choroidal neovascular membrane (CNVM) in his left eye. He was initially treated with intravitreal bevacizumab and had visual acuity improvement and resolution of the subretinal fluid on OCT. After 8 injections, he developed presumed mild inflammation secondary to intravitreal bevacizumab and was switched to combination intravitreal bevacizumab/dexamethasone in his left eye, which consistently demonstrated efficacy in stabilizing his vision and the CNVM without producing intraocular inflammation. The right eye later developed the CNVM and he was started on intravitreal bevacizumab in this eye as well. After 8 injections in the right eye, he experienced a similar inflammatory reaction following intravitreal bevacizumab injections and was switched to combination intravitreal bevacizumab/dexamethasone in the right eye as well. Subsequently, he was switched to intravitreal ranibizumab in the left eye alone, which continued to stabilize his vision and OCT and did not cause an inflammatory reaction as he previously experienced with bevacizumab. After 5 ranibizumab injections, he experienced no inflammatory response that he appeared to have with bevacizumab, but chose to switch back to combination intravitreal bevacizumab and dexamethasone due to financial reasons. Initially, in his clinical course, he experienced consistent visual acuity improvements with intravitreal antivascular endothelial growth factor therapy and continues to enjoy functional vision nearly 7 years after his initial symptoms.
Conclusions
Intravitreal bevacizumab and ranibizumab demonstrated efficacy in this case in the treatment of CNVM associated with Sorsby macular dystrophy.
doi:10.1089/jop.2011.0206
PMCID: PMC4047847  PMID: 23581613
24.  Impact of Intravitreal Injection of Bevacizumab (Avastin) on Rabbit's Choroid and Retina 
Aim:
The aim of the study was to evaluate the impact of intravitreal injection of bevacizumab (Avastin) on chorio-capillaris permeability as well as structure changes in the choroid and the retina of pigmented rabbits.
Material and Methods:
The study included 10 pigmented rabbits (20 clinically free eyes) ranged in weight between 1.2 and 2 kg (mean 1.7±0.05). The rabbits were subjected to intravitreal injection of 5 mg, 0.1mg Avastin in the right eyes (10eyes), while the left eyes (10eyes) were injected with equal volumes of balanced salt solution. 1 week later, Clinical examination and fundus fluorescein angiography (FFA) were done. Histological examination was performed on specimens of retina & choroid of Avastin & BSS injected eyes of sacrificed rabbits using light microscopy (LM) & transmission electron microscopy (TEM). Results were recorded and compared
Results:
Post injection clinical examination of the eyes showed no abnormality of cornea, lens, vitreous and fundus. FFA showed remarkable decrease in background chorio-capillaris fluorescence in 7 eyes (70 percent) injected with Avastin as compared with eyes injected with BSS. No change was observed in regards to retinal vasculature, or abnormal dye leak. LM examination: specimens from Avastin group were evaluated in comparison to control eyes Treated eyes exhibited the same microscopic appearance in most specimens (8/10, 80 percent). The chorio-capillaris layer showed elongated, stretched monolayer of capillaries with flat, elongated endothelial cell lining. The laminae showed closely packed RBCs arranged in a monolayer with ribbon like shape. The surrounding interstitial tissue showed stretched, elongated & compact collagen fibers. The RPE cells were tightly adherent to each other with prominent nuclei. The different retinal layers were in concomitance with the control specimens, however mild to moderate disruption of photoreceptor outer segments together with mild vacuolization in the ganglion cell layer were seen. TEM examination of both control and treated specimens confirmed the findings recorded by LM. The endothelial cell limning of the choriocapillaris exhibited reduced fenestrations in between the cells. TEM also highlighted the compact lamellae of collagen fibers. The RPE cells showed remarkable increase in the number of mitochondria and prominent endoplasmic reticulum. Variable sized melanosomes were also seen
Conclusion:
Though single intravitreal injection of Avastin does not cause appreciable histological changes in rabbit retina and choroid, yet, it imposes definite effect on choriocapillaris permeability as evidenced by FFA and ultra structural changes. Repeated intravitreal injections might alter the hemostasis of the chorio-capillaris RPE complex.
doi:10.4103/0974-9233.51995
PMCID: PMC3038111  PMID: 21346840
Bevacizumab; intravitreal injection; chorio-capillaris; retinal toxicity; vascular endothelial growth factor
25.  Bevacizumab treatment for advanced non-small cell lung cancer: A case report 
Oncology Letters  2013;6(6):1779-1783.
The safety of Avastin in lung cancer (SAiL) study is a multi-center, open-source, stand-alone study. Patients with untreated, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered up to six cycles of chemotherapy combined with bevacizumab-humanized monoclonal antibodies, followed by maintenance therapy with bevacizumab until further progression of the disease. From August, 2006 to July, 2008 there were a total of 2,172 patients enrolled in the study, with a median progression-free survival time of 7.8 months and an overall survival time of 14.6 months. The present study describes the case of a 54-year-old male with lung cancer and T3N0M1 subcutaneous metastasis, which was initially treated with bevacizumab-combined carboplatin/paclitaxel (C/P) therapy and then maintained solely with bevacizumab for five years. Following six cycles of C/P bevacizumab treatment, the therapeutic evaluation revealed a stable disease (SD). The patient was kept on bevacizumab maintenance therapy for 50 months without disease progression until a persistent 3+ proteinuria was diagnosed in a follow-up review, which led to bevacizumab withdrawal and concomitant tumor growth. The present study concluded that the long-term application of bevacizumab monoclonal antibodies (mABs) was safe in a late-stage non-small cell lung cancer patient. The major adverse reaction that was exhibited was proteinuria, which was associated with the cumulative dose of bevacizumab and was able to be reversed by withdrawal. Patients with a prolonged SD may benefit from bevacizumab maintenance therapy.
doi:10.3892/ol.2013.1603
PMCID: PMC3834347  PMID: 24260075
anti-vascular endothelial growth factor; stable disease; safety of Avastin in lung trial; metastasis; chemotherapy

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