Anti-vascular Endothelial Growth factor-A Research Articles

Update on current diagnosis and management of anaplastic thyroid carcinoma.

Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%. However, the undifferentiated or anaplastic type accounting for < 0.2%, usually in elderly individuals, exhibits a dismal prognosis with rapid growth and disappointing outcomes. It is the most aggressive form of thyroid carcinoma, with a median survival of 5 mo and poor quality of life (airway obstruction, dysphagia, hoarseness, persistent pain). Early diagnosis and staging are crucial. Diagnostic tools include biopsy (fine needle aspiration, core needle, open surgery), high-resolution ultrasound, computed tomography, magnetic resonance imaging, [(18)F]fluoro-D-glucose positron emission tomo-graphy/computed tomography, liquid biopsy and microRNAs. The BRAF gene (BRAF-V600E and BRAF wild type) is the most often found molecular factor. Others include the genes RET, KRAS, HRAS, and NRAS. Recent management policy is based on surgery, even debulking, chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or definitive), targeted biological agents and immunotherapy. The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients. Anti-programmed death-ligand 1 antibody immunotherapy, stem cell targeted therapies, nanotechnology achievements and artificial intelligence imple-mentation provide novel promising alternatives. Genetic mutations determine molecular pathways, thus indicating novel treatment strategies such as anti-BRAF, anti-vascular endothelial growth factor-A, and anti-epidermal growth factor receptor. Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care. This neoadjuvant treatment followed by surgery ensures a two-year overall survival of 80%. Prognostic factors for improved outcomes have been found to be younger age, earlier tumor stage and radiation therapy. A multidisciplinary approach is necessary, and the therapeutic plan should be individualized based on surveillance and epidemiology end results.

Angiogenesis and Its Targeting in Glioblastoma with Focus on Clinical Approaches.

Angiogenesis is a characteristic of glioblastoma (GBM), the most fatal and therapeutic-resistant brain tumor. Highly expressed angiogenic cytokines and proliferated microvascular system made anti-angiogenesis treatments a thoroughly plausible approach for GBM treatment. Many trials have proved to be not only as a safe but also as an effective approach in GBM retardation in a certain time window as seen in radiographic response rates; however, they have failed to implement significant improvements in clinical manifestation whether alone or in combination with radio/chemotherapy. Bevasizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, is the only agent that exerts meaningful clinical influence by improving progression-free survival (PFS) and partially alleviate clinical symptoms, nevertheless, it could not prolong the overall survival (OS) in patients with GBM. The data generated from phase II trials clearly revealed a correlation between elevated reperfusion, subsequent to vascular normalization induction, and improved clinical outcomes which explicitly indicates anti-angiogenesis treatments are beneficial. In order to prolong these initial benefits observed in a certain period of time after anti-angiogenesis targeting, some aspects of the therapy should be tackled: recognition of other bypass angiogenesis pathways activated following antiangiogenesis therapy, identification of probable pathways that induce insensitivity to shortage of blood supply, and classifying the patients by mapping their GBM-related gene profile as biomarkers to predict their responsiveness to therapy. Herein, the molecular basis of brain vasculature development in normal and tumoral conditions is briefly discussed and it is explained how "vascular normalization" concept opened a window to a better comprehension of some adverse effects observed in anti-angiogenesis therapy in clinical condition. Then, the most targeted angiogenesis pathways focused on ligand/receptor interactions in GBM clinical trials are reviewed. Lastly, different targeting strategies applied in anti-angiogenesis treatment are discussed.

Antivascular endothelial growth factor-A therapy: a novel personalized treatment approach for psoriasis.

SummaryChronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK’s population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient’s goals. Vascular endothelial growth factor‐A (VEGF‐A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF‐A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF‐A in in vivo models of psoriasis‐like inflammation resulted in disease clearance. Anti‐angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF‐A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF‐A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF‐A, who may be most likely to benefit from anti‐VEGF‐A therapy, offering an opportunity to personalize treatment in psoriasis. Anti‐VEGF‐A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis.

THE ANGIOPOIETIN/TIE PATHWAY IN RETINAL VASCULAR DISEASES: A Review.

To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases. A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites. The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed. Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways.

New Proline, Alanine, Serine Repeat Sequence for Pharmacokinetic Enhancement of Anti-VEGF Single-Domain Antibody.

Therapeutic fragmented antibodies show a poor pharmacokinetic profile that leads to frequent high-dose administration. In the current study, for the first time, a novel proline, alanine, serine (PAS) repeat sequence called PAS#208 was designed to extend the plasma half-life of a nanosized anti-vascular endothelial growth factor-A single-domain antibody. Polyacrylamide gel electrophoresis, circular dichroism, dynamic light scattering, and electrophoretic light scattering were used to assess the physicochemical properties of the newly designed PAS sequence. The effect of PAS#208 on the biologic activity of a single-domain antibody was studied using an in vitro proliferation assay. The pharmacokinetic parameters, including terminal half-life, the volume of distribution, elimination rate constant, and clearance, were determined in mice model and compared with the native protein and PAS#1(200) sequence. The novel PAS repeat sequence showed comparable physicochemical, biologic, and pharmacokinetic features to the previously reported PAS#1(200) sequence. The PAS#208 increased the hydrodynamic radius and decreased significantly the electrophoretic mobility of the native protein without any change in zeta potential. Surprisingly, the fusion of PAS#208 to the single-domain antibody increased the binding potency. In addition, it did not alter the biologic activity and did not show any cytotoxicity on the normal cells. The PAS#208 sequence improved the terminal half-life (14-fold) as well as other pharmacokinetic parameters significantly. The simplicity as well as superior effects on half-life extension make PAS#208 sequence a novel sequence for in vivo pharmacokinetic enhancement of therapeutic fragmented antibodies. SIGNIFICANCE STATEMENT: In the current study, a new proline, alanine, serine (PAS) sequence was developed that showed comparable physicochemical, biological, and pharmacokinetic features to the previously reported PAS#1(200) sequence. The simplicity as well as superior effects on half-life extension make PAS#208 sequence a novel sequence for in vivo pharmacokinetic enhancement of recombinant small proteins.

Nanotherapies for the Treatment of Age-Related Macular Degeneration (AMD) Disease: Recent Advancements and Challenges.

Age-related Macular Degeneration (AMD) is one of the common diseases affecting the posterior part of the eye, of a large population above 45 years old. Anti-Vascular Endothelial Growth Factor- A (Anti-VEGF-A) agents have been considered and approved as therapeutic agents for the treatment of AMD. Due to the large molecular weight and poor permeability through various eye membranes, VEGF-A inhibitors are given through an intravitreal injection, even though the delivery of small therapeutic molecules by topical application to the posterior part of the eye exhibits challenges in the treatment. To overcome these limitations, nanocarrier based delivery systems have been utilized to a large extent for the delivery of therapeutics. Nanocarriers system offers prodigious benefits for the delivery of therapeutics to the posterior part of the eye in both invasive and non-invasive techniques. The nano size can improve the permeation of therapeutic agent across the biological membranes. They provide protection from enzymes present at the site, targeted delivery or binding with the disease site and extend the release of therapeutic agents with prolonged retention. This leads to improved therapeutic efficacy, patient compliance, and cost effectiveness of therapy with minimum dose associated side-effects. This review has summarized various nanocarriers explored for the treatment of AMD and challenges in translation.

Correlation between vascular endothelial growth factor-A expression and tumor location and invasion in patients with colorectal cancer.

Vascular endothelial growth factor-A (VEGF-A) has been observed as the predominant angiogenic factor in colorectal cancer (CRC) and the assessment of microvessel density (MVD) has been used to quantify tumor neoangiogenesis. This study aimed to determine clinicopathological and prognostic significance of both angiogenic markers in the local CRC patients. We analyzed tissue samples obtained from 81 cases with CRC. VEGF-A expression and MVD counts were immunohistochemically detected using anti VEGF-A and CD31. The assessments of both markers were classified as low and high. Correlation between VEGF-A expression and MVD value and clinicopathological characteristics were examined using Chi-square test. The overall survival (OS) was plotted using the Kaplan-Meier method. High VEGF-A expression was found more frequently in the rectal location (P=0.042) and T4 tumors (P=0.041) compared to their counterparts. Older patients tended to show a higher MVD value compared to younger cases (P=0.062). In addition, survival analysis showed that males had a worse OS compared to females (P=0.029), and VEGF-A expression and MVD count did not correlate with patients' survival. There were significant differences of VEGF-A expression according to tumor location and T invasion. Sex, but not angiogenic markers, had an influence on the survival of CRC patients.

Inhibition of Placenta Growth Factor Reduces Subretinal Mononuclear Phagocyte Accumulation in Choroidal Neovascularization.

The cellular immune response driven by mononuclear phagocytes (MPs) is crucial for choroidal neovascularization (CNV) progression. Case reports show that a switch from pure anti-vascular endothelial growth factor-A (VEGF-A) intravitreal treatment to aflibercept, a drug with combined anti-VEGF-A and anti-placenta growth factor (PlGF) activity, can be beneficial for patients who do not respond to anti-VEGF-A alone. Since MPs harbor VEGFR1, we hypothesize that the interplay of P1GF/vascular endothelial growth factor receptor 1 (VEGFR1) in immune cells plays a pivotal role for CNV. CNV was induced with laser, and immune cells and neovascularization were analyzed in vivo and ex vivo. Immunohistochemistry was employed for protein detection. Differential expression of angiogenic factors and macrophage polarization markers were assessed by quantitative PCR (qPCR). One day after laser, intravitreal injection of aflibercept or anti-PlGF was performed. In the early inflammatory phase after laser, Plgf but not Vegfa was significantly upregulated. VEGF-A upregulation is limited to the scar, whereas PlGF shows a wider distribution. M1 (proinflammatory) macrophage markers were upregulated in the early phase of CNV. However, M2 (proangiogenic) markers showed more inconsistent dynamics. We demonstrated that both aflibercept and anti-PlGF treatments decrease the overall amount of activated subretinal MPs, and especially of those expressing PlGF. These data correlated with a reduction in leakage associated to CNV. Aflibercept showed a stronger reduction in both parameters. The results hint at an interplay between PlGF/VEGFR1 and MPs that is important in the early phase of CNV. A combined inhibition of VEGF-A and PlGF is superior to a specific anti-PlGF treatment in terms of subretinal MP recruitment.

Improving treatment of liver metastases by targeting nonangiogenic mechanisms.

A recent study confirms an association between vessel co-option and resistance to bevacizumab, an anti-vascular endothelial growth factor-A (VEGFA) antibody, in patients with liver metastases. The authors suggest a combined therapeutic strategy that reduces co-option in mice.

Bevacizumab as first-line treatment in HER2-negative advanced breast cancer: pros and cons.

Bevacizumab, a humanized, anti-vascular endothelial growth factor-A monoclonal antibody, has shown efficacy in a number of cancers. However, its use in metastatic breast cancer (MBC) remains controversial. A literature review using the PubMed database was performed to update the currently available clinical trials evidence on bevacizumab in the first-line treatment of breast cancer. In addition, the proceedings of selected oncology annual meetings were searched for relevant presentations. This article reviews the available evidence for bevacizumab as first-line therapy for MBC and discusses its current and future applicability in the management of MBC. Three phase III trials (ECOG-2100, AVADO, RIBBON-1) demonstrated that the addition of bevacizumab to chemotherapy is well-tolerated and improves progression-free survival and objective response rates in the first-line setting. These findings were supported by a large clinical practice-based study (ATHENA) and a recent clinical trial in which bevacizumab added to paclitaxel showed notable activity in triple-negative MBC. However, bevacizumab has thus far not demonstrated a significant benefit in overall survival. The addition of bevacizumab to chemotherapy is well-tolerated and produces substantial improvements in overall response rate and progression-free survival, compared with chemotherapy alone, in advanced HER2-negative breast cancer. Nevertheless, it has thus far not demonstrated a significant benefit in overall survival. Whether prolongation of progression-free survival is enough to consider bevacizumab efficacious is unclear. Based on the available clinical trials results, bevacizumab is a part of the complex therapeutic strategy of advanced HER2-negative breast cancer.

Abstract 5198: Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer

Abstract Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have excellent effects on non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, EGFR mutant NSCLC inevitably acquires resistance to EGFR-TKIs such as gefitinib, erlotinib, or afatinib. Previously, we found that bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, enhanced the antitumor effects of gefitinib and afatinib in preclinical lung cancer models (Ichihara et al., Caner Res 2009; Ninomiya et al., Mol Cancer Ther 2013). In a phase II trial of OLCSG1001, we demonstrated relatively longer progression-free survival by adding bevacizumab to gefitinib in the treatment of patients harboring an EGFR exon 19 deletion. Seto et al. (Lancet Oncol 2015) also reported that adding bevacizumab to erlotinib in patients harboring EGFR mutations significantly prolonged progression-free survival. A new anti-angiogenic agent, the anti-human VEGF receptor-2 (VEGFR-2) antibody ramucirumab, has also been used clinically (Garon et al., Lancet 2014). We investigated the effect of an anti-VEGFR-2 antibody combined with erlotinib on the growth of lung cancers harboring EGFR mutations. Materials and Methods: NSCLC cell lines PC-9, which harbors EGFR exon 19 deletion and H3255, which harbors EGFR L858R mutation, were used in this study. Ramucirumab and the anti-murine VEGFR-2 antibody DC101 were kindly provided by Eli Lilly (Indianapolis, IN, USA). BALB/c nu/nu or transgenic mice expressing the delE748-752 mutant version of mouse Egfr driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation of humans (C57BL/6/Egfr15DEL) (Ohashi et al. Cancer Sci 2009), were used for in vivo experiments. For xenograft models, PC-9 or H3255 cells were injected subcutaneously into BALB/c mice. The mice were divided into four treatment groups: vehicle, erlotinib, DC101, or erlotinib combined with DC101. Results: DC101 alone moderately inhibited the growth of PC-9 or H3255 tumor in the xenograft mouse models or suppressed lung cancers in C57BL/6/Egfr15DEL mice. Combined erlotinib and DC101 therapy inhibited the growth of PC-9 tumor in the xenograft mouse models more markedly than did erlotinib or DC101 alone. There were no differences in toxicity between monotherapy and combination therapy. Conclusion: Combination therapy with erlotinib and an anti-VEGFR-2 antibody had a stronger antitumor effect than those of the respective monotherapies in lung cancers harboring EGFR mutations in vivo. Citation Format: Hiroe Kayatani, Kadoaki Ohashi, Takeshi Imao, Kenichiro Kudo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Ktsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura. Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5198.

Tolérance du bévacizumab au cours de l’hypertension artérielle pulmonaire associée à la sclérodermie systémique : à propos d’une observation

IntroductionNo data is available regarding the safety of bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, in patients with pulmonary arterial hypertension (PAH), a condition in which VEGF seems to play a significant and probably protective role. Case reportWe report a patient with a history of systemic sclerosis-associated PAH, stable under bosentan therapy. She was diagnosed with metastatic cervical epidermoid carcinoma and treated by two successive cytotoxic chemotherapy regimens. As these treatments failed to control disease progression, she was started on anti-angiogenic therapy: 3 infusions of bevacizumab 15 mg/kg were administered. Over the course of this treatment, no change in the clinical status or echocardiography parameters was noted. ConclusionThis observation suggests that, under careful clinical and echocardiographic follow-up, bevacizumab therapy can be well tolerated in case of stable and moderate PAH. Decision of treatment should be taken cautiously, as the possibility of PAH worsening is not excluded.

Targeting Platelet-Derived Growth Factor Receptor β+ Scaffold Formation Inhibits Choroidal Neovascularization

Neovascular age-related macular degeneration is among the most common causes of irreversible blindness and manifests with choroidal neovascularization (CNV). Anti-vascular endothelial growth factor-A therapies are only partially effective and their chronic administration may impair functions of the choriocapillaris and retina. Thus, novel therapeutic targets are needed urgently. We have observed in a laser-induced model of CNV that a platelet-derived growth factor receptor β positive (PDGFRβ(+)) scaffold is formed before infiltration of neovessels into this scaffold to form CNV lesions, and that this scaffold limits the extent of neovascularization. Based on these observations we hypothesized that ablation of proliferating PDGFRβ(+) cells to prevent the formation of this scaffold might inhibit CNV growth and present a novel therapeutic approach for neovascular age-related macular degeneration. To test this hypothesis we targeted proliferating PDGFRβ(+) cells through independent distinct approaches after laser injury: i) by using an inducible genetic model to inhibit specifically proliferating PDGFRβ(+) cells, ii) by treating mice with a neutralizing anti-PDGFRβ antibody, iii) by administering an anti-PDGF-AB/BB aptamer, and iv) by using small chemical inhibitor approaches. The results show that therapeutic targeting of proliferating PDGFRβ(+) cells potently inhibits the formation of the pericyte-like scaffold, with concomitant attenuation of CNV. Moreover, we show that early inhibition of PDGFRβ(+) cell proliferation before neovessel formation is sufficient to inhibit scaffold formation and neovascularization.

Epidemiological and Clinical Baseline Characteristics as Predictive Biomarkers of Response to Anti-VEGF Treatment in Patients with Neovascular AMD.

Purpose. To review the current literature investigating patient response to antivascular endothelial growth factor-A (VEGF) therapy in the treatment of neovascular age-related macular degeneration (nAMD) and to identify baseline characteristics that might predict response. Method. A literature search of the PubMed database was performed, using the keywords: AMD, anti-VEGF, biomarker, optical coherence tomography, treatment outcome, and predictor. The search was limited to articles published from 2006 to date. Exclusion criteria included phase 1 trials, case reports, studies focusing on indications other than nAMD, and oncology. Results. A total of 1467 articles were identified, of which 845 were excluded. Of the 622 remaining references, 47 met all the search criteria and were included in this review. Conclusion. Several baseline characteristics correlated with anti-VEGF treatment response, including best-corrected visual acuity, age, lesion size, and retinal thickness. The majority of factors were associated with disease duration, suggesting that longer disease duration before treatment results in worse treatment outcomes. This highlights the need for early treatment for patients with nAMD to gain optimal treatment outcomes. Many of the identified baseline characteristics are interconnected and cannot be evaluated in isolation; therefore multivariate analyses will be required to determine any specific relationship with treatment response.

Overexpression of Cardiomyocyte α1A-Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling.

Stimulation of cardiac α1A-adrenergic receptors (α1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis. Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor. Cardiomyocyte-specific overexpression of the α1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.

Management of colorectal cancer.

Colorectal cancer is one of the most frequent solid tumors in the Western world. Treatment options are dependent on the stage of the disease, the performance status of the patient, and increasingly the molecular makeup of the tumor. In countries with surveillance programs, the incidence rate as well as the mortality rate has gone down because of the earlier stages at which the tumors are detected. For rectal cancer, standard of care differs from that of colon cancer with regard to perioperative treatment. In the metastatic setting, treatment options are uniform for colorectal cancer. Over the years, treatment options have emerged from single-agent 5-fluorouracil (5-FU) treatment to combination regimens using 5-FU and oxaliplatin or irinotecan or both. Treatment efficacy in the metastatic setting has been increased with the introduction of targeted substances. These include (a) the anti-vascular endothelial growth factor-A (anti-VEGF-A) antibody bevacizumab, (b) the anti-epidermal growth factor receptor (anti-EGFR) antibodies cetuximab and panitumumab, (c) the anti-angiogenic multi-kinase inhibitor regorafenib, and (d) the anti-angiogenic compound aflibercept. Anti-EGFR antibodies have shown efficacy only in the subpopulations of tumors that do not have any mutation in KRAS and NRAS exon 2, 3, 4. Physicians have the choice in the first line to use anti-EGFR or anti-VEGF inhibitors in combination with chemotherapy based on treatment goals and patient performance. In recent years, tumor location has been shown to be prognostic and predictive for clinical outcome. Right-sided sporadic colon cancers differ significantly in molecular characteristics and, with the exception of microsatellite instability (MSI-H) tumors, are associated with poor prognosis. Tumors based on hereditary non-polyposis colorectal cancer, on the other hand, have excellent prognosis in stage II and III disease. Recent efforts have focused on the molecular classification of colorectal cancer with the purpose of establishing molecularly defined subgroups.

Local acting Sticky‐trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye

Current therapeutic antiangiogenic biologics used for the treatment of pathological ocular angiogenesis could have serious side effects due to their interference with normal blood vessel physiology. Here, we report the generation of novel antivascular endothelial growth factor-A (VEGF) biologics, termed VEGF “Sticky-traps,” with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects. Using genetic and pharmacological approaches, we demonstrated that Sticky-traps could locally inhibit angiogenesis to at least the same extent as the original VEGF-trap that also gains whole-body access. Sticky-traps did not cause systemic effects, as shown by uncompromised wound healing and normal tracheal vessel density. Moreover, if injected intravitreally, recombinant Sticky-trap remained localized to various regions of the eye, such as the inner-limiting membrane and ciliary body, for prolonged time periods, without gaining access either to the photoreceptors/choriocapillaris area or the circulation. These unique pharmacological characteristics of Sticky-trap could allow for safe treatment of pathological angiogenesis in patients with diabetic retinopathy and retinopathy of pre-maturity.

Aflibercept treatment for patients with exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections (TURF trial)

AimTo determine the efficacy of 2.0 mg aflibercept in the management of patients with recalcitrant exudative age-related macular degeneration (AMD).MethodsIn this prospective, open-label, single-arm clinical trial, patients were seen monthly...

CC chemokine receptor-3 as new target for age-related macular degeneration

CC chemokine receptor-3 (CCR3) is involved in angiogenic processes. Recently, CCR3 was accounted to participate in choroidal neovascularization (CNV) and CCR3 targeting was reported to be superior to standard antivascular endothelial growth factor-A (VEGF-A) administration when tested in an artificially induced CNV in animals. As human CCR3 studies are lacking in age-related macular degeneration (AMD) patients we sought to determine if CCR3 has any association with inflammatory processes that occur in CNV. A total of 176 subjects were included on the basis of inclusion criteria. Real time PCR was used to analyze the single nucleotide polymorphism in CCR3 of AMD (115) and normal controls (n=61). Genotype frequency was adjusted for possible confounders like cigarette smoking, alcohol, meat consumption and other risk factors. Chi-square test was used for analysis of polymorphism. The genotype distribution of CCR3 (rs3091250) polymorphism was significantly different in AMD patients in the Indian population. GT (heterozygous) and TT (homozygous) at the rs3091250 SNP increased risk of AMD as compared to the GG genotypes (OR=4.8, CI 95%=2.2–10.8 and OR=4.1, CI 95%=1.6–10.1 respectively). Subgroup analysis of AMD patients in wet and dry revealed no significant differences. There was no significant difference for rs3091312 in AMD and control group. A significant association between AMD and CCR3 (rs3091250) polymorphism localized on chromosome 3p21.3 was detected. The results suggest the possible contribution of rs3091250, a new predisposing allele in AMD.

Intravitreal ranibizumab as primary treatment for neovascular membrane associated with angioid streaks

Editor, Angioid streaks (AS) represent calcified disruptions of Bruch’s membrane and may result in the development of choroidal neovascularization (CNV) with an estimated prevalence of between 72% and 86% (Bhatnagar et al. 2007). The natural history of CNV associated with AS has a poor prognosis. Although various treatments have been assessed, including argon laser photocoagulation, transpupillary thermotherapy, photodynamic therapy and surgical removal, poor or contradictory results are often reported. In recent years, several studies have reported promising results with off-label use of the intravitreal anti-vascular endothelial growth factor-A (VEGF-A) drug bevacizumab (Avastin™; Genentech, South San Francisco, California, USA) for the treatment of CNV related to AS (Bhatnagar et al. 2007; Apte 2008; Derriman et al. 2008; Neri et al. 2009; Wiegand et al. 2009). It has been hypothesized that ranibizumab (Lucentis®; Genentech), which is an approved anti-VEGF treatment for CNV related to age-related macular degeneration (AMD), would offer an outcome at least similar to that of bevacizumab (Derriman et al. 2008). Herein, we report a case of juxtafoveal CNV caused by AS treated successfully with intravitreal ranibizumab. A 70-year-old woman referred from abroad to the retina department of Jules Gonin University Eye Hospital with a 1-month history of visual distortion affecting her left eye. Her ocular history was significant for CNV in the right eye with rapid progression, status post-treatment with intravitreal injection of bevacizumab. Visual acuity was 20/200 in the right eye and 20/20 in the left eye. Fundus examination showed angioid streaks with a grey lesion in both eyes, subretinal haemorrhage and subsensory fluid nasally to the fovea consistent with CNV in the left eye and a disciform scar surrounded by retinal pigment epithelium atrophy in the right eye. Fluorescein angiography (FA) revealed a juxtafoveal classic CNV associated with leakage and hyperfluorescence corresponding to the AS on the left eye and a staining of disciform scarring with no active leakage in the macula of the right eye. Indocyanine green angiography (ICG) highlighted the presence of AS that radiated from the peripapillary area to the macula and midperipheral fundus in both eyes (Fig. 1). Colour photograph and angiography findings of the left eye at baseline and at the last follow-up (27 months). Baseline: colour photograph shows angioid streaks (AS) and a grey lesion with subretinal haemorrhage nasally to the fovea consistent with choroidal neovascularization (CNV) (A); fluorescein angiography (FA) shows staining of the AS radiating from the optic nerve (C) with evidence of active CNV nasally to the macula with late leakage (E). Last follow-up: colour fundus photograph shows the resolution of submacular haemorrhage (B) while FA shows the absence of exudation from CNV (D, F). Note that indocyanine green angiography highlights the presence of AS that radiate from the peripapillary area to the macula (G, H). After informed written consent was provided, three intravitreal injections of ranibizumab (0.5 mg) were administered at monthly intervals in the left eye, despite good visual acuity (VA) considering the history of rapid progression of CNV in her right eye. One month after the third injection, VA remained 20/20 with resolution of subjective visual distortion; FA revealed complete regression of the neovascular complex. VA, FA and ICG findings remained stable until the last follow-up at 27 months. No further injections were required during the follow-up period. As in CNV caused by AMD, VEGF-A may play an important role in the pathogenesis of CNV caused by AS. Ranibizumab is a specific, affinity-mature fragment of a recombinant, humanized immunoglobulin (Ig) G1 monoclonal antibody that neutralizes all active forms of VEGF-A. It has been found to be effective in the treatment of exudative AMD, demonstrating encouraging signs of biological activity, with acceptable safety. However, as far as we are aware, the current medical literature encompasses only one other report of CNV associated with AS treated with ranibizumab, in which Derriman et al. (2008) reported stability of VA for 6 months after three intravitreal injections of ranibizumab (0.5 mg) spaced at monthly intervals. In our case, treatment with three monthly interval intravitreal injections of ranibizumab resulted in complete resolution of CNV for a period of 27 months. Ranibizumab may be an effective treatment of CNV related to AS; nevertheless, further clinical trials are required to determine more accurately its clinical benefit and its safety in this clinical entity.