Systemic Bevacizumab Research Articles

This issue of Acta

This issue of Acta

A phase 1 study of hepatic arterial infusion of oxaliplatin in combination with systemic 5‐fluorouracil, leucovorin, and bevacizumab in patients with advanced solid tumors metastatic to the liver

Liver metastases in patients with cancer are associated with poor survival. The authors of this report conducted a phase 1 study of hepatic arterial infusion (HAI) oxaliplatin combination therapy in patients with advanced cancer and liver metastases. Treatment consisted of escalating doses of HAI oxaliplatin 60 mg/m(2) to 175 mg/m(2) and intra-arterial heparin 3000 IU (Day 1); leucovorin 200 mg/m(2) intravenously (iv) and 5-fluorouracil 300 mg/m(2) bolus plus 600 mg/m(2) iv (Days 1 and 2); and bevacizumab 10 mg/kg iv (Day 3). A conventional "3 + 3" design was used. Fifty-seven patients were treated, including 30 women and 27 men. The median age was 57 years, and the patients had received a median of 3 prior therapies (range, 1-7 prior therapies). The most common cancer was colorectal (n = 29). Overall, 204 cycles were administered (median per patient, 2 cycles; range, 1-17 cycles). The maximum tolerated dose (MTD) of HAI oxaliplatin was 140 mg/m(2). Dose-limiting toxicities were grade 4 thrombocytopenia (n = 1) and grade 4 hypokalemia (n = 1) at 150 mg/m(2) (n = 5). Thirty-three patients (58%) had no toxicity greater than grade 1. The most common toxicities were thrombocytopenia (n = 19), fatigue (n = 15), nausea/vomiting (n = 6), constipation (n = 6), and diarrhea (n = 4). Of 55 patients who were evaluable for response (according to Response Evaluation Criteria in Solid Tumors), 4 patients (7%) had a partial response (PR), and 32 patients (58%) had stable disease (SD), including 15 patients (48%) who had SD for >/=4 months. Of 28 patients with colorectal cancer, 3 patients (11%) had a PR, and 9 patients (32%) had SD for >/=4 months. HAI oxaliplatin combined with systemic 5-fluorouracil, leucovorin, and bevacizumab had antitumor activity in patients with advanced cancer and liver metastases, and the current results indicated that this combination warrants further study. Cancer 2010. (c) 2010 American Cancer Society.

Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy

Striae distensae (stretch marks) are a common complication seen in patients on chronic corticosteroid therapy. Under certain circumstances, primary brain tumor patients require chronic corticosteroid therapy and can suffer from striae distensae. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A) is now more widely used for the treatment of primary brain tumors. In this paper, we present four cases of ulcerated striae distensae in primary brain tumor patients on concurrent corticosteroid and bevacizumab therapy. Because of bevacizumab's effects on wound healing and its recent accelerated approval for recurrent glioblastoma multiforme (GBM), the most common malignant primary brain tumor in adults, this novel skin complication should be considered in patients on concurrent corticosteroid and bevacizumab therapy.

Early loss of pregnancy after intravitreal bevacizumab injection

e report two cases of womenwho suffered an early loss ofpregnancy (at 7 and 10 days, respec-tively) following intravitreal bev-acizumab injection.Case 1: A 29-year-old Whitewoman presented to our departmentwith a sudden deterioration of visionin the left eye (LE). She was a knowntype 1 diabetes subject under regularinsulin injections with well-controlleddiabetes (glycosylated haemoglobin[HbA1c] = 6%, normal lipid profile)and no diabetes-related complications.Her past medical and gynaecologicalhistory was otherwise unremarkable.She was the mother of a 9-month-oldboy (non-breast feeding). She hadundergone a full panretinal photoco-agulation (PRP) in the right eye (RE)and some sessions of PRP in the LEfor bilateral proliferative diabetic reti-nopathy.On examination, best correctedvisual acuity (BCVA) was 6⁄12 REand 6⁄36 LE. Anterior segment exam-ination was unremarkable and dil-ated fundoscopy revealed an inferiorvitreous haemorrhage in the LE.Bevacizumab was administered intra-vitreally (1.25 mg) with a view tocontinuing the PRP therapy in theinferior retina 2–4 weeks following theinjection. Five days later, gynaecologi-cal examination including bHCG(b-human chorionic gonadotrophin)(2750) and ultrasound confirmed a5-week pregnancy of which the patientwas unaware. Seven days after thebevacizumab injection, she suffered anearly loss of pregnancy.Case 2: A 25-year-old healthymyope () 10 D LE, ) 7 D RE) pre-sented with blurred vision in the LEand BCVA of 20⁄25 in the RE and20⁄50 LE. Fundus examination dem-onstrated an elevated subfoveal lesionin the LE and myopic chorioretinaland peripapillary atrophies bilaterally.Fundus fluorescein angiography andindocyanine green angiography con-firmed choroidal neovascularization inthe LE. Bevacizumab was adminis-tered intravitreally (1.25 mg). Oneweek later the subject underwent agynaecological examination. ElevatedbHCG levels and ultrasound wereconsistent with a 4-week pregnancy ofwhich the patient was unaware. Tendays after the intravitreal injection,she suffered a miscarriage.Over recent years, the use of bev-acizumab has expanded to include thetreatment of diabetic retinopathy(Avery et al. 2006). Systemic bev-acizumab is teratogenic in rabbits atdoses twice the recommended i.v.human dose (US Food and DrugAdministration 2005) and althoughsystemic absorption (when adminis-tered intravitreally) is believed to beminimal, recent research has demon-strated that intravitreal 1.25 mg bev-acizumab may reach the systemiccirculation in plasma concentrationsof 100 ng⁄ml (Csaky 2007).Recently, Rosen et al. (2009)reported the absence of fetal side-effects after exposure to intravitrealbevacizumab during the second tri-mester. Although the latter representsan important observation, the effectof bevacizumab exposure during thefirst trimester is unknown. Moreover,a case of metrorrhagia 2 weeks afterintravitreal Avastin injection has beenreported (Rodrigues et al. 2007).Once it is in the circulation, bev-acizumab, although it is incapable ofcrossing the placenta barrier, may acton placenta circulation by inhibitingVEGF-A. This would explain its tera-togenic effect. The short periodbetween the intravitreal injection andthe spontaneous abortion, as well asthe lack of risk factors for miscarriagein both our patients (age 35 years, prior miscarriage,prior elective termination of preg-nancy, prior ectopic pregnancy, priorpelvic surgery, infection etc.) comprisethe main reasons for suspicion of anaetiological correlation between bev-acizumab injection and early loss ofpregnancy.Although such a correlation cannotbe established unless further studiesare performed, we believe that pre-treatment counselling should include adiscussion with all premenopausalwomen outlining the possible risk ofmiscarriage.

Unexpected increased biliary toxicity when systemic bevacizumab is added to hepatic arterial infusion.

3559 Background: Hepatic arterial infusion (HAI) with floxuridine + dexamethasone can be added safely and effectively to systemic (SYS) oxaliplatin + irinotecan in unresectable colorectal cancer liver metastases (CLM) and after CLM resection. HAI is also feasible in unresectable intrahepatic cholangiocarcinoma (primary liver, PL). Bevacizumab (Bev) is an active agent that was added to these HAI regimens to increase efficacy (disease-free survival) in CLM and PL. Methods: We combined Bev with HAI in 3 separate trials: (1) phase II trial of unresectable CLM with best SYS, (2) phase II trial in PL (no SYS), and (3) phase II randomized trial ± Bev after CLM resection with best SYS. The phase II trials of unresectable CLM and PL were compared to prior HAI trials (no Bev). The phase II trial after CLM resection compared two arms. Fisher's exact test was used to assess the association of clinicopathologic variables, e.g., Fong score, previous SYS, dose of HAI, KPS, blood tests, and toxicity data (grade 3-4 NCI CTCAEv3.0) with/without Bev. Bilirubin toxicity was reported as ≥ 2mg/dl. Multivariate analysis to further characterize risk of hepatic toxicity was not possible due to small numbers of events. Results: In all 3 trials patients exhibited similar characteristics. In univariate analyses, no clinicopathologic variable was significantly associated with increased risk of hepatic toxicity. Usual Bev toxicity (e.g., increased clotting and hypertension) was seen as expected. However, increased hepatic toxicity was also noted with the addition of Bev (Table). Conclusions: Although our analyses were limited by sample size, we found unexpected increased biliary toxicity with Bev+HAI±SYS resulting in increased biliary stenting. Impaired healing of HAI-induced biliary injury due to angiogenesis inhibition may be the mechanism of increased biliary toxicity. Efficacy data will be presented. Studies HAI ± SYS HAI ± SYS + BEV p value Colorectal adjuvant Stents 0 4 0.05 (n=73; 38 with Bev) Total bilirubin ≥ 2 0 5 0.02 SGOT 5 5 1.00 Colorectal unresectable Stents 0 3 0.06 (n=76; 30 with Bev) Total bilirubin ≥ 2 1 7 0.005 SGOT 6 0 0.08 Primary liver unresectable* Stents 0 2 0.15 (n=56; 22 with Bev) Total bilirubin ≥ 2 2 5 0.10 *No SYS SGOT 0 5 0.006 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Pfizer, sanofi-aventis

Systemic bevacizumab leads to resolution of diabetic macular edema.

The purpose of this study is to report a case of diabetic macular edema that resolved after systemic bevacizumab. This is an observational case report of a patient with diabetic macular edema. After initiation of systemic bevacizumab for a central nervous system glioblastoma, the diabetic macular edema resolved. Systemic bevacizumab may result in the resolution of macular edema secondary to diabetes.

Von Hippel–Lindau disease: treatment of retinal haemangioblastomas by targeted therapy with systemic bevacizumab

von Hippel–Lindau disease: treatment of retinal haemangioblastomas by targeted therapy with systemic bevacizumab

Treatment of Subretinal Neovascular Membrane in a Patient With Membranoproliferative Glomerulonephritis Type II

A 29-year-old woman with membranoproliferative glomerulonephritis type II presented with decreased vision due to choroidal neovascular membrane. She was treated with monthly intravitreal injections of bevacizumab. Although there was dramatic improvement in her vision after the third injection, it continued to improve through the ninth monthly injection. Despite recent reports of renal side effects of systemic bevacizumab, patients with preexisting renal disease treated by the authors did not demonstrate any loss of renal function 1 year after treatment.

Complete and Durable Response of Choroid Metastasis from Non-small Cell Lung Cancer with Systemic Bevacizumab and Chemotherapy

Ocular metastasis from lung cancer is uncommon. We report a patient with metastatic non-small cell lung cancer who was found to have a metastatic lesion in the choroid at the time of presentation. The patient was treated with carboplatin, gemcitabine, and bevacizumab. After three cycles of chemotherapy, radiologic imaging and ophthalmologic examination demonstrated complete resolution of the choroid lesion. This case report demonstrates the durable response of choroidal metastasis from non-small cell lung cancer to systemic bevacizumab and chemotherapy.

Systemic bevacizumab (Avastin) therapy for exudative neovascular age-related macular degeneration. The BEAT-AMD-Study

Background:Double-blinded, randomised, prospective, pilot-study to determine the effect of systemic bevacizumab therapy.Methods:Subjects with fibrovascular pigment epithelial detachment, subfoveal choroidal neovascularisation extending under the geometric centre of the foveal avascular zone...

CHANGES IN RETINAL SENSITIVITY IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION AFTER SYSTEMIC BEVACIZUMAB (AVASTIN) THERAPY

To evaluate changes in central retinal sensitivity in patients with neovascular age-related macular degeneration after systemic bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) therapy. For all eyes, the central 12 x 12 degrees visual field was recorded using the MP 1 Microperimeter (Nidek, Gamagori, Japan) at baseline and 1 week, 1 month, 3 months, and 6 months after initial treatment. Patients received systemic anti-vascular endothelial growth factor (VEGF) therapy with three initial bevacizumab infusions at 2-week intervals. Retreatment during follow-up was performed only in cases of choroidal neovascularization recurrence. Seven patients (12 eyes) received bevacizumab infusions at a dose of 5 mg/kg, and 7 patients (9 eyes), at a dose of 2.5 mg/kg. Of 41 stimulation points, a mean absolute scotoma of 15 missed stimulation points was measured at baseline, which decreased to 10 missed stimulation points at month 3 (-5; P = 0.005) and to 11 stimulation points at month 6 (-4; P = 0.106). The mean absolute scotoma size (in % of total tested area) decreased from 33% to 22% (-11%; P = 0.011) at month 3 and to 23% (-10%, P = 0.123) at month 6. Mean differential light threshold increased significantly throughout the observation period from 3.8 dB at baseline to 5.5 dB (+1.7 dB; P = 0.012) at month 6. Systemic bevacizumab therapy induced a significant increase in mean retinal sensitivity at month 6 of follow-up and a significant decrease of mean absolute scotoma size at month 3. The MP 1 Microperimeter proved to be a valuable tool in the evaluation of functional benefits and retinal safety of anti-VEGF therapy with systemic bevacizumab.

382. Enhanced Local Control of Sarcomas by Combination of Systemic Bevacizumab and Intratumroal Oncolytic HSV

382. Enhanced Local Control of Sarcomas by Combination of Systemic Bevacizumab and Intratumroal Oncolytic HSV

Radiofrequency Ablation and Chemoembolization for Hepatocellular Carcinoma

To provide an up-to-date review of the technique, efficacy, safety and clinical applications for radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). A thorough review of the literature was performed as related to RFA and TACE for the treatment of HCC. We mixed these findings with our own extensive research and clinical experience on this subject by drawing from a pool of more than 1000 patients treated with both modalities. TACE has been shown with the work of Llovet, Camma, and Lo to provide a significant survival benefit for patients with unresectable HCC. The former showed a 1-, 2-, and 3-year survival at 57%, 31%, and 26% in the treatment group vs. 32%, 11%, and 3% in the supportive treatment alone group, respectively. Repeatedly, RFA has been shown to be very effective in the treatment of small (<or=3 cm) HCC lesions with a complete response rate of about 90%. Studies have shown that RFA may be equivalent to surgical resection in this subgroup of patients. For both modalities, patient selection and proper technique are important in minimizing the possible complications associated with them, which rarely includes liver failure, abscess formation, and hemorrhage. RFA and TACE have both been shown to provide a survival benefit for patients with unresectable HCC. More recent studies have paired these modalities with surgical resection with favorable results. Refined technique, improvements in technology, and research on better-targeted chemotherapy will likely result in further improved survival benefit. Additionally, the scope of this treatment is broadening to include resectable patients, patients awaiting liver transplantation, and, in combination with other systemic (bevacizumab, sorafenib, etc) or locoregional (RFA-TACE combination, RFA-resection etc) treatments.

Development of Vitreous Haemorrhage during Treatment with Bevacizumab for Metastatic Rectal Cancer

Bevacizumab is a recombinant humanized monoclonal antibody with activity against vascular endothelial growth factor used in the treatment of various cancers. This case report describes a 68-year-old [corrected] male with rectal cancer who developed a vitreous haemorrhage during treatment with bevacizumab. After vitrectomy the vitreous haemorrhage subsided and visual acuity was restored. The patient had evidence of age-related macular degeneration (AMD), which may have induced the development of vitreous haemorrhage. This implies that AMD might serve as a risk factor for vitreous haemorrhage in cancer patients treated with systemic bevacizumab. Ophthalmological examination to identify AMD lesions may be necessary prior to administration of bevacizumab. Vitrectomy could serve as a management tool for bevacizumab-associated vitreous haemorrhage.

Intravenous Bevacizumab Causes Regression of Choroidal Neovascularization Secondary to Diseases Other Than Age-related Macular Degeneration

To investigate the safety, tolerability, and bioactivity of intravenous infusions of bevacizumab in patients with choroidal neovascularization (CNV) attributable to causes other than age-related macular degeneration. Nonrandomized clinical trial. Ten patients with CNV received infusions of 5 mg/kg of bevacizumab. The primary efficacy outcome measure was change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study letters read at 4 meters) at 24 weeks and secondary measures were changes from baseline in excess foveal thickness (center subfield thickness), area of fluorescein leakage, and area of CNV. Infusions were well tolerated and there were no ocular or systemic adverse events. At baseline, median VA was 25.5 letters read at 4 meters (20/80) and median foveal thickness was 346 mum. At the primary endpoint (24 weeks), median VA was 48.5 letters (20/32), representing four lines of improvement from baseline (P = .005), median foveal thickness was 248 mum representing a 72% reduction in excess foveal thickness (P = .007). Four of nine patients had complete elimination of fluorescein leakage, three had near complete elimination (reductions of 91%, 88%, and 87%), two had modest reductions, and one had no reduction. All patients except one showed a reduction in area of CNV with a median reduction of 43%. Despite the small number of patients studied, the marked improvement in VA accompanied by prominent reductions in foveal thickness, fluorescein leakage, and area of CNV suggest a beneficial effect. It may be worthwhile to consider further evaluation of systemic bevacizumab in young patients with CNV.

Systemic Bevacizumab for Retinal Angiomatous Proliferation Associated with Retinal Pigment Epithelial Detachment

To report the off-label use of systemic bevacizumab in a patient with stage 3 retinal angiomatous proliferation (RAP) associated with a vascularized pigmented epithelium detachment (PED). Interventional case report. The patient was treated with systemic bevacizumab after obtaining fully informed consent. At 3 months post-treatment, the authors observed an improvement of one line (seven letters) in visual acuity and total regression of the PED on ocular coherence tomography. No adverse effects were observed. Systemic bevacizumab therapy appears to be safe and effective in the treatment of RAP associated with PED during this short follow-up period of 3 months. The authors recommend a large trial with long-term follow-up to confirm the promising results and evaluate the occurrence of adverse effects associated with systemic bevacizumab.

Regression of radiation-induced macular edema after systemic bevacizumab

Case report: A 59-year-old patient with a coexisting primary choroidal melanoma and colorectal cancer was treated with external beam radiation (EBR) of his choroidal melanoma and systemic chemotherapy with leukovorin/5 fluorouracil (FU) for treatment of his metastatic colorectal cancer. Eight months following EBR, he showed evidence of radiation retinopathy with macular edema. Optical coherence tomography (OCT) showed macular edema and subretinal fluid. Subsequently, systemic bevacizumab (5 mg/kg) was added to his leukovorin/5FU chemotherapy. After the addition of bevacizumab, OCT showed complete resolution of the macular edema and subretinal fluid. Comments: Bevacizumab may have a role in the treatment of radiation retinopathy, but further investigation is needed before any definitive conclusions can be made.

Choroidal neovascularization secondary to Sorsby fundus dystrophy treated with systemic bevacizumab (Avastin®)

A case of choroidal neovascularization (CNV) secondary to Sorsby fundus dystrophy (SFD) treated with systemic bevacizumab (Avastin). A 41-year-old woman presented with CNV secondary to SFD in her better eye. The patient received three initial infusions of bevacizumab at a dose of 5 mg/kg at 2 week intervals and one additional infusion because of CNV recurrence at the 7 month follow-up. At 16 month follow-up, visual acuity had improved from 20/50 at baseline to 20/25; optical coherence tomography and fluorescein angiography showed no evidence of CNV activity. Systemic bevacizumab seems to be a promising treatment option for CNV secondary to SFD.

Intravitreal bevacizumab (Avastin) treatment is safe in terms of intraocular and blood pressure: authors' reply

Editor, W e thank Ziemssen et al. (2007) for their interest and valuable comments on our recent article (Kernt et al. 2007). We agree completely that when using intravitreal anti-vascular endothelial growth factor drugs (VEGF) – especially ‘off-label’– one needs to be aware of possible systemic side-effects. In late 2005, when we started collecting data for our study, few reports on treatment by intravitreal bevacizumab existed and no evidence on safety or possible side-effects with regard to intraocular (IOP) or blood pressure (BP) was available. In order to improve patient safety in this situation, our study was designed to collect relevant safety data in a consecutive small patient group. We apologize for the limited design in terms of patient numbers but do believe, because of the completed follow-up, that our data offer a valuable contribution to the safety of intravitreal bevacizumab. We wish to emphasize our complete agreement on the need for sufficient BP management. This is especially true for patients such as those in our reported patient group who suffer from neovascular age-related macular degeneration (AMD) or from diabetic retinopathy (DR), both usually with significant comorbidity. Systemic hypertension is without doubt one of the major causes for morbidity and mortality in the Western world (Ramsay et al. 1999). Therefore, in our inand out-patients we emphasize tight BP control. Being an ophthalmological referral centre this means frequent referrals to internal medicine or the general practitioner treating the patient. The data shown in our study as ‘baseline’ prove that in many patients BP control remains unsatisfactory, although most patients were on at least one form of BP medication. No changes in BP medication occurred during follow-up, data that were not presented because of space limitations and the focus on IOP in an ophthalmological publication. A question was also raised about whether intraindividual BP variability and diurnal oscillations were considered. (The same is also true for IOP.) Baseline measurements of BP and IOP were always taken at hospitalization (approximately 10:00 hr); the intravitreal bevacizumab injection was performed between 14:00 hr and 15:00 hr. Therefore, a similar diurnal cycle-phase can be assumed for all patients. The BP data were indeed distributed normally; intraindividual information was used by anova analysis. Posthoc paired testing was corrected for multiple testing. In the first 6 hr after injection, BP measurements were meant to accompany IOP measurements and to accustom patients with the procedure rather than to detect any change. All patients were hospitalized for at least 1 day at the time of the study, making any return visits unnecessary for the first 24 hr. From our point of view, the out-patient followup data at 2, 6 and 12 weeks are more relevant because a significant increase in BP after systemic bevacizumab treatment is known to occur after several weeks (Michels et al. 2005; Hurwitz & Saini 2006). We agree with Ziemssen et al. (2007) that the ‘baseline’ measurement may be influenced by stress and several other factors such as diurnal changes. However, the first BP measurement was taken several hours before the surgical treatment. In most single BP measurements – including those taken at home – the physician or hospital has to cope with a similar bias. Moreover, the variance analysis can detect any changes over time and is not dependent on only one baseline. On multiple posthoc paired testing, any changes occurring after several weeks would be clinically relevant, while the observed early decreases in BP may represent some of the effects already discussed. In summary, patient safety is a major concern, especially when the treatment is ‘off-label’ and must include all possible side-effects. Therefore, we thank Ziemssen et al. (2007) for their comments regarding BP and the opportunity to further illustrate some previously unaddressed points. We believe that the limited number of patients included is the main limitation of our study and therefore relatively rare effects cannot be assessed. Nevertheless, we believe that our data show validly that a significant increase in IOP or BP does not occur with intraocular bevacizumab. Still further investigations with larger patient numbers are needed to investigate any relatively rare complications and to assess patient safety completely.

This issue of Acta

This issue of Acta emphasizes retinal disease, with a particular focus on the development of new treatment modalities. Two editorials − by Morten la Cour and Anders Kvanta, respectively − deal with emerging new treatments. Our review article is a critical appraisal of new therapies for neovascular age-related macular degeneration and is written by Italian and American ophthalmologists. The cover figure shows a magnetic resonance image of a large inclusion cyst in the orbit (see Hussin et al.). Martin Vinten and colleagues, in Copenhagen, report that intravitreal triamcinolone constricts the retinal blood vessels. This pharmacological effect of triamcinolone may be important in its mechanism of action in diabetic macular oedema and other diseases. Ålborg's Knudsen documents the thickness of the macular region in normal subjects and those with diabetes with and without macular oedema and demonstrates that thickness measurements can indeed be used to diagnose diffuse macular oedema. Neubauer et al., based in Munich and Thessaloniki, describe findings of a correlation between fluorescein leakage and retinal thickening on optical coherence tomography in patients with diabetic macular oedema. Eydís Ólafsdottir and associates, in Iceland and Sweden, report on the diabetes population in the Laxå community in Sweden, where screening for both diabetes mellitus and diabetic eye disease has created an optimal situation for the prevention of diabetic blindness. Helsinki's Sirpa Loukovaara et al. continue their study on diabetic retinopathy in pregnancy and find that progression of retinopathy is associated with a low concentration of glycodelin, a glycoprotein secreted from endometrial glands and involved with the immune response. Parodi et al., Trieste, describe atrophic changes in the retinal pigment epithelium following photodynamic therapy in myopic individuals. Osaka-based Arimura et al. have developed novel charts to evaluate metamorphopsia and claim to be able to quantify metamorphopsia in patients with macular hole. The letters to the editor include a description from German authors Spandau et al. of the use of intravitreal bevacizumab (Avastin®) for branch retinal vein occlusion and age-related macular degeneration. Meanwhile, Kernt et al., Munich, find intravitreal bevacizumab to be safe in terms of intraocular and blood pressure. Writing from Odense, Pedersen et al. report a case of choroidal metastasis in multiple endocrine neoplasia. Helsinki-based Raivio et al. used transscleral cyclocoagulation combined with anterior retinal cryocoagulation in patients with neovascular glaucoma with good results. Bjärnhall et al., in Uppsala and Hiroshima, measured the mean transit time of fluorescein in the retinal circulation of patients with primary open-angle glaucoma and normal-tension glaucoma. They report findings of a correlation between neuronal atrophy and circulation that was similar in both types of glaucoma. Spanish authors Ferreras et al. continue the search for the optimum diagnostic criteria in glaucoma and suggest that frequency doubling perimetry may be helpful. Ozturk et al., writing from Turkey, report their findings that brimatoprost and Cosopt® are similar in their ability to lower intraocular pressure and both are well tolerated. Thomas Olsen, in Århus, finds that the optical coherence interferometry of the Zeiss IOLMaster increases the accuracy of intraocular lens (IOL) power calculations. Budapest's Kovács et al. deal with IOL power calculation in combined cataract and vitreous operations and point out that macular thickness must be taken into account in preoperative calculations. Langenbucher et al., of Erlangen-Nürnberg, may provide more mathematics than most readers of Acta enjoy, but present a comprehensive calculation scheme for retinal image size after implantation of toric (IOLs). Japanese authors Miyata et al. suggest that sharp IOL edges are required to prevent posterior capsular opacification and do not induce anterior capsular contraction. Writing from Sweden, Fagerholm et al. describe a new type of corneal opacities in a small Swedish family. Fernández de Castro and associates, South Carolina, USA, report that ocular wavefront aberrations vary greatly from subject to subject and treatment must be carefully individualized. Denmark-based Sirbikaite and Ehlers' letter to the editor points out the usefulness of Lacrytest® for semiquantitative diagnosis of ocular allergens. Ziylan et al., in Turkey, highlight the risk of isoamitropic amblyopia in highly hyperopic children and describe the use of spectacles for treatment. Lübeck's von Buelow et al. describe a case of systemic bevacizumab (Avastin®) treatment for a retinal haemangioma.