Molecular Imaging of Melanoma VEGF-expressing Tumors through [99mTc]Tc-HYNIC-Fab(Bevacizumab).

BACKGROUND: Angiogenesis is a process that many tumors depend on for growth, development, and metastasis. Vascular endothelial growth factor (VEGF) is one of the major players in tumor angiogenesis in several tumor types, including melanoma. VEGF inhibition is achieved by bevacizumab, a humanized monoclonal antibody that binds with high affinity to VEGF and prevents its function. In order to successfully enable in vivo VEGF expression imaging in a murine melanoma model, we previously labeled bevacizumab with [99mTc]Tc. We observed that this was feasible, but it had prolonged blood circulation and delayed tumor uptake. OBJECTIVE: The aim of this study was to develop a radiolabeled Fab bevacizumab fragment, [99mTc]Tc-HYNICFab( bevacizumab), for non-invasive in vivo VEGF expression molecular imaging. METHODS: Flow cytometry was used to examine VEGF presence in the murine melanoma cell line (B16-F10). Bevacizumab was digested with papain for six hours at 37°C to produce Fab(bevacizumab), which was then conjugated to NHS-HYNIC-Tfa for radiolabeling with [99mTc]Tc. Stability and binding affinity assays were also evaluated. Biodistribution and single photon emission computed tomography/computed tomography (SPECT/CT) were performed at 1, 3, and 6 h (n = 4) after injection of [99mTc]Tc-HYNIC-Fab(Bevacizumab) in normal and B16-F10 tumor-bearing C57Bl/6J mice. RESULTS: Using flow cytometry, it was shown that the B16-F10 murine melanoma cell line has intracellular VEGF expression. Papain incubation resulted in the complete digestion of bevacizumab with good purity and homogeneity. The radiolabeling yield of [99mTc]Tc-HYNIC-Fab(bevacizumab) was 85.00 ± 6.06%, with a specific activity of 291.87 ± 18.84 MBq/mg (n=3), showing in vitro stability. Binding assays demonstrated significant intracellular in vitro VEGF expression. Fast blood clearance and high kidney and tumor uptake were observed in biodistribution and SPECT/CT studies. CONCLUSIONS: We present the development and evaluation of [99mTc]Tc-HYNIC-Fab(bevacizumab), a novel molecular VEGF expression imaging agent that may be used for precision medicine in melanoma and potentially in other VEGF-expressing tumors.

Trifluridine-tipiracil plus bevacizumab versus trifluridine-tipiracil monotherapy for chemorefractory metastatic colorectal cancer: a systematic review and meta-analysis.

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.

The serum LDH level and KELIM scores are potential predictors of a benefit from bevacizumab first-line therapy for patients with advanced ovarian cancer.

OBJECTIVE: The survival benefit of first-line treatment with bevacizumab in advanced ovarian cancer patients are multifaceted. In our study, we aimed to identify potential markers of bevacizumab efficacy to help predict which patients would experience survival benefits. METHODS: This was a retrospective analysis of 114 patients examined from January 1, 2015, to March 1, 2023, and data on clinical, biological, and imaging variables, such as ascites, serum LDH, and CA125, were extracted from electronic medical records. We performed a correlation analysis and principal component analysis to investigate correlations among variables and reduce their dimensionality. Then, univariate and multivariate Cox proportional hazards regression analyses were used to identify the predictors of progression-free survival. RESULTS: Favorable KELIM score (≥ 1, HR 0.376, 95% CI [0.202-0.700], p = 0.002), which indicated better chemosensitivity, and lower LDH levels (≤ 210 U/L, HR 38.73, 95% CI [6.108-245.6], p < 0.001) were found to be independent predictors of a treatment benefit with bevacizumab in patients with advanced ovarian cancer. Regardless of LDH level, patients with favorable KELIM scores had a higher progression-free survival (PFS) benefit (p = 0.18). Among patients with unfavorable KELIM scores, those with higher LDH levels had the lowest PFS benefit (median: 11.5 months, p = 0.0059). CONCLUSION: Patients with poor chemosensitivity and low LDH levels are more likely to benefit from first-line bevacizumab treatment. The combination of the two markers can be a helpful predictor of patients who are most likely to benefit from treatment and a guide for treatment decisions-making. Retrospectively registered: 2020-MD-371, 2020.10.12.

Unleashing the potential: transarterial chemoembolization combined with intra-arterial infusion of bevacizumab for unresectable hepatocellular carcinoma.

BACKGROUND: The purpose of this study is to compare the efficacy and safety of transarterial chemoembolization (TACE) alone with transarterial chemoembolization combined with the arterial infusion of bevacizumab (TACE + Bev) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: A retrospective analysis was conducted on 446 uHCC patients treated with TACE or TACE + Bev between January 2021 and March 2023. The study evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events in both treatment groups. RESULTS: Finally, the TACE group comprised 295 patients, and the TACE + Bev group comprised 151 patients. Patients in the TACE + Bev group exhibited significantly prolonged median PFS (7.9 months vs. 10.3 months, P = 0.013) and median OS (16.1 months vs. 21.4 months, P = 0.041), improved ORR (26.8% vs. 37.7%, P = 0.017) and DCR (71.5% vs. 80.8%, P = 0.033) compared to the TACE group. Multifactorial Cox analysis identified alpha-fetoprotein (AFP) > 400 ng/ml as an independent prognostic factor for PFS and OS. Meanwhile, portal vein cancer thrombosis and distant metastasis are poor prognostic factors for OS. The overall incidence of adverse events was similar between the two groups. CONCLUSION: In comparison with the TACE group, the TACE + Bev group demonstrated efficacy in improving outcomes for patients with uHCC with a manageable safety profile.

Experience with the use of intravitreal bevacizumab in cases with type I retinopathy of prematurity in a Latin American country.

In retinopathy of prematurity (ROP) type I, the use of intravitreal bevacizumab (IVB), which is an inhibitor of endothelial growth factor (VEGF), has become popular despite not being a therapy approved by regulatory agencies. However, IVB has shown positive effects in halting disease progression at lower costs compared to other anti-VEGF therapies (ranibizumab or aflibercept). In this report, we present the experience during the treatment with IVB of 102 Colombian children with ROP type I, with a success rate of 98% (100). Complications occurred in 3.9% (4). Finally, we conclude that a single dose of IVB is an effective therapy for the management of ROP type I, with a lower risk of complications and retreatment.

Hypertension as predictive factor for bevacizumab-containing first-line therapy in metastatic breast and colorectal cancer in BRECOL (GEICAM/2011-04) study.

BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.

Bevacizumab improved prognosis for advanced EGFR-mutant lung adenocarcinoma with brain metastasis receiving cerebral radiotherapy.

OBJECTIVE: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. MATERIALS AND METHODS: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. RESULTS: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS. CONCLUSION: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy.

Comparison of antiangiogenic agents (ranibizumab, aflibercept, bevacizumab and ziv-aflibercept) in the therapeutic response to the exudative form of age-related macular degeneration according to the treat-and-extend protocol- true head-to-head study.

PURPOSE: To evaluate the structural and functional changes in eyes with neovascular age related macular degeneration (nAMD) in a real-world setting, using Treat and Extend protocol (T&E), comparing four antiangiogenic agents. METHODS: Prospective, observational, case series study performed in 131 patients with the exudative form of nAMD. Patients were randomly assigned into four groups according to the antiangiogenic agent. During the first year, all eyes received at least 3 monthly intravitreal injections of antiangiogenic agents, and afterwards, were submitted to the T&E. RESULTS: There was statistically significant difference (p < 0.05) between pre- and post-treatment in the best corrected visual acuity measurements by drug used. Patients who used aflibercept had significantly fewer injections than patients using the other drugs (mean = 9.03). No significant difference was observed between the drugs bevacizumab, ranibizumab and ziv-aflibercept. With regard to biomarkers, patients who used aflibercept and had lower baseline central retinal thickness, absence of hyperreflective foci and no subretinal hyperreflective material had the lowest number of injections. CONCLUSION: Results indicate that over 2 years, Intravitreal aflibercept on T&E provided better visual and anatomical improvements when compared to other drugs used in this study with significantly fewer injections.

Isquemia anastomótica por bevacizumab. Casos clínicos

Objetivo: Presentar dos casos de isquemia anastomótica tardía por bevacizumab y compararlo con la literatura actual. Casos clínicos: Se exponen dos pacientes con cáncer de recto metastásico, con manejo neoadyuvante, quirúrgico y adyuvancia que incluye bevacizumab, que presentan complicaciones isquémicas anastomóticas, evidenciadas con endoscopia, imágenes más biopsias dirigidas, resolviéndose en forma quirúrgica y biopsiando sitios perianastomóticos con cambios isquémicos. Discusión: Existe evidencia en la literatura que reporta isquemias y filtraciones anastomóticas tardías con el uso de bevacizumab. Parece prudente considerar y sospechar en forma oportuna esta complicación, especialmente, en pacientes con factores de riesgo. Conclusiones: Se debe considerar eventos isquémicos en territorios quirúrgicos, al uso de Bevacizumab. Mayor hincapié en pacientes con factores de riesgo como malnutrición, irradiación o sexo masculino. Considerar estudio dirigido anastomótico previo al inicio de bevacizumab. Dar relevancia a los tiempos de suspensión y reinicio de bevacizumab para evaluación de posibles complicaciones isquémicas.

Objective: To present two cases of late anastotomotic breakdown by bevacizumab and compare it with the current literature. Case report: Two patients with metastatic rectal cancer, with neoadjuvant, surgical and adjuvant management including bevacizumab, presenting anastomotic ischemic complications, evidenced with endoscopy, images and directed biopsies, surgically resolved and taking biopsy of perianastomotic sites with ischemic changes. Discussion: There is evidence in the literature reporting late anastomotic ischemia and leaks with the use of bevacizumab. It seems prudent to consider and suspect this complication in a timely manner, especially in patients with risk factors. Conclusions: Ischemic events in surgical territories should be considered when using bevacizumab. Greater emphasis on patients with risk factors such as malnutrition, irradiation or male sex. Anastomotic-directed study prior to initiation of bevacizumab should be considered. To highlight bevacizumab suspension and restart times for the evaluation of possible ischemic complications.

Review of real-world evidence of dual inhibition of VEGF-A and ANG-2 with faricimab in NAMD and DME.

Management of vitreoretinal disorders (e.g., neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME]) have assumed the standard therapy of lifelong anti-VEGF injections with drugs like aflibercept, brolucizumab, ranibizumab and bevacizumab. However, the burden imposed on patients is a major deterrent for continual therapy and recovery. Faricimab, a bispecific antibody, blocking both VEGF-A and Ang-2 molecules, produces a comparable functional and anatomical results, with less injections, significantly reducing patient burden. Visual acuity, safety, adverse effects, and anatomical outcomes are discussed in the pivotal clinical trials (YOSEMITE/RHINE and TENAYA/LUCERNE), and early data from real-world studies (TRUCKEE, TAHOE, FARWIDE-DME, FARETINA and others). In YOSEMITE and RHINE, faricimab demonstrated non-inferior vision gains, better anatomical outcomes compared to aflibercept every 8 weeks. Faricimab in the personalized treatment interval (PTI), after week 96, achieved 12-week interval in 78.1% of the patients and 16-week interval in 62.3%. TENAYA and LUCERNE reported comparable best corrected visual acuity (BCVA) improvement and better anatomic outcomes during head-to-head phase, parallel to aflibercept, at its 8-week treatment schedule. Faricimab in the PTI regimen, after week 96 achieved 12-week interval in 77.8% of the patients and 16-week interval in 63.1%. Safety of faricimab has been comparable to aflibercept in these pivotal trials. Real-world data supports the data from the pivotal studies regarding the efficacy and safety profile of faricimab in heterogenous real world patient population. Moreover, in previously treated patients, it also demonstrated a faster fluid resolution, good safety profile. Considering faricimab has demonstrated anatomic and durability benefit in the treatment of nAMD and DME, additional data from ongoing extension clinical trials, AVONELLE-X and RHONE-X will help understand longer term outcomes for patients treated with faricimab as well as patients switching from aflibercept to faricimab after finishing the pivotal trials. Longer term data from the real-world studies will also continue to contribute to our understanding of long-term efficacy, safety and durability in the real world patient population.

Preoperative co-application of bevacizumab and tissue plasminogen activator in vitrectomy for proliferative diabetic retinopathy

ABSTRACT Purpose: To investigate the clinical benefits of the co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy. Methods: Patients who underwent vitrectomy for proliferative dia-betic retinopathy complications were preoperatively given in-travitreal injection with either bevacizumab and tissue plasminogen activator (Group 1) or bevacizumab alone (Group 2). Primary outcomes were surgery time and number of intraoperative iatrogenic retinal breaks. Secondary outcomes included changes in the best-corrected visual acuity and postoperative complications at 3 months postoperatively. Results: The mean surgery time in Group 1 (52.95 ± 5.90 min) was significantly shorter than that in Group 2 (79.61 ± 12.63 min) (p<0.001). The mean number of iatrogenic retinal breaks was 0.50 ± 0.59 (0-2) in Group 1 and 2.00 ± 0.83 (0-3) in Group 2 (p<0.001). The best-corrected visual acuity significantly improved in both groups (p<0.001). One eye in each group developed retinal detachment. Conclusion: Preoperative co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy shortens the surgery time and reduces the number of intraoperative iatrogenic retinal breaks.

Effectiveness of treatment of exudative age-related macular degeneration with anti-vascular endothelial growth factor drugs / Efetividade do tratamento da doença macular relacionada à idade exsudativa com drogas antifactor de crescimento endotelial vascular

ABSTRACT Objective: To characterize the effectiveness of anti-vascular endothelial growth factor drugs in exudative age-related macular degeneration. Methods: Retrospective longitudinal study of 54 patients with age-related macular degeneration receiving bevacizumab or aflibercept. Demographic data, visual acuity, and central retinal thickness measurements were collected. Improvement/stability of visual acuity and reduction in retinal thickness configured satisfactory responses. Results: Among the 60 eyes studied, there was no difference (p = 0.262) in satisfactory response when using bevacizumab (48.5%) or aflibercept (63.0%). Snellen's visual acuity, letter gain, and retinal thickness showed improvement or maintenance in 55.0%, 32.8%, and 78.3% of cases, respectively. The percentage of improvement/maintenance was higher in eyes with an initial visual acuity of < Snellen 20/400 (70.0% versus 40.0%; p = 0.002). Conclusion: A higher percentage of improvement/stabilization of visual acuity and macular thickness was observed in patients with age-related macular degeneration, with better response in patients with visual acuity worse than Snellen 20/400.

RESUMO Objetivo: Caracterizar a efetividade de medicamentos antifactor de crescimento endotelial vascular na degeneração macular relacionada à idade exsudativa. Métodos: Estudo longitudinal retrospectivo em 54 pacientes com degeneração macular relacionada à idade que usaram bevacizumab ou aflibercept. Foram coletados dados demográficos, da acuidade visual e da espessura central da retina. Melhora/estabilidade da acuidade visual e redução da espessura configuraram respostas satisfatórias. Resultados: Entre 60 olhos estudados, não houve diferença (p = 0,262) de acordo com o uso de bevacizumab (48,5%) ou aflibercept (63,0%). Acuidade visual segundo Snellen, ganho de letras e espessura retiniana demonstraram melhora ou estabilidade em 55,0%, 32,8% e 78,3% dos casos, respectivamente. Entre os olhos com acuidade visual inicial < 20/400, o percentual de melhora/estabilidade foi superior (70,0% versus 40,0%; p = 0,002). Conclusão: Em pacientes com degeneração macular relacionada à idade, foi percebida uma maior proporção de melhora ou estabilização da acuidade visual e espessura macular, com melhor resposta entre os pacientes com visão pior que 20/400.

In Silico and In Vitro Evaluation of Bevacizumab Biosimilar MB02 as an Antitumor Agent in Canine Mammary Carcinoma.

Canine mammary carcinomas (CMC) are associated with major aggressive clinical behavior and high mortality. The current standard of care is based on surgical resection, without an established effective treatment scheme, highlighting the urgent need to develop novel effective therapies. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis and progression in the majority of solid cancers, including human and canine mammary carcinomas. The first therapy developed to target VEGF was bevacizumab, a recombinant humanized monoclonal antibody, which has already been approved as an anticancer agent in several human cancers. The goal of this work was to establish the therapeutic value of MB02 bevacizumab biosimilar in CMC. First, through different in silico approaches using the MUSCLE multiple-sequence alignment tool and the FoldX protein design algorithm, we were able to predict that canine VEGF is recognized by bevacizumab, after showing an extremely high sequence similarity between canine and human VEGF. Further, by using an ELISA-based in vitro binding assay, we confirmed that MB02 biosimilar was able to recognize canine VEGF. Additionally, canine VEGF-induced microvascular endothelial cell proliferation was inhibited in a concentration-dependent manner by MB02 biosimilar. These encouraging results show a high potential for MB02 as a promising therapeutic agent for the management of CMC.

Relative cerebral blood volume as response predictor in the treatment of recurrent glioblastoma with anti-angiogenic therapy.

BACKGROUND: Glioblastoma is one of the most common brain tumors in adult populations, usually carrying a poor prognosis. While several studies have researched the impact of anti-angiogenic therapies, especially anti-VEFG treatments in glioblastoma, few have attempted to assess its progress using imaging studies. PURPOSE: We attempted to analyze whether relative cerebral blood volume (rCBV) from dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) could predict response in patients with glioblastoma undergoing Bevacizumab (BVZ) treatment. METHODS: We performed a retrospective study evaluating patients with recurrent glioblastoma receiving anti-angiogenic therapy with BVZ between 2012 and 2017 in our institution. Patients were scheduled for routine MRIs at baseline and first-month follow-up visits. Studies were processed for DSC-MRI, cT1, and FLAIR images, from which relative cerebral blood volume measurements were obtained. We assessed patient response using the Response Assessment in Neuro-Oncology (RANO) working group criteria and overall survival. RESULTS: 40 patients were included in the study and were classified as Bevacizumab responders and non-responders. The average rCBV before treatment was 4.5 for both groups, and average rCBV was 2.5 for responders and 5.4 for non-responders. ROC curve set a cutoff point of 3.7 for rCBV predictive of response to BVZ. Cox Multivariate analysis only showed rCBV as a predictive factor of OS. CONCLUSION: A statistically significant difference was found in rCBV between patients who responded and those who did not respond to BVZ treatment. rCBV may be a low-cost and effective marker to assess response to Bevacizumab treatment in GBM.

Ocular Syphilis with Retinal and Disc Neovascularization Treated with Bevacizumab: A Case Report.

We report the findings observed in a young woman with ocular syphilis complicated with retinal and disc neovascularization successfully treated with intravitreal bevacizumab. Fluorescein angiography revealed in both eyes intense hyperfluorescence at the level of the disc, multifocal venous wall staining, multifocal paravenous leakage, multiple peripheral saccular venular dilations, diffuse retinal and macular edema, and retinal and disc neovascularization. There was no evidence of retinal ischemia in both eyes. After antibiotic and corticosteroid treatment, the neovascularization persisted in both eyes. Three consecutive doses of intravitreal bevacizumab were administered, with total regression of the retinal and disc neovascularization. Disc and retinal neovascularization along with nonocclusive retinal vasculitis may be a form of presentation of ocular syphilis. Combination of specific treatment, oral corticosteroids, and intravitreal bevacizumab may be useful for treating this clinical manifestation.

Bevacizumab effect on viability of free groin flaps in rats / Efeito do bevacizumabe na viabilidade de retalho inguinal livre em ratos

Introduction: Bevacizumab is among the most frequently used drugs in cancer treatment. There is evidence that some anti-angiogenic drugs reduce flap survival, but it is unclear whether this applies to Bevacizumab. We investigated the effect of Bevacizumab on the viability of free flaps in rats. Methods: The animals were randomly assigned to one of three groups. The Graft group received intravascular saline and was submitted to a full-thickness skin graft. The Flap-Saline and the Flap- BVZ groups underwent a free groin flap after receiving, respectively, intravascular saline solution or intravascular administration of Bevacizumab. Results: The Graft group showed a lower percentage of the viable area (22.81%) relative to the Flap- Saline (83.98%; p<0.0001) and the Flap-BVZ groups (60.50%; p=0.0048). The lowest vascular pedicle patency was observed in the Flap-BVZ group, but the difference relative to the Flap-Saline was not significant (arteries, p=0.0867; veins, p=0.9999). A significant difference was observed in the occurrence of necrosis (p=0.0010), which was higher in the histological samples of the Graft (87.50%) and the Flap- BVZ (60.00%) relative to the Flap-Saline Group (0%). Inflammation occurred less frequently in the Flap-Saline (33.33%) compared to the Graft (87.5%) and Flap- BVZ group (70.00%), but the difference did not reach significance (p=0.0588). No significant differences emerged in the occurrence of hemorrhage or intraluminal thrombosis. Conclusion: The increase in inflammation, decrease in patency and reduction of viable area, though not significant, are in line with the histological analysis and call for further research on the potential adverse effects of the drug.

Introdução: Bevacizumabe é um dos fármacos mais utilizados no tratamento do câncer. Existem evidências de que drogas antiangiogênicas reduzem a taxa de sobrevivência dos retalhos, porém não está claro se isso se aplica ao bevacizumabe. Investigamos o efeito de bevacizumabe na viabilidade de retalhos livres em ratos. Método: Os animais foram randomizados em três grupos. O grupo Enxerto recebeu injeção intravenosa de soro fisiológico 0,9% (SF 0,9%) e foi submetido a uma enxertia de pele total. Os grupos Retalho-SF e Retalho-BVZ foram submetidos a retalhos inguinais livres e receberam injeções intravenosas, respectivamente, de SF 0,9% e Bevacizumabe. Resultados: O grupo Enxerto apresentou menor percentual de área de retalho viável (22,81%) em relação ao grupo Retalho-SF (83,98%; p<0,0001) e Retalho-BVZ (60,50%; p=0,0048). Os pedículos do grupo Retalho-BVZ apresentaram menor patência, mas a diferença em relação ao grupo Retalho-SF não foi significante (artérias, p=0,0867; veias, p=0,9999). A ocorrência de necrose foi significativamente maior nos grupos Enxerto (87,50%) e Retalho-BVZ (60,00%) em relação ao grupo Retalho-SF (0%) (p=0,0010). A ocorrência de inflamação foi menor no grupo Retalho-SF (33,33%) em relação aos grupos Enxerto (87,5%) e Retalho-BVZ (70,00%), porém essa análise não atingiu significância (p=0,0588). Não houve diferenças significantes na ocorrência de hemorragia ou trombose intraluminal entre os grupos. Conclusão: O aumento da inflamação, redução da patência e das áreas viáveis dos retalhos, apesar de não significantes, corroboram com efeitos deletérios do bevacizumabe evidenciados na análise histológica e demandam futuros estudos dos potenciais efeitos adversos da droga.

Staphylococcus hominis: a rare cause of endophthalmitis / Staphylococcus hominis: uma causa rara de endoftalmite

ABSTRACT Staphylococcus hominis (S. hominis) is a coagulase-negative Staphylococci and an infrequent cause of endophthalmitis. Due to its ability to produce biofilm, especially in diabetic patients, strains may acquire antibiotic resistance. We present two cases of S. hominis endophthalmitis, one with acute endophthalmitis after intravitreal bevacizumab injection and one with chronic endophthalmitis following undiagnosed penetrating ocular trauma. Although there are only four published S. hominis endophthalmitis cases in the literature, to the best of our knowledge, there has been no previously published case after intravitreal bevacizumab.

RESUMO Staphylococcus hominis (S. hominis) é um estafilococo coagulase-negativo e uma causa pouco frequente de endoftalmite. Devido à sua capacidade de produzir biofilme, especialmente em pacientes diabéticos, cepas dessa bactéria podem adquirir resistência a antibióticos. Este relato apresenta dois casos de endoftalmite por S. hominis: um de endoftalmite aguda após injeção intravítrea de bevacizumabe e outro de endoftalmite crônica após trauma ocular penetrante não diagnosticado. Embora existam apenas quatro casos de endoftalmite por S. hominis publicados na literatura, até onde sabemos não houve nenhum caso publicado anteriormente após bevacizumabe intravítreo.

Prospective evaluation of the effectiveness of combined treatment of macular edema secondary to retinal vein occlusion with intravitreal bevacizumab and dexamethasone implants / Estudo intervencionista prospectivo para avaliar a eficácia da associação do bevacizumabe intravítreo ao implante de dexametasona para edema macular secundário à oclusão da veia retiniana

ABSTRACT Purpose: To evaluate the effectiveness of in­­­travitreal bevacizumab injections following a single dexamethasone implant in the treatment of macular edema secondary to branch and central retinal vein occlusion. Methods: This was a prospective interventional non-comparative study, 44 eyes of patients with naïve macular edema related to branch and central retinal vein occlusion were treated with a dexamethasone implant. Patients were followed-up at four-week intervals from the second to the sixth month. If persistent or recurrent macular edema occurred during this period, the patient was treated with intravitreal bevacizumab injections on an as-needed basis. The outcome measures were best-corrected visual acuity and central macular thickness changes. Results: The mean best-corrected visual acuity changed from 0.97 ± 0.33 LogMAR at baseline to 0.54 ± 0.40 at the six-month post-implant examination (p<0.00001). Improvement ≥3 Snellen lines were seen in 20 eyes (45.54%). The mean central macular thickness at baseline was 670.25 ± 209.9 microns. This had decreased to 317.43 ± 112.68 microns at the six-month follow-up (p<0.00001). The mean number of intravitreal bevacizumab injections received in the six months post-implant was 2.32. The mean time from dexamethasone implant to first anti-VEGF injection was 3.45 months. Conclusions: Intravitreal bevacizumab injections following a single dexamethasone implant were found to improve best-corrected visual acuity and central macular thickness in patients with macular edema due to branch and central retinal vein occlusion at six months, with few intravitreal injections required.

RESUMO Objetivo: Avaliar a eficácia da combinação de in­jeções intravítreas de bevacizumabe em olhos com edema macular secundário à oclusão de ramo e da veia central da retina após um único implante de dexametasona. Métodos: Foi realizado um estudo prospectivo intervencionista não comparativo com 44 olhos de pacientes com edema macular relacionado à oclusão de ramo e veia central da retina, sem tratamento prévio e tratados com um único implante de dexametasona, que foram acompanhados em intervalos de quatro semanas do segundo ao sexto mês. Se fosse constatado edema macular persistente ou recorrente durante esse período, os pacientes eram tratados com injeções intravítreas de bevacizumabe em um regime ajustado conforme a necessidade. Foram estudadas a melhor acuidade visual corrigida e alterações da espessura macular central. Resultados: A média da melhor acuidade visual corrigida mudou de 0,97 ± 0,33 LogMAR iniciais para 0,54 ± 0,40 no exame de 6 meses (p<0,00001). Vinte olhos (45,54%) melhoraram 3 linhas de Snellen ou mais. A média da espessura macular central inicial foi de 670,25 ± 209,9 μm e diminuiu para 317,43 ± 112,68 μm na visita de 6 meses (p<0,00001). O número médio de injeções intravítreas de bevacizumabe em 6 meses foi de 2,32 e o tempo médio entre o implante de dexametasona e a primeira injeção de anti-VEGF foi de 3,45 meses. Conclusão: Injeções intravítreas de bevacizumabe após um único implante de dexametasona podem proporcionar um aumento da melhor acuidade visual corrigida e diminuição da espessura macular central aos 6 meses em pacientes com edema macular devido à oclusão de ramo e da veia central da retina, com poucas injeções intravítreas.

99mTc-HYNIC/Cy7-Fab(Bevacizumab): su empleo como agente de imagen en mieloma múltiple / 99mTc-HYNIC/Cy7-Fab(Bevacizumab): its use as an imaging agent in Multiple Myeloma / 99mTc-HYNIC/Cy7-Fab (Bevacizumab): seu uso como agente de imagem em mieloma múltiplo

Introducción: el mieloma múltiple es un trastorno hematológico maligno y el segundo cáncer de la sangre más frecuente. El proceso de la angiogénesis tumoral es fundamental para el crecimiento y metástasis de muchos tipos de tumores, incluido en mieloma múltiple. Se sabe que la sobreexpresión del factor de crecimiento endothelial vascular se encuentra asociado a un mal pronóstico en esta patología, representando un blanco clave para la terapia anti-angiogénica en mieloma múltiple. El anticuerpo monoclonal Bevacizumab es capaz de unirse con gran afinidad al factor de crecimiento endothelial vascular bloqueando su acción. Objetivo: evaluar el Fab(Bevacizumab) marcado con 99mTc o Cy7 como potenciales agentes de imagen moleculares de la expresión de factor de crecimiento endothelial vascular en mieloma múltiple. Material y métodos: la expresión de factor de crecimiento endothelial vascular fue analizada mediante citometría de flujo en la línea celular huaman de mieloma múltiple, la MM1S. Fab(Bevacizumab) fue producido mediante digestión de Bevacizumab con papaína, conjugado a NHS-HYNIC-Tfa y radiomarcado con 99mTc. Se realizaron estudios de biodistribución y de tomografía computarizada por emisión del fotón simple. A su vez, Fab(Bevacizumab) fue marcado con Cy7 para obtener imágenes de fluorescencia in vivo hasta 96 horas. Resultados: el análisis por citometría de flujo en la línea celular MM1S reveló que la expresión de factor de crecimiento endothelial vascular es predominantemente intracelular. Los estudios de biodistribución y SPECT/CT del complejo 99mTc-HYNIC-Fab(Bevacizumab) mostraron una rápida eliminación sanguínea y una significativa captación a nivel renal y tumoral. Las imágenes por fluorescencia empleando Cy7-Fab(Bevacizumab) permitieron la visualización tumoral hasta 96 h p.i. Conclusiones: logramos visualizar la expresión de factor de crecimiento endothelial vascular in vivo en mieloma múltiple mediante el empleo del fragmento Fab del anticuerpo anti-VEGF (Bevacizumab) marcado con 99mTc y Cy7. Estos nuevos agentes de imagen molecular podrían ser empleados potencialmente en el ámbito clínico para la estadificación y el seguimiento de pacientes con mieloma múltiple, mediante la visualización radioactiva in vivo de la expresión de factor de crecimiento endothelial vascular en todo el cuerpo. La imagen óptica de estos trazadores mejoraría el muestreo tumoral y podría guiar la extirpación quirúrgica.

Introduction: Multiple myeloma is a hematologic malignancy and the second most common blood cancer. The process of tumor angiogenesis is central to the growth and metastasis of many types of tumors, including multiple myeloma. Overexpression of vascular endothelial growth factor is known to be associated with poor prognosis in this pathology, representing a key target for anti-angiogenic therapy in multiple myeloma. The monoclonal antibody Bevacizumab is able to bind with high affinity to vascular endothelial growth factor blocking its action. Objective: to evaluate 99mTc- or Cy7-labeled Fab(Bevacizumab) as potential molecular imaging agents of vascular endothelial growth factor expression in multiple myeloma. Methods: Vascular endothelial growth factor expression was analyzed by flow cytometry in the multiple myeloma huaman cell line, MM1S. Fab(Bevacizumab) was produced by digestion of Bevacizumab with papain, conjugated to NHS-HYNIC-Tfa and radiolabeled with 99mTc. Biodistribution and single photon emission computed tomography studies were performed. In turn, Fab(Bevacizumab) was labeled with Cy7 to obtain in vivo fluorescence images up to 96 hours. Results: Flow cytometry analysis in the MM1S cell line revealed that vascular endothelial growth factor expression is predominantly intracellular. Biodistribution and SPECT/CT studies of the 99mTc-HYNIC-Fab(Bevacizumab) complex showed rapid blood clearance and significant renal and tumor uptake. Fluorescence imaging using Cy7-Fab(Bevacizumab) allowed tumor visualization up to 96 h p.i. Conclusions: we were able to visualize vascular endothelial growth factor expression in vivo in multiple myeloma using the Fab fragment of the anti-VEGF antibody (Bevacizumab) labeled with 99mTc and Cy7. These new molecular imaging agents could potentially be employed in the clinical setting for staging and monitoring of patients with multiple myeloma by in vivo radioactive visualization of vascular endothelial growth factor expression throughout the body. Optical imaging of these tracers would improve tumor sampling and could guide surgical excision.

Introdução: O mieloma múltiplo é uma malignidade hematológica e o segundo câncer de sangue mais comum. O processo de angiogênese tumoral é fundamental para o crescimento e a metástase de muitos tipos de tumores, incluindo o mieloma múltiplo. Sabe-se que a superexpressão do fator de crescimento endotelial vascular está associada a um prognóstico ruim no mieloma múltiplo, representando um alvo importante para a terapia antiangiogênica no mieloma múltiplo. O anticorpo monoclonal Bevacizumab é capaz de se ligar com alta afinidade ao fator de crescimento endotelial vascular e bloquear sua ação. Objetivo: avaliar o Fab(Bevacizumab) marcado com 99mTc ou Cy7 como possíveis agentes de imagem molecular da expressão do fator de crescimento endotelial vascular no mieloma múltiplo. Métodos: A expressão do fator de crescimento endotelial vascular foi analisada por citometria de fluxo na linha celular de mieloma múltiplo MM1S. O Fab(Bevacizumab) foi produzido pela digestão do Bevacizumab com papaína, conjugado com NHS-HYNIC-Tfa e radiomarcado com 99mTc. Foram realizados estudos de biodistribuição e tomografia computadorizada por emissão de fóton único. Por sua vez, o Fab(Bevacizumab) foi marcado com Cy7 para geração de imagens de fluorescência in vivo por até 96 horas. Resultados: A análise de citometria de fluxo na linha celular MM1S revelou que a expressão do fator de crescimento endotelial vascular é predominantemente intracelular. Os estudos de biodistribuição e SPECT/CT do complexo 99mTc-HYNIC-Fab(Bevacizumab) mostraram uma rápida depuração sanguínea e uma captação renal e tumoral significativa. A imagem de fluorescência usando Cy7-Fab(Bevacizumab) permitiu a visualização do tumor até 96 horas p.i. Conclusões: Conseguimos visualizar a expressão do fator de crescimento endotelial vascular in vivo no mieloma múltiplo usando o fragmento Fab do anticorpo anti-VEGF (Bevacizumab) marcado com 99mTc e Cy7. Esses novos agentes de imagem molecular poderiam ser usados no cenário clínico para o estadiamento e o monitoramento de pacientes com mieloma múltiplo, visualizando radioativamente a expressão do fator de crescimento endotelial vascular in vivo em todo o corpo. A geração de imagens ópticas desses traçadores melhoraria a amostragem do tumor e poderia orientar a excisão cirúrgica.

Intravitreal bevacizumab plus propranolol for neovascular age-related macular degeneration (the BEVALOL study): a phase I clinical trial.

BACKGROUND: Given the persistently large public health impact of neovascular age-related macular degeneration (nARMD) despite many years of anti-VEGF therapy as the first-line treatment and the demonstrated ability of b-blockers to reduce neovascularization, a synergistic effect between an anti-VEGF agent and an intravitreal beta-blocker is important to investigate in the quest for therapeutic alternatives that maximize efficacy and/or reduce costs. The main purpose of this study is to investigate the safety of a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) to treat nARMD. METHODS: Prospective phase I clinical trial that included patients with nARMD. Comprehensive ophthalmic evaluation was performed at baseline and included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), biomicroscopy of the anterior and posterior segments, binocular indirect ophthalmoscopy, color fundus photography, spectral domain optical coherence tomography (OCT), OCT angiography (OCT-A), fluorescein angiography (Spectralis, Heidelberg), and full-field electroretinography (ERG). All eyes were treated with a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) within 1 week of baseline evaluation. The patients were reexamined at weeks 4, 8 and 12, and clinical evaluation and SD-OCT were performed at all follow-up visits. Additional injections of combination bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) were administered at weeks 4 and 8. At the final study evaluation (week 12), color fundus photography, OCT-A, fluorescein angiography, and full-field ERG were repeated. RESULTS: Eleven patients (11 eyes) completed all study visits of the 12 week study. Full field ERG b-waves did not show significant (p < 0.05) changes at week 12 compared to baseline. During the 12 week follow-up period, none of the study eyes developed intraocular inflammation, endophthalmitis or intraocular pressure elevation more than 4 mmHg over baseline. Mean ± SE BCVA (logMAR) was 0.79 ± 0.09 at baseline and was significantly (p < 0.05) improved to 0.61 ± 0.10 at week 4; 0.53 ± 0.10 at week 8; and 0.51 ± 0.09 at week 12. Mean ± SE central subfield thickness (CST) (µm) was 462 ± 45 at baseline and was significantly (p < 0.05) lower at 4, 8 and 12 weeks (385 ± 37; 356 ± 29 and 341 ± 24, respectively). CONCLUSIONS: In this 12 week trial of a combination of intravitreal bevacizumab and propranolol for treatment of nARMD, no adverse events or signals of ocular toxicity were observed. Further studies using this combination therapy are warranted. Trial Registration Project registered in Plataforma Brasil with CAAE number 28108920.0.0000.5440 and approved in ethics committee of Clinics Hospital of Ribeirao Preto Medicine School of São Paulo University-Ribeirão Preto, São Paulo, Brazil (appreciation number 3.999.989 gave the approval).