Efficient Assessment of Tumor Vascular Shutdown by Photodynamic Therapy on Orthotopic Pancreatic Cancer Using High-Speed Wide-Field Waterproof Galvanometer Scanner Photoacoustic Microscopy.

To identify the vascular alteration by photodynamic therapy (PDT), the utilization of high-resolution, high-speed, and wide-field photoacoustic microscopy (PAM) has gained enormous interest. The rapid changes in vasculature during PDT treatment and monitoring of tumor tissue activation in the orthotopic pancreatic cancer model have received limited attention in previous studies. Here, a fully two-axes waterproof galvanometer scanner-based photoacoustic microscopy (WGS-PAM) system was developed for in vivo monitoring of dynamic variations in micro blood vessels due to PDT in an orthotopic pancreatic cancer mouse model. The photosensitizer (PS), Chlorin e6 (Ce6), was utilized to activate antitumor reactions in response to the irradiation of a 660 nm light source. Microvasculatures of angiogenesis tissue were visualized on a 40 mm2 area using the WGS-PAM system at 30 min intervals for 3 h after the PDT treatment. The decline in vascular intensity was observed at 24.5% along with a 32.4% reduction of the vascular density at 3 h post-PDT by the analysis of PAM images. The anti-vascularization effect was also identified with fluorescent imaging. Moreover, Ce6-PDT increased apoptotic and necrotic markers while decreasing vascular endothelial growth factor (VEGF) expression in MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. The approach of the WGS-PAM system shows the potential to investigate PDT effects on the mechanism of angiographic dynamics with high-resolution wide-field imaging modalities.

Cost-effectiveness of the anti-vascular endothelial growth factor intravitreal injection and panretinal photocoagulation for patients with proliferative diabetic retinopathy in South Korea.

BACKGROUND: We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea. METHODS: We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first. RESULTS: In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was $95,456 per quality-adjusted life-year (QALY) for PRP first, $34,375 per QALY for anti-VEGF injection first, and $33,405 per QALY for anti-VEGF injection only from a healthcare perspective. From the societal and payer perspective, strategy (2) was more cost-saving and effective than (1). In the probabilistic sensitivity analysis, only-PRP was cost-effective up to the willingness-to-pay (WTP) of about $42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy. CONCLUSION: In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.

Lenvatinib in the treatment of unresectable hepatocellular carcinoma: a systematic review of economic evaluations.

PURPOSE: This aim of this study was to conduct a systematic review of economic evaluations comparing lenvatinib to other vascular endothelial growth factor (VEGF) inhibitors and other treatment options in the management of unresectable hepatocellular carcinoma (uHCC). METHODS: A comprehensive literature search was conducted using highly sensitive search syntax. The titles and abstracts of all records were studied and screened to identify eligible economic evaluations. To enable comparison across different countries, the results of economic evaluations make it possible to compare, the costs and ICER of all studies were converted into 2022 US dollars, and a 3% annual increase for inflation was applied. The quality of the studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. This study is conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Lenvatinib was found to be cost-effective (ICER = dominant) compared to most drugs in the included studies, except in studies where it was compared with donafenib or when the price of sorafenib was significantly discounted (e.g., with a 90% discount, the value of ICER was + 104,669 USD). CONCLUSION: Lenvatinib was generally cost-effective in most studies, but not compared to donafenib or sorafenib (if the price sorafenib was significantly discounted).

Economic Aspects in the Management of Diabetic Macular Edema in Italy.

Background: Diabetic Macular Edema (DME) is the most common cause of vision loss in diabetic patients. Currently, the Vascular Endothelial Growth Factor inhibitors (anti-VEGFs) are used as the first line of DME treatment and corticosteroid implants are usually used as a second-line treatment. These implants are a safe and effective therapeutic option that can improve the quality of life of DME patients by reducing the intravitreal injections number. We determined the economic impact related to DME, also from the social perspective, and the consequences of the increased use of the dexamethasone implant. Methods: The analysis compares two scenarios: the first based on the current rate of recourse to the therapeutic alternatives available in the Italian healthcare setting (as is) and the second based on the assumption of an increased recourse to dexamethasone implants (to be). The results are expressed both in terms of the resource absorption associated with the two scenarios and in terms of the cost differential yielded by their comparison. Results: The increased use of the dexamethasone implant allows considerable savings in terms of healthcare professionals' time, follow-up and productivity lost by patients/caregivers. These savings would reduce healthcare costs for the management of DME patients in Italy by €2,058,238 in 5 years. Conclusions: To optimize the healthcare resources allocation, it is necessary to implement treatments that yield not only cost reductions but also a clinical benefit for patients. The dexamethasone implant use is an example of DME management that generates value for patients, health system and society.

Assessment of Choroidal Neovascularization Perfusion: A Pilot Study With Laser Speckle Flowgraphy.

Purpose: The purpose of this study was to quantify perfusion in the area of choroidal neovascularization (CNV) using laser speckle flowgraphy (LSFG) before and after intravitreal anti-vascular endothelial growth factor (VEGF) injection. Methods: Retrospective case series. Fifteen eyes of 15 patients with treatment-naïve CNV due to age-related macular degeneration (AMD) and with available LSFG images were included. The main outcome was the mean blur rate (MBR) quantified as a measure of perfusion within the CNV area observed on indocyanine green angiography. Twelve patients had available longitudinal data until one month after the injection, used to evaluate changes in perfusion, central macular thickness (CMT), visual acuity, and ocular perfusion pressure. Reproducibility of LSFG measurements was investigated at each time point from two images taken within five minutes. Results: Intraclass correlation coefficients for LSFG measurements were higher than 0.8 indicating excellent reproducibility. There was a significant decrease in perfusion after one week (-26.4 ± 14.4%; P = 0.027), whereas, after one month, perfusion was no longer significantly different from baseline (P = 0.121). CMT showed a progressive decrease over the follow-up period. Changes in perfusion were strongly correlated with changes in CMT after one week, but not thereafter. Conclusions: This pilot study suggests a method to select a region in the CNV area to quantify perfusion using LSFG. MBR could represent a parameter possibly related to regrowth of the CNV after anti-VEGF treatment. Large-scale studies are needed to assess the usefulness of LSFG in defining re-treatment criteria for neovascular AMD. Translational Relevance: LSFG technology to quantify perfusion could provide useful biomarkers for therapeutic management of CNV.

Real-World Effectiveness and Real-World Cost-Effectiveness of Intravitreal Aflibercept and Intravitreal Ranibizumab in Neovascular Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Real-World Studies.

INTRODUCTION: Treatment of neovascular age-related macular degeneration (nAMD) has evolved with the advent of anti-vascular endothelial growth factor agents such that intravitreally administered aflibercept and ranibizumab (RBZ) have become the standard of care. Randomized clinical trials (RCTs) have demonstrated the benefits of these agents in nAMD; however, results achieved under RCT protocols may not always be replicated in clinical practice. Assessing real-world outcomes is important to estimate the effectiveness and cost-effectiveness of these two agents. Our objective was to assess the real-world effectiveness of intravitreally administered aflibercept and RBZ in treatment-naive patients with nAMD and determine the cost-effectiveness of intravitreally administered aflibercept versus RBZ in a real-world setting. METHODS: A multistage approach was undertaken. A systematic literature review (SLR) was completed to identify studies describing real-world outcomes in patients with nAMD treated intravitreally with aflibercept or RBZ. A meta-analysis of data identified in the SLR generated a pooled estimate of the effectiveness of intravitreally administered aflibercept and RBZ at 52 weeks and an estimate of treatment burden (injection frequency and monitoring). The impact of treatment effect modifiers, such as baseline visual acuity (VA) and age, were corrected through a multivariable meta-regression. A Markov state transition model was developed to estimate the real-world cost-effectiveness of intravitreally administered aflibercept using results from the pooled estimates for effectiveness and treatment burden as primary inputs. The analysis considered the perspective of the French National Healthcare System. RESULTS: Patients treated intravitreally with aflibercept had a mean age of 79.52 years and mean baseline VA of 55.80 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. At week 52, mean VA gain was 5.30 ETDRS letters in patients reporting an average of 7.10 intravitreal injections of aflibercept and 8.65 visits (injection and/or monitoring). RBZ-treated patients were younger (77.28 years), with a lower mean baseline VA (52.81 ETDRS letters). At week 52, mean VA gain from baseline was 4.24 ETDRS letters, with an average of 5.88 injections and 10.10 visits (injection and/or monitoring). After correcting for differences in age (77.28 years) and baseline VA (52.81 ETDRS letters) and considering the current clinical practice with aflibercept and RBZ, the mean VA gain was 6.57 ETDRS letters for patients treated intravitreally with aflibercept and 4.42 ETDRS for patients treated intravitreally with RBZ. The cost-effectiveness analysis showed that intravitreally administered aflibercept is a more effective treatment option with an incremental gain in quality-adjusted life years (QALYs) (4.918 versus 4.880) and an incremental cost-effectiveness ratio (ICER) of €27,087 per QALY. CONCLUSIONS: The analysis identified differences in the overall treatment approach and how ophthalmologists use intravitreally administered aflibercept and RBZ in clinical practice. These differences ultimately influence the mean real-world effectiveness of the two agents. Intravitreal treatment with aflibercept (injection frequency and patients follow-up) was consistent and in line with the European label recommendations. Patients treated intravitreally with aflibercept in clinical practice reported a mean gain in VA of similar magnitude to the mean VA gain reported in the pivotal RCT. Conversely, treatment with RBZ varied significantly across the different studies. On average, RBZ-treated patients reported a low injection frequency and a frequent follow-up, driven in part by the high number of patients treated with pro re nata (PRN) regimens. RBZ-treated patients reported gains in VA versus baseline; however, the magnitude of the gain in VA was not comparable to the VA gains reported in the RBZ pivotal RCT. Intravitreal treatment with aflibercept was associated with better mean VA outcomes and an incremental gain in QALYs compared with RBZ and can be considered cost-effective for the treatment of nAMD in patients in France despite a higher price for each individual intravitreal injection of aflibercept compared with RBZ. FUNDING: Bayer AG, Basel.

Evaluation of retinal function improvement in neovascular age-related macular degeneration after intravitreal aflibercept injections with the use of the assessment of retinal sensitivity: The use of the assessment of retinal sensitivity in anti-VEGF treatment - a STROBE-compliant observational study.

This study compares 2 methods of macular function evaluation: the microperimetric examination (mean central retinal sensitivity and fixation stability) and the distance best-corrected visual acuity (BCVA) examination, which is the most frequently used method of assessing macular function in patients with newly diagnosed wet age-related macular degeneration (AMD) who have been treated with anti-vascular endothelial growth factor (VEGF) drug (aflibercept).Prospective analysis was conducted on 44 eyes of 44 patients treated with intravitreal injection of anti-VEGF (aflibercept) because of newly diagnosed neovascular AMD. According to the research protocol, all patients had a 6-month follow-up. The response to treatment was monitored functionallybyMP-1 microperimetry, fixation, and distance BCVA assessment after injection. Improvement of retinal sensitivity and BCVA was found under aflibercept treatment. There was statistically significant improvement in retinal sensitivity in the MP-1 study 3 and 6 months from the beginning of anti-VEGF therapy. Moreover, a significant improvement in retinal sensitivity between 3 and 6 months of observation was demonstrated. At the same time, up to 3 months from the beginning of treatment, BCVA improved significantly compared to the baseline value. In the 6th month of the study BCVA remained stable without further significant improvement.Microperimetric examination with medium sensitivity and fixation stability assessment is a very valuable test determining the retinal function. It is clear that examining the macular morphology itself in modern diagnostics is not enough to assess retinal function. Microperimetry technique is a valuable tool for functional long-term evaluation of retinal function (also for a period of more than 3 months).

The economic and humanistic burden of patients in receipt of current available therapies for nAMD.

AIM: To determine the economic and humanistic burden of neovascular age-related macular degeneration (nAMD) in a cohort of patients treated with anti-VEGF in Europe and the US. PATIENTS & METHODS: 79 respondents from the EU and 63 from the US with a self-reported diagnosis of nAMD and in current receipt of treatment, as reported in an international, general population survey, were compared with non-nAMD controls. RESULTS: Anti-VEGF-treated nAMD patients in the EU had a greater utilization of healthcare resources, poorer quality of life and greater overall activity impairment versus non-nAMD controls. In the US cohort, treated nAMD patients had significantly greater resource utilization for ophthalmologist visits only. CONCLUSION: The burden of care associated with nAMD on EU and US healthcare systems, and on patients who are in receipt of nAMD therapy, is significant and likely to be unsustainable.

Economic outcomes of sequences which include monoclonal antibodies against vascular endothelial growth factor and/or epidermal growth factor receptor for the treatment of unresectable metastatic colorectal cancer.

BACKGROUND: Patients with unresectable, metastatic colorectal cancer with wild type Kirsten ras mutational status are eligible for sequential treatments which include monoclonal antibodies as first line (1L), second line (2L), or third line (3L) regimens. OBJECTIVE: To compare the economic outcomes of different sequences which include monoclonal antibodies for the treatment of unresectable metastatic colorectal cancer. METHODS: Individual drug regimens for 1L, 2L, and 3L treatments were compiled according to the clinical studies in the Summary of Product Characteristics for monoclonal antibodies. They were combined into plausible treatment sequences. Health outcomes were approximated using additive median PFS benefit, and economic outcomes were calculated with a treatment sequencing costing tool. Limitations of the analysis include the clinical trial data sources, cost assumptions, and the additive PFS approach. RESULTS: Seventeen sequences were evaluated. Results of the analysis show that sequences including 1L anti-EGFRs generally have relatively low-to-medium health outcomes at the highest comparative sequence costs compared to sequences including 2L anti-EGFRs, which have lower health outcomes at the lowest cost. Sequences including 3L anti-EGFRs (sequential bevazicumab-based 1L and 2L) have the highest health outcomes, with potential cost savings of €5972-€11,676 if replacing 2L anti-EGFRs or an additional cost of €5909-€12,708 if replacing 1L anti-EGFR regimens. CONCLUSION: Clinical sequences consisting of 1L and 2L line bevacizumab followed by 3L anti-EGFR potentially yield the greatest health outcomes associated with a reasonable trade-off in additional cost when replacing 1L anti-EGFRs and are potentially cost-saving if replacing 2L anti-EGFRs, per patient per lifetime. To maximize health outcomes, optimal sequences include anti-EGFRs as 3L regimen, with an approximately equivalent trade-off in costs between the most costly (anti-EGFR 2L) and least costly (anti-EGFR 1L) sequences.

What is new in the management of wet age-related macular degeneration?

INTRODUCTION OR BACKGROUND: The hallmark of wet age-related macular degeneration (AMD) is choroidal neovascularization (CNV). The key cytokine involved in the pathogenesis of CNV is vascular endothelial growth factor (VEGF). Since 2005, antiVEGF therapy has revolutionized the management of this condition. SOURCES OF DATA: A systematic computerized literature search was conducted on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). AREAS OF AGREEMENT: AntiVEGF therapy has resulted in improvement in visual function and performance. Currently, practitioners are spoilt for choice of these agents. AREAS OF CONTROVERSY: Bevacizumab is unlicensed for intraocular use but has a better market share than ranibizumab in the treatment of wet AMD as it is approximately 40 times cheaper than ranibizumab, if aliquoted into smaller doses for intraocular use. This has stirred up questions on indemnity, safety, dosing, treatment regimen and quality control, despite the fact that well-designed clinical trials have shown that both drugs are equally effective. Another dilemma for the physicians is the choice of treatment regimens with antiVEGF agents that include fixed dosing, optical coherence tomography (OCT)-guided re-treatment, treat and extend or a combination of proactive and reactive dosing. Real-life outcomes of physician-dependent OCT-guided re-treatment with these agents are inferior to outcomes reported in clinical trials. GROWING POINTS: A recently food and drug administration-approved antiVEGF agent, aflibercept, is rapidly becoming a popular choice as well-designed randomized clinical trials indicate that eight weekly fixed dosing of aflibercept is non-inferior to monthly ranibizumab. AREAS TIMELY FOR DEVELOPING RESEARCH: Options for reducing the frequency of repeated intravitreal injections are being explored. Combination therapy with photodynamic therapy and epimacular brachytherapy seem scientifically plausible due to their synergistic effects. However, so far the results on these combinations have not shown any superior visual outcomes to antiVEGF monotherapy, and the practicalities of delivering these therapies are formidable. So, research into other novel therapeutic approaches such as pigment epithelium-derived factor and designed ankyrin repeat proteins are gaining momentum.

Comparing treatments for age-related macular degeneration: safety, effectiveness and cost.

Comparative effectiveness research (CER) has received widespread attention and federal funding because of its potential to inform and improve treatment decisions. Since 2005, patients and their ophthalmologists have faced a dilemma in treating age-related macular degeneration (AMD)--the leading cause of blindness in the United States. Two closely related drugs have produced dramatic improvements in vision; one has been rigorously tested for use in AMD patients, while the other has been rigorously tested for use in cancer patients, but is now widely used to treat AMD. One drug costs 40 times as much as the other. This Issue Brief summarizes a CER study comparing these drugs head-to-head, and provides the most definitive evidence to date about the safety and effectiveness of the two alternatives.

Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment.

Vascular endothelial growth factor (VEGF) is thought to provide neuroprotection to the traumatically injured spinal cord. We examined whether supplementing the injured environment with VEGF(165) via direct intraspinal injection into the lesion epicenter during the acute phase of spinal cord injury (SCI) results in improved outcome. The effect of treatment was investigated using longitudinal multi-modal magnetic resonance imaging (MRI), neurobehavioral assays, and end-point immunohistochemistry. We observed on MRI that rats treated with VEGF(165) after SCI had increased tissue sparing compared to vehicle-treated animals at the earlier time points. However, these favorable effects were not maintained into the chronic phase. Histology revealed that VEGF(165) treatment resulted in increased oligodendrogenesis and/or white matter sparing, and therefore may eventually lead to improved functional outcome. The increase in spared tissue as demonstrated by MRI, coupled with the possible remyelination and increased neurosensory sensitivity, suggests that VEGF(165) treatment may play a role in promoting plasticity in the sensory pathways following SCI. However, VEGF-treated animals also demonstrated an increased incidence of persistent allodynia, as indicated on the von Frey filament test.

Current thoughts on angiogenesis.

Research into the distinct phases of the process of angiogenesis has informed the development of growth factor therapy and tissue-engineered products, but more studies are needed to ensure the development of new therapeutic strategies.

[Therapeutic modalities of age-related macular degeneration]. / Idôskori maculadegeneratio kezelési lehetôségei.

Age-related macular degeneration has become a leading cause of legal blindness in the industrial countries. Some hundred thousands of people are estimated to be suffering from the disease in Hungary as well. Earlier the different forms were considered as distinct diseases. Since the whole scale and pathomechanism of age-related macular degeneration has been clarified, and at the same time the therapeutic modalities have been developed in a lot of cases, there is good chance of maintaining or even improving visual acuity. The author describes the different forms of the disease, and then writes about the treatment modalities which proved to be effective, or which have been introduced recently in detail. He emphasises the harmful role of smoking among prevention methods. Conservative treatment beside antioxidants includes the so-called metabolic therapy nowadays. Different types of laser treatment are widely used, while irradiation to a smaller extent. The role of traditional surgical intervention is also limited, but the use of anti-vascular endothelial growth factors is very promising. Costs of different methods are also referred to.