Age-related macular degeneration and resource utilization in the Brazilian public healthcare system: a real-world retrospective study

Background Age-related macular degeneration (AMD) is a disease that causes damage in the macular region of the retina, leading to irreversible blindness. This study aims to understand the profile and care of patients with AMD and its cost at the Brazilian public health system to identify AMD-care needs. Methods This is a retrospective observational study of AMD with real-world data from the Brazilian public healthcare system, using DATASUS claim databases. Patients with AMD were selected from 01/Jan/2014 to 31/Jan/2020; had at least one claim of ICD10 code H35.3 (Degeneration of macula and posterior pole), and were submitted to one of two procedures exclusively available for AMD patients - optical coherence tomography (OCT) and medical treatment of retinal disease (antiangiogenic); aged ≥18 years at first ICD10 claim, and presenting at least 1 year of follow-up in the database. We described patients’ characteristics, healthcare resource utilization and cost, and the antiangiogenic intravitreal treatment received by AMD patients, including the number of doses and interval time between them. Results Patients searching for AMD treatment since 2014 were mostly females (59%), white (61%), and a mean age of 72 years. They were mainly located in the Southeast (87%), and few patients were found in the North (1%) and Central-West (1.5%) regions, probably reflecting where the Brazilian guideline to treat AMD (Protocolo Clínico e Diretrizes Terapêuticas - PCDT) was incorporated as routine care for AMD. The average antiangiogenic dose of 2.5 antiangiogenic therapies within a year was below the expected. Most injections had an interval time of 20 to 40 days between doses, although some patients were treated more than 100 days. Another setback is that patients traveled longer distances for OCT and antiangiogenic treatment than overall AMD-healthcare, between 10 and 100 km. Conclusions AMD patients seem to be undertreated, as they receive a mean of 2.5 doses of antiangiogenic treatment within a year. Inequalities among regions are evident, as the Southeast and South regions comprise almost all patients receiving the treatment from the public health system, probably reflecting the region with more access to AMD care according to PCDT recommendations.

Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy

The combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.

Solitary fibrous tumor: molecular hallmarks and treatment for a rare sarcoma

Solitary fibrous tumor (SFT) is a rare soft tissue sarcoma subtype which mainly affects adults in the fifth and sixth decades of life. Originally part of a spectrum of tumors called hemangiopericytomas, classification has been refined such that SFTs now represent a distinct subtype. The identification of NAB2-STAT6 fusion in virtually all SFTs has further aided to define this rare subgroup. SFTs have a spectrum of behavior from benign to malignant, with evidence suggesting risk of metastases related to age at diagnosis, extent of necrosis, mitotic rate and tumor size. The standard treatment for localized disease is surgical excision with or without radiotherapy. Retrospective and prospective evidence suggests antiangiogenic treatment is effective for unresectable disease. Further translational work is required to understand the biology driving the differential behavior and identify more effective treatments for patients with metastatic disease.

Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma

With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.

18F-RGD PET/CT and Systemic Inflammatory Biomarkers Predict Outcomes of Patients With Advanced NSCLC Receiving Combined Antiangiogenic Treatment

BackgroundThe aim of this study was to evaluate 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (18F-RGD PET/CT) and serum inflammation biomarkers for predicting outcomes of patients receiving combined antiangiogenic treatment for advanced non-small cell lung cancer (NSCLC).MethodsPatients with advanced NSCLC underwent 18F-RGD PET/CT examination and provided blood samples before treatments commenced. PET/CT parameters included maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean), peak standard uptake value (SUVpeak) and metabolic tumor volume (MTV) for all contoured lesions. Biomarkers for inflammation included pretreatment neutrophil-to-lymphocyte ratio (PreNLR), pretreatment platelet-to-lymphocyte ratio (PrePLR), and pretreatment lymphocyte-to-monocyte ratio (PreLMR). Receiver operating characteristic (ROC) curve analysis was used to describe response prediction accuracy. Logistic regression and Cox’s regression analysis was implemented to identify independent factors for short-term responses and progression-free survival (PFS).ResultsThis study included 23 patients. According to ROC curve analysis, there were significant correlations between the SUVmax, SUVmean, and 18F-RGD PET/CT MTV and short-term responses (p<0.05). SUVmax was identified using logistic regression analysis as a significant predictor of treatment sensitivity (p=0.008). Cox’s multivariate regression analysis suggested that high SUVpeak (p=0.021) and high PreLMR (p=0.03) were independent PFS predictors. Combining SUVpeak and PreLMR may also increase the prognostic value for PFS, enabling us to identify a subgroup of patients with intermediate PFS.Conclusion18F-RGD uptake on PET/CT and serum inflammation biomarker pretreatment may predict outcomes for combined antiangiogenic treatments for advanced NSCLC patients. Higher 18F-RGD uptake and higher PreLMR also appear to predict improved short-term responses and PFS. Combining biomarkers may therefore provide a basis for risk stratification, although further research is required.

Novel Nutrition-Based Nomograms to Assess the Outcomes of Lung Cancer Patients Treated With Anlotinib or Apatinib

BackgroundPrevious studies have indicated that the changes in body composition during treatment are prognostic in lung cancer. The question which follows is it may be too late to identify vulnerable patients after treatment and to improve outcomes for these patients. In our study, we sought to explore the alterations of body composition and weight before the outset of the antiangiogenic treatment and its role in predicting clinical response and outcomes.MethodsIn this retrospective study, 122 patients with advanced lung cancer treated with anlotinib or apatinib were analyzed. The changes in weight and body composition including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) for 3 months before the outset of antiangiogenic treatment and other clinical characteristics were evaluated with LASSO Cox regression and multivariate Cox regression analysis, which were applied to construct nomograms. The performance of the nomograms was validated internally by using bootstrap method with 1,000 resamples models and was assessed by the concordance index (C-index), calibration plots, decision curve analysis (DCA).ResultsThe median progression-free survival (PFS) and overall survival (OS) were 128 (95% CI 103.2–152.8) days and 292 (95% CI 270.9–313.1) days. Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastases, the Glasgow Prognostic Score (GPS), clinical response, therapeutic regimen, and ΔL1SMI per 90 days were significantly associated with PFS, while ECOG PS, GPS, clinical response, therapeutic regimen, ΔL1SMI per 90 days were identified for OS. The C-index for the nomograms of PFS and OS were 0.763 and 0.748, respectively. The calibration curves indicated excellent agreement between the predicted and actual survival outcomes of 3- and 4-month PFS and 7- and 8-month OS. DCA showed the considerable value of the model.ConclusionNomograms were developed from clinical features and nutritional indicators to predict the probability of achieving 3-month and 4-month PFS and 7-month and 8-month OS with antiangiogenic therapy for advanced lung cancer. Dynamic changes in body composition before the initiation of treatment contributed to early detection of poor outcome.

A Reassessment of the Therapeutic Potential of a Dopamine Receptor 2 Agonist (D2-AG) in Endometriosis by Comparison against a Standardized Antiangiogenic Treatment

Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been shown to cause a shift of the immature vessels towards a more mature phenotype but not a significant reduction in the amount of vascularization and size of lesions. These has raised concerns on whether the antiangiogenic effects of these compounds confer a therapeutic value for endometriosis. In the belief that antiangiogenic effects of D2-ags in endometriosis were masked due to non-optimal timing of pharmacological interventions, herein we aimed to reassess the antiangiogenic therapeutic potential of D2-ags in vivo by administering compounds at a timeframe in which vessels in the lesions are expected to be more sensitive to antiangiogenic stimuli. To prove our point, immunodeficient (NU/NU) mice were given a D2-ag (cabergoline), anti-VEGF (CBO-P11) or vehicle (saline) compounds (n = 8 per group) starting 5 days after implantation of a fluorescently labeled human lesion. The effects on the size of the implants was estimated by monitoring the extent of fluorescence emitted by the lesion during the three-week treatment period. Subsequently mice were sacrificed and lesions excised and fixed for quantitative immunohistochemical/immunofluorescent analysis of angiogenic parameters. Lesion size, vascular density and innervation were comparable in D2-ag and anti-VEGF groups and significantly decreased when compared to control. These data suggest that D2-ags are as powerful as standard antiangiogenic compounds in interfering with angiogenesis and lesion size. Our preliminary study opens the way to further exploration of the mechanisms beneath the antiangiogenic effects of D2-ags for endometriosis treatment in humans.