Growth Factor Inhibitors Research Articles

Real-world experience with atezolizumab plus bevacizumab (A+/-B) in Hispanic patients with advanced hepatocellular carcinoma (HCC) at a Hispanic-majority cancer center.

549 Background: Combination of atezolizumab (A), a programmed death-ligand 1 (PD-L1) inhibitor, and bevacizumab (B), a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated efficacy for first-line treatment for HCC. However, real-world data on the outcomes of this combination therapy in diverse patient populations, particularly in Hispanic U.S. patients, remains limited. This study aims to evaluate the clinical outcomes of patients intended to treat with A+/-B at a Hispanic-majority U.S. cancer center. Methods: This retrospective study of patients diagnosed with advanced unresectable HCC who received treatment with A+B at a Hispanic-serving NCI-designated cancer center. Patients were included if they received at least one dose of A, either as monotherapy or in combination with B, between January 2019 and April 2022. Demographic and clinical data, including age, gender, ethnicity, liver disease etiology, Child-Pugh (CP) classification, comorbidities, and treatment details, were collected. The primary endpoints were the overall response rate (ORR) and complete response (CR) rate. Statistical analyses were conducted to evaluate the association between baseline characteristics and clinical outcomes. The median overall survival (mOS) evaluated by Kaplan-Meier Method. Results: 38 patients received at least A (84% A+B, 6 patients had B held due to bleeding risk after consent). Median age 65 years (45-90). 32 (84%) patients were male. 22 (58%) patients were Hispanic. 45% had HCV-related liver disease. 32% had CP B with no statistically significant association between CP Class and ethnicity. 53% had concurrent diabetes. 26% patients had obesity. The median time on treatment was 7.5 mo (1- 24 mo) with no statistical difference between Hispanics and non-Hispanics (9 vs 6 mo, p 0.70). CR 37% with ORR of 42%. Using Fisher’s exact test, no association was noted between obesity, ethnicity, treatment option or CP class to occurrence of complete or partial response. mOS was 19 mo. There was no statistical difference in mOS between CP A and CP B (19 vs 10 mo, p value 0.6) and no difference between Hispanics (14 mo) vs non-Hispanics (19 mo) (p 0.5), using log rank test. Conclusions: This real-world analysis of a Hispanic-majority U.S. cohort of patients with advanced HCC shows 42% ORR and 37% CR. The findings suggest that this regimen is effective across a diverse patient population, including those with comorbid conditions, such as liver dysfunction (CP B 32%), HCV (45%), diabetes (53%, and obesity (26%). Limitations are the small study population and retrospective nature of the study. Evaluation of toxicity data is ongoing. Further prospective studies are needed to identify biomarkers of outcomes in Hispanic patients with HCC, which is ongoing at our cancer center (NCT03894917).

Exploring factors behind patient non-adherence to intravitreal anti-VEGF injections in macular diseases.

In recent years, intravitreal injections (IVT) of vascular endothelial growth factor (VEGF) inhibitors have become the standard of care for several macular disorders. Frequently, the therapeutic course requires numerous injections, posing a burden on patients. Non-adherence to treatment may result in reduced visual outcomes, therefore understanding and addressing the underlying causes is imperative. A cross-sectional study of patients who missed their scheduled appointment for anti-VEGF IVT as part of the routine management of their macular disease at a single tertiary center between November 2020 and February 2021. A telephone survey was conducted and patient medical charts were reviewed for ophthalmological data. A total of 100/556 (18%) patients who failed to attend their scheduled anti-VEGF IVT appointments were documented. Among these subjects, the average age was 66 (SD ±14) years with a nearly equal gender distribution of 49:51 F:M ratio. Reported no-show reasons included concurrent illness (39%), administrative issues such as missing financial coverage forms or scheduling problems (28%), and lack of motivation (11%). Additionally, 73% of patients who missed appointments expressed a need for accompaniment, and 74% resided outside the hospital city. Study results highlight modifiable factors contributing to no-shows to anti-VEGF IVT, such as poor transportation access, complicated administrative processes, and difficulty rescheduling missed appointments. Understanding potential obstacles to anti-VEGF IVT therapy, particularly those that are preventable, can enhance adherence and potentially improve the clinical outcome.

Adenosine diphosphate stimulates VEGF-independent choroidal endothelial cell proliferation: A potential escape from anti-VEGF therapy

We hypothesized that a strategy employing tissue-specific endothelial cells (EC) might facilitate the identification of tissue- or organ-specific vascular functions of ubiquitous metabolites. An unbiased approach was employed to identify water-soluble small molecules with mitogenic activity on choroidal EC. We identified adenosine diphosphate (ADP) as a candidate, following biochemical purification from mouse EL4 lymphoma extracts. ADP stimulated the growth of bovine choroidal EC (BCEC) and other bovine or human eye-derived EC. ADP induced rapid phosphorylation of extracellular signal-regulated kinase in a dose- and time-dependent manner. ADP-induced BCEC proliferation could be blocked by pretreatment with specific antagonists of the purinergic receptor P2Y1 but not with a vascular endothelial growth factor (VEGF) inhibitor, indicating that the EC mitogenic effects of ADP are not mediated by stimulation of the VEGF pathway. Intravitreal administration of ADP expanded the neovascular area in a mouse model of choroidal neovascularization. Single-cell transcriptomics from human choroidal datasets show the expression of P2RY1, but not other ADP receptors, in EC with a pattern similar to VEGFR2. Although ADP has been reported to be a growth inhibitor for vascular EC, here we describe its growth-stimulating effects for BCEC and other eye-derived EC.

Case report: Successful therapy with recombinant human vascular endostatin in an elderly man with colon telangiectasia and idiopathic thrombocytopenic purpura

An 83-year-old male presented to our Digestive System Department with a 5-day history of severe gastrointestinal (GI) bleeding and a 14-year history of idiopathic thrombocytopenic purpura (ITP) with low platelet levels. Colonoscopy revealed extensive telangiectasias throughout the colon, particularly in the transverse and ascending segments. Standard treatment with proton-pump inhibitors and somatostatin proved ineffective. Additionally, conventional therapies such as estrogen and thalidomide were contraindicated due to the comorbidity of ITP. Endoscopic hemostasis was also difficult to perform because of the widespread nature of the lesions. However, after the innovative use of four courses of recombinant human vascular endostatin (Endostar) therapy, the colon telangiectasia was completely resolved, and the patient reported no GI bleeding for 2 years. Managing severe GI bleeding with a rare etiology is particularly challenging, especially in patients with contraindications to conventional treatments due to comorbidities. In this case, a vascular endothelial growth factor (VEGF) inhibitor was successfully applied to treat a refractory and rare GI bleeding, which may offer a novel therapeutic approach for similar cases.

A Study on Endometrial Polyps Recurrence Post-Hysteroscopic Resection: Identification of Influencing Factors and Development of a Predictive Model.

This study aimed to explore influencing factors and develop a predictive model of endometrial polyps (EP) recurrence after hysteroscopic resection. This retrospective study included 180 patients who underwent hysteroscopic resection for EP between January 2021 to December 2023. The patients were divided into a modeling group (n = 135) and a validation group (n = 45) in a 3:1 ratio. The patients in the modeling group were further divided into a recurrence group (n = 35) and a non-recurrence group (n = 100) based on whether their polyps recurred. General information on patients was compared between the two groups. Univariate and multiple logistic regression analyses were conducted to identify factors influencing EP recurrence post-hysteroscopic resection. A predictive model was developed, and the receiver operating characteristic (ROC) curve analysis was performed to determine the clinical utility of the model. Comparison of baseline characteristics between the modeling and validation groups showed no statistically significant differences (p > 0.05). However, 35 patients in the modeling group had recurrence, while 12 patients experienced recurrence in the validation group. Binary logistics regression analysis revealed matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), hypoxia-inducible factor-1α (HIF-1α) and platelet-derived growth factor (PDGF) as independent predictors for polyp recurrence (p < 0.05). Furthermore, a model formula, p = eZ/1 + eZ, was developed. The slope of the calibration curve of this model in both groups were straight lines close to 1, indicating that the model's predicted recurrence risk strongly agreed with the actual risk. ROC analysis demonstrated that the area under the curve in the modeling group was 0.902, with standard error of 0.028 (95% confidence interval (CI): 0.885-0.954). The model yielded the Youden value of 0.79, with a sensitivity of 82.96% and a specificity of 95.66%. Moreover, the area under the curve in the validation group was 0.871, with a standard error of 0.040 (95% CI: 0.859-0.920). However, the model showed the Youden value of 0.59, with a sensitivity of 79.29% and a specificity of 79.96%. The Decision Curve Analysis (DCA) demonstrated significant clinical advantages of the model. This study identified the influencing factors of EP recurrence and successfully constructed a predictive model based on these factors. After validation, the model demonstrates significant clinical utility.

The Landscape of Vascular Endothelial Growth Factor Inhibition in Retinal Diseases.

Ever since the US Food and Drug Administration (FDA) approved the first vascular endothelial growth factor (VEGF) antagonist 2 decades ago, inhibitors of VEGF have revolutionized the treatment of a variety of ocular disorders involving pathologic neovascularization and retinal exudation. In this perspective, we evaluate the current status of anti-VEGF therapies and the real-world challenges encountered with maintaining therapeutic outcomes. Finally, we describe novel VEGF-based and combinatorial approaches that are in clinical development.

Outliers of Treatment Frequency in Retinal Vein Occlusion: 24-Month Comparative Analysis of Fight RetinalBlindness! Practitioners.

We aimed to describe a 2-year outcome of eyes managed by practitioners benchmarked using a funnel plot by their frequency of treatment using vascular endothelial growth factor (VEGF) inhibitors for naive retinal vein occlusion (RVO). A multicentre, international, observational study of 29 doctors in 12 countries managing 1110 eyes with RVO commencing VEGF inhibitors between 1 January 2012-2022 tracked in the Fight Retinal Blindness! registry. We identified 3 outlying 'intensive' practitioners (managing 350/1110 eyes [32%]), 22 'typical' practitioners (604/1110, [54%]) and 4 outlying 'relaxed' practitioners (156/1110, [14%]) with respective 24-month outcomes in Branch and Central RVO including the primary outcome, mean adjusted change in visual acuity (VA) in BRVO: +16.2, +13.6, +9.3 letters (p < 0.01) and CRVO: +14.2, +12.7, +4.8 letters (p < 0.01); adjusted change in macular thickness in BRVO -179, -150, -159 μm (p < 0.01) and CRVO -324, -283, -232 μm (p < 0.01); time-in-range with VA > 68 letters in BRVO 90, 78, 68 weeks (p < 0.01) and CRVO 69, 60, 54 weeks (p = 0.04); median injections 18, 13 and 10; median final injection intervals, BRVO 6, 9, 10 weeks and CRVO 6, 9 and 12 weeks; with no significant difference in adverse outcomes. At 24 months, the intensive practitioners were treating RVO using VEGF inhibitors with twice the frequency of the relaxed practitioners; however, their patients had gained twice (BRVO) to three times (CRVO) more letters of VA.

Potential Use of Plasma Rich in Growth Factors in Age-Related Macular Degeneration: Evidence from a Mouse Model.

Background and Objectives: Age-related macular degeneration (AMD) is the leading cause of low vision and legal blindness in adults in developed countries. Wet AMD can be successfully treated using vascular endothelial growth factor (VEGF) inhibitors; however, dry AMD currently has no effective treatment. The purpose of this study is to analyze the efficacy of intraocular injection of plasma rich in growth factors (PRGF) in an AMD mouse model induced by intraperitoneal administration of sodium iodate. Materials and Methods: Intravitreal application of PRGF (experimental group) and saline (control group) was performed immediately after intraperitoneal injection of sodium iodate. Retinographies were performed at 2 and 7 days after treatment administration. The eyes were retrieved for histological and immunohistological analysis. Statistical analysis was performed to compare the outcomes between the study groups. Results: In comparison to saline solution, PRGF significantly decreased the depigmentation of the RPE, showing a more reddened retina. PRGF intravitreal treatment significantly reduced the glial fibrillary acidic protein (GFAP) stained processes, suggesting a significant reduction in the risk of scar formation. Moreover, the myofibroblast invasion into the RPE cell layer was significantly reduced in the PRGF-treated group of mice. There was a tendency for better preservation of the photoreceptors in the PRGF group. Conclusions: Within the limitations of this study, intravitreal injection of PRGF provided significant protection against the degeneration of the photoreceptors and the RPE induced by the systemic administration of NaIO3.

Development of a UPLC-MS/MS method for the determination of sulfatinib and its no interaction with myricetin in rats.

Sulfatinib is a novel oral tyrosine kinase inhibitor (TKI) with selective inhibition of fibroblast growth factor (FGFR), colony-stimulating factor 1 receptor (CSF-1R) and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. It has been approved for the therapy of neuroendocrine tumors arising in the non-pancreatic (December 2020) and pancreatic (June 2021) glands. Until now, there has no research on the determination of sulfatinib in biological medium by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The current study validated a sensitive and reliable quantitative detection of sulfatinib in plasma using UPLC-MS/MS for the first time, and investigated the interaction with myricetin in rats. Acetonitrile was used to precipitate the plasma protein, and lenvatinib was employed as the internal standard (IS). The method demonstrated that sulfatinib presented high linearity over the concentration of 11-2,000ng/mL with the lower limit of quantification (LLOQ) of 1ng/mL. It was validated methodologically that the precision, matrix effect, stability, accuracy and extraction recovery were all within the allowable values. Moreover, male Sprague-Dawley (SD) rats were assigned randomly to assess the interaction between sulfatinib (30mg/kg) and myricetin (50mg/kg). Nevertheless, no significant differences of the main pharmacokinetic parameters were revealed. This may be due to insufficient doses of myricetin, or failure of myricetin to act in a timely manner in vivo. The findings contributed to a better understanding of the metabolism and drug-drug interaction of sulfatinib, but the presence or absence of interactions needs to be confirmed by further studies.

Phase 1b Dose Escalation Study of Sozinibercept Inhibition of Vascular Endothelial Growth Factors C and D With Aflibercept for Diabetic Macular Edema.

Sozinibercept inhibits vascular endothelial growth factors (VEGFs) C and D. This study evaluated outcomes following switching from anti-VEGF-A monotherapy to intravitreal injections of three dose levels of sozinibercept in combination with aflibercept in patients with diabetic macular edema (DME). A phase 1b, open-label, multicenter dose-escalation study with a 24-week follow-up. Patients received 3 loading doses of aflibercept (2 mg) in combination with sozinibercept (0.3, 1, or 2 mg) once every 4 weeks and were followed through week 24. The primary endpoint was safety, and secondary endpoints included mean change from baseline in best-corrected visual acuity (BCVA) and anatomic changes on imaging. Nine patients received sozinibercept in combination with aflibercept after a mean (SD) of 6.3 (2.4) injections of previous anti-VEGF-A. Sozinibercept combination therapy was well tolerated with no dose-limiting toxicities. Mean change in BCVA at week 12 was +7.7 letters (95% confidence interval [CI], 2-13.3) from baseline (65 letters [SD 5.5]) with a dose response for increasing doses of sozinibercept. At week 12, central subfield thickness (CST) was decreased by -71 µm (95% CI, -117 to -26) from baseline (434 µm [SD 58]), and 6 of 9 (67%) patients had a ≥50% reduction in excess foveal thickness. In prior-treated patients with center-involved DME, switching to sozinibercept in combination with aflibercept was well tolerated with improved visual and anatomic outcomes. This first-in-human study builds upon basic research by providing safety and preliminary efficacy of sozinibercept (anti-VEGF-C/-D) in combination with aflibercept for DME.

Preclinical evaluation of NG101, a potential AAV gene therapy for wet age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over the age of 55. Approximately 10%-15% of AMD patients develop choroidal neovascularization (CNV), leading to wet AMD (wAMD), which accounts for nearly 90% of AMD-related blindness. Inhibition of vascular endothelial growth factor (VEGF) is the standard treatment for wAMD. However, the frequent administration of the current treatment imposes a significant burden on wAMD patients. Therefore, there is an unmet need for treatments that require less-frequent administration. Here, we present findings on the safety and efficacy of NG101, a recombinant adeno-associated virus (rAAV) vector encoding aflibercept, an anti-VEGF agent, for wAMD therapy. A single subretinal injection of NG101 effectively reduced CNV lesion leakage and size at doses as low as 1×106 in mouse and 3×109 viral genomes per eye in cynomolgus monkeys. In cynomolgus monkeys, NG101-derived aflibercept expression in ocular tissues persisted for 1 year post-injection, indicating sustained therapeutic potential. Biodistribution analysis revealed that NG101 was primarily localized in ocular tissues. Only mild and transient ocular inflammatory responses were observed. Overall, these findings suggest that NG101, with its efficacy at low doses and sustained expression, is a promising therapeutic candidate for wAMD.

Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease.

A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84 %) and Type 1 diabetes (16 %), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyzes in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.

Real-world therapy and persistence of patients with neovascular age-related macular degeneration and diabetic retinopathy or diabetic macular edema: a German claims data analysis.

Vascular endothelial growth factor (VEGF) inhibition is the current and high-volume standard-of-care for patients with neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR) with diabetic macular edema (DME). This study assessed the impact of non-persistence in anti-VEGF treatment using claims data from two German states. This study identified adults with nAMD or DR/DME and incident anti-VEGF treatment (= index) in January 2015-June 2019 using the German AOK PLUS claims database (January 2014-June 2021, ~ 3.5 million insured). Baseline characteristics were observed within 12months before index. Patient follow-up lasted ≥ 24months or until death. Non-persistence (gap of ≥ 180days) was calculated using Kaplan-Meier estimation. Cox regression identified variables linked to non- persistence. The study analysed reimbursed anti-VEGF treatments, thus excluding off-label use of bevacizumab. 5,498 patients diagnosed with nAMD (mean age, 80.09years; male, 37.50%; mean Charlson Comorbidity Index [CCI] score, 3.07) and 484 patients with DR/DME (mean age, 67.14; male, 58.88%; mean CCI score, 4.54) were identified. Non-persistence to anti-VEGF treatment within 12months after index occurred in 51.38% of nAMD patients and 62.60% of DR/DME patients, with mean times to first gap of 11.28 and 8.98months, respectively. Cox regression revealed factors associated with non-persistence, including higher age, female gender, higher care needs, longer AMD history, and the use of ranibizumab. Epidemiologic and ophthalmologic factors associated with anti-VEGF non-persistence were successfully identified in the first year of therapy. The analyzed dataset can potentially be enriched with additional health insurance database sets under the used criteria to gain more understanding of anti-VEGF non-persistence.

Anti-Vascular Endothelial Growth Factor Combined with Ocular Steroid Therapy for Persistent Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

Purpose: Our purpose was to appraise the efficacy and safety of intravitreous vascular endothelial growth factor inhibitor (anti-VEGF) therapy combined with steroids for persistent diabetic macular edema. Methods: A systematic review was conducted of the research evaluating the combination therapy of anti-VEGF and steroids for persistent diabetic macular edema compared to anti-VEGF alone. A meta-analysis was performed using a protocol registered in PROSPERO (CRD42023476333). Continuous and binary variables were extracted. Results were expressed as the mean difference (MD) and risk ratio (RR). Results: A total of 9 trials with 537 eyes were included. The MDs of improvement in best-corrected visual acuity (BCVA) at 1/2/3/6/9/12 months between the combined and monotherapy groups were 1.33 (95% CI [-1.31,3.96]), 3.03 (95% CI [0.01, 6.06]), -0.37 (95% CI [-4.74, 4.00]), -1.37 (95% CI [-4.65, 1.91]), 1.05 (95% CI [-3.68, 5.77]), and 1.70 (95% CI [-3.52, 6.93]). The MDs concerned with a central retinal thickness (CMT) decline in at 1/2/3/6/9/12 months between the two groups were -47.33, 95% CI [-94.35, -0.32]), -89.19 (95% CI [-114.38, -64.00]), -58.84 (95% CI [-96.93, -20.74]), -57.23 (95% CI [-102.62, -11.84]), -40.59 (95% CI [-80.59, -0.58]), and -38.89 (95% CI [-77.38, -0.40]), respectively. Furthermore, the combined group obtained higher relative risks of experiencing events with high intraocular pressure and progressed cataracts. Conclusions: Anti-VEGF combined with ocular steroids showed a significant advantage in improving the retinal anatomical structure compared to anti-VEGF monotherapy for persistent diabetic macular edema. However, as the treatment period extended, the combination treatment was no more effective than monotherapy after 2 months, with more severe side effects.

OXIDANTS AND BLOOD-RETINAL BARRIER: PROGRESSION AND MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY

Diabetic retinopathy is a microvascular complication of the eye that arises as a consequence of poor control of hyperglycemia in patients with diabetes mellitus. This condition is characterized by progressive damage to the blood vessels of the retina, leading to increased vascular permeability, microaneurysms, intraretinal hemorrhages and, in more advanced stages, neovascularization. Depending on its degree of progression, it can be classified into a non-proliferative form, more frequent in the initial stages, and a proliferative form, which appears in advanced stages and is associated with a higher risk of severe visual loss. Regarding its pathophysiology, chronic hyperglycemia triggers a series of harmful metabolic and molecular pathways, such as the accumulation of reactive oxygen species, which cause oxidative stress and jointly contribute to endothelial damage and dysfunction of the blood-retinal barrier. Patients with this complication require strict and continuous glycemic control using hypoglycemic drugs capable of reducing the osmolar disturbances characteristic of diabetes, combined with specific ocular therapies such as endothelial growth factor inhibitors, which slow down neovascularization and consequently reduce the likelihood of blindness. However, even with treatment protocols, diabetic retinopathy remains the leading cause of blindness in adults worldwide, underlining the importance of prevention and early diagnosis. This study was based on the bibliographic method, collecting scientific medical data from specialized journals such as PUBMED and Scielo published between 2018 and 2023. The results highlight the close relationship between hyperglycemic states and diabetic retinopathy. Thus, it is concluded that it is essential to develop new therapies that attack not only the advanced symptoms of the disease, but also the early molecular changes that occur during the early stages of diabetic retinopathy, effectively combating the cause and effect of the pathology.

Dose-, stage- and sex- difference of prenatal prednisone exposure on placental morphological and functional development

Prednisone, a synthetic glucocorticoid, is commonly used to treat autoimmune diseases in pregnant women. However, some studies suggest that the use of prednisone during pregnancy may lead to adverse pregnancy outcomes. In this study, we established PPE mouse models at different doses (0.25, 0.5, 1.0 mg/kg·d) and different stages (whole pregnancy, early pregnancy and middle-late pregnancy) and determined outcomes on the placenta and fetus. The results of our study indicated that at the highest dose of 1 mg/kg PPE using a GD 0–18 dosing regime, PPE caused placental morphological changes measured as a decrease in placental weight relative to controls and a decrease in the placenta junctional zone (JZ)/labyrinth zone (LZ) ratio. No changes were observed on the fetuses for number of live, stillborn, and absorbed fetuses between the experimental groups and the control group. In the placentas at some doses, there were decreases in cell proliferation markers measured at the RNA and protein level by Western blot and increased apoptosis. Measures of gene expression at the mRNA level showed altered nutrients (including glucose, amino acid, and cholesterol) transport gene expressions with the most significant change associated with the male placentas at high-dose and whole pregnancy PPE group. It was further found that PPE led to the inhibition of the insulin-like growth factor 2 (IGF2)/insulin-like growth factor 1 receptor (IGF1R) signaling pathway, which was well correlated with the indicators of cell proliferation, syncytialization and nutrient (glucose and amino acid) transport indices. In conclusion, PPE can alter placental morphology and nutrient transport function, with differences in effect related to dose, stage and gender. Differential gene expressions measured for genes of the IGF2/IGF1R signaling pathway suggested this pathway may be involved in the effects seen with PPE. This study provides a theoretical and experimental basis for enhancing the understanding of the effects of prednisone use on placenta during human pregnancy but does not currently raise concerns for human use as effects were not seen on the fetuses and while the effects on cell proliferation are informative they were inconsistent and the differential effects on female and male placentas unexplained suggesting that further work is required to elucidate if these findings have relevance for human use of PPE during pregnancy.

Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting

Fibrinolysis influences the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM). Here we show that activation of plasmin, a key fibrinolytic agent, by annexin A2 (ANXA2) distinctly impacts progression of BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via modulation of the extracellular matrix (ECM) in the BMM. The dense ECM in a BMM with decreased plasmin activity entraps insulin-like growth factor (IGF) 1 and reduces mTORC2-dependent signaling and proliferation of B-ALL cells. Conversely, B-ALL conditions the BMM to induce hepatic generation of plasminogen, the plasmin precursor. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, reduces tumor burden and prolongs survival, including in xenogeneic models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy.

Fibroblast growth factor receptor inhibitor-induced hyperphosphatemia: Lessons for the nephrologist.

Fibroblast growth factor inhibitors (FGFRi) are novel cancer drugs that offer new hope for patients with advanced biliary tract cancers and metastatic urothelial tumors. Despite their effectiveness, they often cause hyperphosphatemia. We investigated the incidence and characteristics of hyperphosphatemia in patients treated with FGFRi at Northwell Health, comparing findings with clinical trials and the FDA Adverse Event Reporting System database. 94% of patients in our series developed hyperphosphatemia, predominantly grade 2. The time-to-onset of hyperphosphatemia was longer than noted in clinical trials. Patients on erdafitinib showed a higher-than-expected incidence and grade of hyperphosphatemia. Collaboration between nephrologists and oncologists is crucial for optimizing treatment benefits and managing side effects. Further research is warranted to refine management strategies and to understand the clinical implications of hyperphosphatemia.

Computer Modeling of Bevacizumab Drug Distribution After Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action in the vitreous. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.

Outlier ophthalmologists in the treatment of neovascular age-related macular degeneration with intravitreal therapy

BackgroundTo compare individual ophthalmologists grouped as outliers or non-outliers based on the mean 12-month visual acuity (VA) outcomes for their patients with neovascular age-related macular degeneration (nAMD).MethodsThis prospectively designed database...