Growth Factor Inhibitors Research Articles

Longitudinal Systemic Bevacizumab Therapy Produces Cost Savings and Improves Quality-Adjusted Life Expectancy in the Care of Patients with Hereditary Hemorrhagic Telangiectasia with Moderate-to-Severe Bleeding

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is the second-most-common hereditary bleeding disorder worldwide, afflicting 1 in 5000 or 1.4 million persons. Unlike peer disorders hemophilia and von Willebrand disease, there are no FDA or EMA-approved therapies. The current standard-of-care (SOC) consists of red blood cell (RBC) transfusion, IV iron supplementation, and local hemostatic procedures (i.e., nasal, gastrointestinal). However, bleeding pathophysiology is amenable to vascular endothelial growth factor inhibition, and IV bevacizumab has shown great promise as a disease-modifying therapeutic. The multisite, international InHIBIT-Bleed study employed a pre- versus post-bevacizumab design and was the largest clinical study of HHT (n=238). InHIBIT-Bleed demonstrated that longitudinal systemic bevacizumab significantly improved clinical symptoms, raised hemoglobin levels, and nearly abrogated IV iron infusion and RBC transfusion need for patients with HHT. Although bevacizumab is an expensive biologic agent with a financial barrier to access, we hypothesized that reduction in health resource utilization and improvement in transfusion dependence will improve quality-of-life for patients with HHT at costs commensurate with added clinical value. Accordingly, we conducted the first cost-effectiveness analysis of bevacizumab therapy in HHT. Methods: For this independent analysis free of industry influence, we built a Markov simulation of adult patients with HHT to examine the cost-effectiveness of bevacizumab added to SOC versus SOC alone, over a lifetime time-horizon and across accepted willingness-to-pay (WTP) thresholds. Costs were assessed in 2023 US dollars. We employed study data for pre- and post-bevacizumab that included descriptive statistics for 1) hemostatic procedures, 2) hospitalizations, 3) emergency department visits, 4) RBC transfusions, and 5) iron infusions. Treatment-specific patient time and lost wages were also accounted for across IV infusions, emergency department visits, hospitalizations, and hemostatic procedures. Probabilities of RBC- and iron-related adverse events were sourced from hemovigilance reports, the 2015 National Blood Collection and Utilization Survey and 2008-2017 World Health Organization's VigiBase. Ferric carboxymaltose was used as the base-case iron supplement, and a scenario analysis examined ferumoxytol. Effectiveness was calculated in QALYs, and employed age-adjusted utilities derived using HHT-specific EQ-5D index values, with the 2019 Global Burden of Disease Study used to account for the degree of anemia improvement reported with bevacizumab. The primary outcome was the incremental cost-effectiveness ratio (ICER), or incremental net monetary benefit (iNMB) if intervention was found to be cost-saving. The secondary outcome was the aggregated patient time spent receiving HHT-specific care. We concluded by conducting deterministic and probabilistic sensitivity analyses, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations. Results: In the base-case, bevacizumab versus SOC cost $959,000 and $1,533,000 while accruing 24.1 and 21.8 QALYs, respectively. The iNMB with bevacizumab was $916,000 [95% credible interval $454,000-$1,994,000] and $1,004,000 [95% CI $473,000-$2,237,000] from the US health system and societal perspectives, respectively, at a WTP of $150,000/QALY. Bevacizumab also saves patients 125 hours per year lived. Deterministic sensitivity analysis revealed that no parameter variance changes the model result. In probabilistic sensitivity analysis bevacizumab was favored in 100.0% of 10,000 Monte Carlo iterations: saving cost with increased QALYs in 99.6% and cost-effective in the remaining 0.4% of iterations (Figure 1). Similar cost-savings were found in the scenario analysis with ferumoxytol. Conclusion: By reducing the need for hemostatic procedures, hospitalizations, emergency visits, RBC transfusions, and iron infusions, bevacizumab is, unusually, a cost-saving intervention that also improves the quality-adjusted life expectancy of patients with HHT. Bevacizumab also saves patient time spent on receiving HHT-specific care. Collecting long-term follow-up data to evaluate continued response to bevacizumab will help assess its value versus future advances in the care of patients with HHT.

Vascular Cell Adhesion Molecule-1 (VCAM-1) contributes to macular fibrosis in neovascular age-related macular degeneration through modulating macrophage functions

BackgroundNeovascular age-related macular degeneration (nAMD) is a major cause of blindness in the elderly. The disease is due to the growth of abnormal blood vessels into the macula, leading to the loss of central vision. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors (e.g., anti-VEGF) is the standard of care for nAMD. However, nearly 50% of patients do not respond or respond poorly to the therapy. More importantly, up to 70% of nAMD patients develop macular fibrosis after 10 years of anti-VEGF therapy. The underlying mechanism of nAMD-mediated macular fibrosis is unknown although inflammation is known to play an important role in the development of abnormal macular blood vessels and its progression to fibro-vascular membrane. In this study, we measured the intraocular levels of adhesion molecule VCAM-1, ICAM-1, CD44, CD62L, and CD62P in nAMD patients with and without macular fibrosis and investigated the link between the levels of adhesion molecule and clinical features (e.g., visual improvement, retinal thickness, etc.). We further investigated the effect of VCAM-1 in macrophage function in vitro and the development of subretinal fibrosis in vivo using a two-stage laser-induced protocol.ResultsThe aqueous levels of ICAM-1, VCAM-1, CD44, and CD62L were significantly higher in nAMD patients compared to cataract controls. The aqueous level of VCAM-1 (but not other adhesion molecules) was significantly higher in patients with macular fibrosis than those without and the level correlated positively with the retinal thickness. VCAM-1 was highly expressed at the lesion site in the mouse model of subretinal fibrosis. Blocking VCAM-1 or its receptor VLA-4 significantly prevented macrophage infiltration and reduced subretinal fibrosis in vivo. VCAM-1 induced macrophage migration and upregulated the expression of Arg-1, Mmp12 and Il6 but down-regulated the expression of iNOS and Il1b in macrophages.ConclusionsVCAM-1 may contribute to the development of macular fibrosis in nAMD patients by modulating macrophage functions, including migration and profibrotic polarization.

Role of mammalian target of rapamycin in the formation and progression of retinopathy of prematurity-like vascular abnormalities in neonatal rats

Retinopathy of prematurity (ROP), a retinal disease that can occur in premature infants, can lead to severe visual impairment. In this study, we examined the preventive and therapeutic effects of mammalian target of rapamycin complex 1 (mTORC1) inhibition on abnormal retinal blood vessels in a rat model of ROP. To induce ROP-like vascular abnormalities, rats were subcutaneously treated with KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on postnatal day 7 (P7) and P8. KRN633-treated (ROP) rats were treated subcutaneously with the mTORC1 inhibitor rapamycin according to preventive and therapeutic protocols, i.e., from P11 to P13 (P11–P13) and from P14 to P20 (P14–P20), respectively. To compare with the effects of VEGF inhibition, KRN633 was administered according to similar protocols. Changes in retinal vasculature, phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity, and the proliferative status of vascular cells were evaluated at P14 and P21 using immunohistochemistry. Rapamycin treatment from P11 to P13 prevented increases in arteriolar tortuosity, capillary density, and the number of proliferating vascular cells, and eliminated pS6 immunoreactivity in ROP rats. KRN633 treatment at P11 and P12 (P11/P12) also prevented the appearance of ROP-like retinal blood vessels. Rapamycin treatment from P14 to P20 failed to attenuate arteriolar tortuosity but prevented increases in capillary density and proliferating vascular cell number at the vascular front, but not at the central zone. KRN633 treatment from P14 to P20 significantly reduced abnormalities in the retinal vasculature; however, the effects were inferior to those of KRN633 treatment on P11/P12. These results suggest that activation of the mTORC1 pathway in proliferating endothelial cells contributes to the appearance and progression of ROP-like retinal blood vessels. Therefore, inhibition of mTORC1 may be a promising approach for selectively targeting abnormal retinal blood vessels in ROP.

Colorectal Cancer: Disease Process, Current Treatment Options, and Future Perspectives.

Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university's online library. The keywords were "Colorectal Cancer" AND "disease process" OR "disease mechanisms" OR "Current Treatment" OR "Prospects". Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low-medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin®), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux®) and panitumumab (Verbitix®). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells.

A mild catalyzed imino Diels-Alder reaction for the synthesis of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide derivatives as regulators of Quorum Sensing in Pseudomonas aeruginosa

Bacterial resistance is one of the major global public health problems. In addition, virulence factors promoted multiple drug resistance through cell-to-cell communications by molecules within microbial communities, denominated Quorum Sensing (QS). The regulation of QS by small molecules appears as a therapeutic alternative through the use of synthetic analogs of agonists. The present work developed the construction of a series of derivatives of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl) formamide (1a-h) via Povarov-type sequential reactions to deliver the tetrahydroquinoline (THQ) derivatives in moderate to good yields (24–78%). To evaluate the potential in molecular diversity of THQ-type autoinducers, a study of these agents as potential inhibitors of bacterial growth and virulence factors involved in QS systems on P. aeruginosa was carried out both as antibacterial evaluation on E. coli strain. THQs showed significant activity values for molecules with halogen substituents at the C-6 position (-F, -Cl, and I), revealing at a concentration of 75 µg/mL a percentage inhibition between 27 and 40%. Furthermore, autoinducers with halogen substitutes in phenotypic studies on P. aeruginosa showed good results. Also, they exhibited weak formation of both biofilm and low pyocyanin formation, which are indicators of virulence in P. aeruginosa. Overall, the results suggest that compound N-(6-fluor-2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide (1a) stands out as the most representative within this series of THQ derivatives.

NIMG-74. COMPARING VOLUMETRIC GROWTH-RATE AND RANO CRITERIA IN DETERMINING THE RESPONSE OF MENINGIOMA TO BEVACIZUMAB THERAPY

Abstract Meningioma is the most prevalent primary tumor in the central nervous system (CNS). Although mostly benign, 15- 20% are aggressive and tend to recur and progress despite surgery and adjuvant radiation. Recent publications show that bevacizumab, a vascular endothelial growth factor inhibitor, effectively treats these refractory meningiomas. The standard method to monitor treatment’s effect on imaging is Response Assessment in Neuro-Oncology criteria (RANO). Recently, an alternative tool called 3D volumetric growth rate (3DVGR) has emerged. Our aim is to compare the effectiveness of conventional RANO criteria and the 3DVGR measure in evaluating the response to bevacizumab treatment in patients with refractory meningiomas. We will also assess their correlation with clinical outcomes over a period of up to 9 months. 68 MRI scans of 20 patients with aggressive meningiomas treated with bevacizumab were evaluated. For each tumor both RANO and 3DVGR were conducted in two subsequent head MRI studies acquired prior to the initiation of bevacizumab treatment and then in at least one exam within 6 months post-treatment. Measurements were obtained using PACS and BRAIN LAB software by two radiologists. A total of 43 lesions derived from 20 patients were included in the analysis. The mean age was 65.5; mean number of radiation treatments was 2.66; mean number of pre-surgical treatments was 2.7 and mean number of bevacizumab cycles was 22.7. All lesions showed a decrease or stabilization in growth rate compared to baseline. More specifically, 34 out of 43 lesions (79%) showed a negative growth rate value indicating decrease in tumor size. Comparison of treatment response using RANO criteria was not always in concordance with the 3DVGR measurement and showed inaccurate correlation with clinical outcome. 3DVGR measure seems to be more precise compared to RANO criteria. Furthermore, our results show great promise for treatment of refractory meningiomas with bevacizumab.

Vascular Growth Factor Inhibition with Bevacizumab Improves Cardiac Electrical Alterations and Fibrosis in Experimental Acute Chagas Disease.

Chagas disease (CD) caused by Trypanosoma cruzi is a neglected illness and a major reason for cardiomyopathy in endemic areas. The existing therapy generally involves trypanocidal agents and therapies that control cardiac alterations. However, there is no treatment for the progressive cardiac remodeling that is characterized by inflammation, microvasculopathy and extensive fibrosis. Thus, the search for new therapeutic strategies aiming to inhibit the progression of cardiac injury and failure is necessary. Vascular Endothelial Growth Factor A (VEGF-A) is the most potent regulator of vasculogenesis and angiogenesis and has been implicated in inducing exacerbated angiogenesis and fibrosis in chronic inflammatory diseases. Since cardiac microvasculopathy in CD is also characterized by exacerbated angiogenesis, we investigated the effect of inhibition of the VEGF signaling pathway using a monoclonal antibody (bevacizumab) on cardiac remodeling and function. Swiss Webster mice were infected with Y strain, and cardiac morphological and molecular analyses were performed. We found that bevacizumab significantly increased survival, reduced inflammation, improved cardiac electrical function, diminished angiogenesis, decreased myofibroblasts in cardiac tissue and restored collagen levels. This work shows that VEGF is involved in cardiac microvasculopathy and fibrosis in CD and the inhibition of this factor could be a potential therapeutic strategy for CD.

Cardiovascular events following vascular endothelial growth factor inhibitor therapy with sunitinib or pazopanib in patients with renal cell carcinoma - a nationwide registry-based follow-up study

Abstract Background Use of oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) with focus on sunitinib and pazopanib approved for treatment of patients with renal cell carcinoma (RCC) may be associated with cardiovascular events. However, there are limited data on the risk related to treatment with sunitinib or pazopanib. Purpose The aim of this study was to examine the risk of cardiovascular events in patients with RCC treated with sunitinib and pazopanib compared with age- and sex-matched population control subjects without cancer (1:2 ratio). Methods Patients with RCC treated with sunitinib or pazopanib from 2011 through 2018 were identified within the Danish National Patient Registry. Multivariable Cox regression standardized to the age, sex, selected comorbidity and pharmacotherapy distributions of all included subjects were used to derive absolute one-year risks of selected cardiovascular events. Results A total of 3,642 patients were included in the analysis, of whom 1,214 had RCC treated with sunitinib or pazopanib, and 2,428 were population control subjects without cancer. Differences in age, sex, prior acute coronary syndrome (ACS), chronic obstructive pulmonary disease, and peripheral artery disease were insignificant (all P>0.05), whereas patients with RCC more frequently had prior hypertension (51.2% vs. 35.2%), diabetes (17.1% vs. 10.3%), and transient ischemic attack (TIA) or stroke (7% vs. 4.5%), all P<0.05. Absolute risk of ACS was 1.4% for patients with RCC vs. 1.0% for controls (P=0.54), stroke/TIA 1.7% vs. 0.8% (P=0.10), and ventricular arrhythmia 0.3% vs. 0.1% (P=0.70). In contrast, risk of hypertension was significantly elevated with 50.7% vs. 41.8% for patients with RRC vs. controls (P<0.001), and this risk was similarly elevated when excluding patients with prior hypertension (30.7% vs. 5.4%, P<0.001). Similarly, risks of atrial fibrillation or flutter (AF) with 5.6% vs. 2.8% (P<0.001) and heart failure (HF) with 0.7% vs. 0.3% (P<0.001) were significantly elevated in patients with RCC versus controls.Risk of venous thromboembolism (VTE) was 5.6% vs. 0.9% (P<0.001) for patients with RCC versus controls. All-cause mortality risk was 40.1% vs. 2.6% (P<0.001). The corresponding relative risks for one-year outcomes are shown in Figure 1. Conclusions Patients with RCC treated with sunitinib or pazopanib did not have a significantly higher risk of ACS, stroke/TIA or ventricular arrhythmia when compared to age- and sex-matched controls. In contrast, risks of hypertension, AF, HF, and VTE at 1 year compared with population control subjects were significantly elevated. Risk of HF risk was however limited in absolute numbers and the clinical significance of the evaluated risk of this endpoint as well as other endpoints should be interpreted in the context of a significantly high 1-year mortality risk of around 40% in patients with RCC versus only around 2.5% in population controls.Figure 1

Proteome Analysis of Bevacizumab Intervention in Experimental Central Retinal Vein Occlusion.

Bevacizumab is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the management of macular edema in central retinal vein occlusion (CRVO). Studying retinal protein changes in bevacizumab intervention may provide insights into mechanisms of action. In nine Danish Landrace pigs, experimental CRVO was induced in both eyes with argon laser. The right eyes received an intravitreal injection of 0.05 mL bevacizumab (n = 9), while the left control eyes received 0.05 mL saline water (NaCl). Retinal samples were collected 15 days after induced CRVO. Label-free quantification nano-liquid chromatography-tandem mass spectrometry identified 59 proteins that were regulated following bevacizumab treatment. Following bevacizumab intervention, altered levels of bevacizumab components, including the Ig gamma-1 chain C region and the Ig kappa chain C region, were observed. Changes in other significantly regulated proteins ranged between 0.58-1.73, including for the NADH-ubiquinone oxidoreductase chain (fold change = 1.73), protein-transport protein Sec24B (fold change = 1.71), glycerol kinase (fold change = 1.61), guanine-nucleotide-binding protein G(T) subunit-gamma-T1 (fold change = 0.67), and prefoldin subunit 6 (fold change = 0.58). A high retinal concentration of bevacizumab was achieved within 15 days. Changes in the additional proteins were limited, suggesting a narrow mechanism of action.

A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer

BackgroundAlthough different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers. ObjectiveTo evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer. Design, setting, and participantsWe conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy. InterventionPatients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results and limitationsCohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3–4 and no grade 5 events. ConclusionsThe first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC. Patient summaryWe conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

P2 X 7 receptor is a critical regulator of extracellular ATP-induced profibrotic genes expression in rat kidney: implication of transforming growth factor-β/Smad signaling pathway

This study was designed to investigate the potential of extracellular adenosine 5′-triphosphate (ATP) via the P2 X 7 receptor to activate the renal fibrotic processes in rats. The present study demonstrates that administration of ATP rapidly activated transforming growth factor-β (TGF-β) to induce phosphorylation of Smad-2/3. Renal connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA and protein expressions were also increased following ATP administration. A decrease in TGF-β amount in serum as well as renal Smad-2/3 phosphorylation was noticed in animals pre-treated with the specific antagonist of P2 X 7 receptor, A 438,079. In addition, a significant reduction in mRNA and protein expression of CTGF and TIMP-1were also observed in the kidneys of those animals. Collectively, the current findings demonstrate that ATP has the ability to augment TGF-β-mediated Smad-2/3 phosphorylation and enhance the expression of the pro-fibrotic genes, CTGF and TIMP-1, an effect that is largely mediated via P2 X 7 receptor.

Bevacizumab combined with platinum-based chemotherapy in primary or relapsed ovarian cancer patients: Meta-analysis and literature to review.

Earlier, patients with advanced ovarian cancer were treated with a combination of cytoreductive surgery and platinum-based chemotherapy, which had significant outcomes in the past until an increase in relapse and resistance to treatment, which led to the use or development of bevacizumab (a vascular endothelial growth factor inhibitor) in the treatment of primary or relapsed ovarian cancer. This study includes five-phase three randomized controlled clinical trials designed to study the impact of bevacizumab in combination with platinum-based chemotherapy compared with platinum-based chemotherapy alone. This study demonstrated significant improvement in the progression-free span but no improvement in overall survival in the treatment group when compared with the control group. Also, adverse effects reported with combination therapy were tolerable and easily manageable by decreasing the infusion rate or by decreasing the frequency of infusion.

Management of Central and Peripheral Nervous System Tumors in Patients with Neurofibromatosis.

Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.

AAV2-antiVEGFscFv gene therapy for retinal neovascularization

Retinal neovascularization (NV) may lead to irreversible vision impairment, the main treatment for which is the inhibition of vascular endothelial growth factor (VEGF). Existing drugs show limited clinical benefits because of their high prices and short half-lives, which increase the financial burden and medical risks to patients. Gene therapy on the basis of adeno-associated viruses is a promising approach to overcome these limitations because ofthe nonintegrative nature, low immunogenicity, and potential long-term gene expression of adeno-associated viruses. In this study, we constructed a novel recombinant adeno-associated virus with the single-chain fragment variable (scFv) fragment ofthe anti-VEGF antibody, AAV2-antiVEGFscFv, consisting ofthe VH and VL structural domains of IgG. AAV2-antiVEGFscFv effectively inhibited NV, retinal leakage, and retinal detachment in oxygen-induced retinopathy (OIR) mice, Tet/opsin/VEGF double-transgenic mice, and VEGF-induced rabbit NV models. AAV2-antiVEGFscFv also significantly suppressed VEGF-induced inflammation. Furthermore, we showed that AAV2-antiVEGFscFv could be sustainably expressed for a prolonged period and exhibited low immunotoxicity invivo. This study indicates that AAV2-antiVEGFscFv could be a potential approach for NV treatment and provides strong support for preclinical research.

In Vitro Cytotoxic Potential of Ethanol Extract of Dictyopteris acrostichoides Against Human Cancer Cells

AbstractEthanol extracts of Caulerpa racemose (Forsskål) J.Agardh, 1873, Dictyopteris acrostichoides (J.Agardh) Bornet, 1885, Halimeda opuntia (Linnaeus) J.V.Lamouroux, 1816, and Polycladia myrica (S.G.Gmelin) Draima, Ballesteros, F.Rousseau & T.Thibaut, 2010, were tested for their cytotoxicity against human hepatoma, human breast adenocarcinoma, and human colon adenocarcinoma cell lines. Dictyopteris acrostichoides displayed cytotoxicity against human hepatoma, human breast adenocarcinoma, and human colon adenocarcinoma with IC50 values of 11.65, 9.28, and 16.86 µg/ml, respectively, in comparison to doxorubicin as a positive control (IC50 5.72, 5.17, and 5.81 µg/ml, respectively). Metabolic profiling of the D. acrostichoides extract characterized seventeen metabolites. In silico analysis indicated 1-(3-oxo-undecyldisulfanyl)-undecan-3-one was the most active epidermal growth factor receptor inhibitor, while 1-(3-oxo-undecyldisulfanyl)-undecan-3-one and di(3-acetoxy-5-undecenyl) disulfide were the most active vascular endothelial growth factor inhibitors. Furthermore, the ethanol extract of D. acrostichoides was tested against epidermal growth factor receptor kinase (IC50 0.11 µg/ml) compared to lapatinib as a positive control (IC50 0.03 µg/ml), and against vascular endothelial growth factor (IC50 0.276 µg/ml) compared to sorafenib as a positive control (IC50 0.049 µg/ml). Graphical Abstract

Twenty-four-month real-life treatment outcomes of polypoidal choroidal vasculopathy versus type 1 macular neovascularization in Caucasians.

To compare 24-month real-world outcomes of Vascular Endothelial Growth Factor (VEGF) inhibitors for Polypoidal Choroidal Vasculopathy (PCV) and type 1 Macular Neovascularization (MNV) in a Caucasian population. Retrospective analysis from a prospectively designed observational database. Data from Italian centres participating in the Fight Retinal Blindness! (FRB!) project were collected. Treatment-naïve PCV or type 1 MNV commencing treatment after January 2009 were included. The primary outcome was 24-month visual acuity (VA) change; other outcomes included baseline characteristics, number of anti-VEGF injections, time to lesion inactivation and proportion of active visits. A total of 322 eyes (114 PCVs) from 291 patients were included. Median [Q1, Q3] VA at baseline was comparable (70 [55, 75.8] vs. 70 [58.8, 75] letters, p = 0.95). Adjusted VA change at 2 years was higher in PCV (mean [95% CI], +1.2 [-1.6, 4.1] vs. -3.6 [-6, -1.2] letters, p = 0.005). PCV received fewer anti-VEGF injections over the first 24 months of treatment than type 1 MNV (median [Q1, Q3], 8 [5, 10] vs. 9 [7, 12.2] injections, p = 0.001), inactivated earlier (median [Q1, Q3], 235 [184, 308] vs. 252 [169, 343] days, p = 0.04) and was less frequently graded 'active' (62% vs. 68% of visits, p = 0.001). PCV had slightly better VA outcomes over 24 months of treatment than type 1 MNV after receiving less anti-VEGF injections. These results suggest a possible overlap of the two clinical entities with similar visual prognosis in Caucasians.

Retraction of cystoid macular edema from the fovea after intravitreal anti-VEGF therapy for birdshot chorioretinopathy.

To report the effect of anti-vascular endothelial growth factor inhibitor (anti-VEGF) on fovea-involving cystoid macular edema in a patient with Birdshot chorioretinopathy. A 42-year-old male patient presented to our hospital with bilateral posterior uveitis with retinal vasculitis, cystoid macular edema and optic disc edem a. He was diagnosed with birdshot chorioretinopathy based on clinical appearance and tissue type HLA-A29. The patient underwent vitrectomy in the right eye without any change in visual acuity. Retinal leakage was reduced by oral prednisolone, which could not be tapered below 50 mg per day without relapse. Oral prednisolone, topical dexamethasone and subtenonal kenalog were associated with intraocular pressure rise in both eyes. Hence, his uveitis responded to steroids, but there was no detectable effect of any steroid-sparing immunomodulatory drugs. The patient had been on oral prednisolone 50 mg for five years when it was decided to attempt intravitreal VEGF inhibitor injection therapy. The anti-VEGF therapy diminished cystoid macular edema in the fovea and improved the visual acuity. Here we report for the first time the long-term outcomes of anti-VEGF injections on fovea-involving cystoid macular edema in Birdshot chorioretinopathy to keep steroid at the minimal possible doses and preserve a satisfying visual acuity level.

Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma

Background & aimsCombination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME).MethodsWe established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database.ResultsThe number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells.ConclusionsIn this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

Periocular and ocular surface nonmelanoma skin cancer

Periocular and ocular surface nonmelanoma malignancies, including basal cell carcinoma (BCC), squamous cell carcinomas (SCC), and ocular surface squamous neoplasia (OSSN), are rare, but their management requires special considerations. The most common periocular malignancy is BCC, which constitutes 80% to 96% of tumors, followed by SCC, which represents 5% to 10% of tumors. OSSN represents a spectrum of diseases that encompass dysplastic alteration to the squamous epithelium of the eye. OSSN ranges from squamous dysplasia to conjunctival intraepithelial neoplasia/carcinoma in situ to invasive SCC, which is the most common ocular malignancy. These tumors can be staged using the eighth edition of the American Joint Committee on Cancer categorization system. The standard of care for periocular malignancies is Mohs micrographic surgery, while medical management with 5-fluorouracil (5-FU), interferon alfa-2b (INF), and mitomycin C (MMC) or “no touch” surgical excision are options for OSSN. Systemic therapies, including sonic hedgehog inhibitors for BCC and epidermal growth factor inhibitors and immune-checkpoint inhibitors for SCC, can be utilized for advanced disease. Recurrence rates are higher for periorbital and ocular malignancies than their respective cutaneous counterparts. These carcinomas and their respective treatments have unique side effects and considerations in an effort to preserve visual function.

Genomic and Molecular Characteristics of Ovarian Carcinosarcoma.

Ovarian carcinosarcoma (OCS) is a rare malignancy with a poor prognosis. It is a biphasic tumor with malignant epithelial and mesenchymal components. A few mutations commonly seen in cancer have been identified in OCS, including TP53, PIK3CA, c-myc, ZNF217, ARID1A, and CTNNB1. Some OCS tumors have shown vascular endothelial growth factor positivity and limited HER2 expression. There is evidence of homologous recombination deficiency in OCS. This malignancy can be categorized as copy number high but has not been shown to have a high tumor mutational burden. There are mixed findings regarding the presence of biomarkers targeted by immune checkpoint inhibitors in OCS. For treatments other than systemic chemotherapy, the data available are largely based on in vitro and in vivo studies. In addition, there are case reports citing the use of poly-ADP ribose polymerase inhibitors, vascular endothelial growth factor inhibitors, and immunotherapy with varying degrees of success. This review paper will discuss the molecular and genomic characteristics of OCS, which can guide future treatment strategies.