Cost-utility of ranibizumab versus aflibercept for treating Greek patients with visual impairment due to diabetic macular edema.

BACKGROUND: To conduct a cost-utility analysis of ranibizumab versus aflibercept for the treatment of patients with visual impairment due to diabetic macular edema (DME) in the Greek setting. METHODS: A Markov model was adapted to compare the use of ranibizumab 0.5 mg (pro re nata-PRN and treat and extend-T&E) to aflibercept 2 mg (every 8 weeks after five initial doses) in DME. Patients transitioned at a 3-month cycle among nine specified health states (including death) over a lifetime horizon. Transition probabilities, utilities, as well as DME-related mortality were extracted from relevant clinical trials, a network meta-analysis and other published studies. The analysis was conducted from payer perspective and as such only costs reimbursed by the payer were considered (year 2014). The incremental cost per quality-adjusted life year (QALY) gained and the net monetary benefit was the main outcome measures. RESULTS: Τhe use of PRN and T&E ranibizumab regimens were shown to be cost saving comparing to aflibercept (by €2824 and €22, respectively), and more beneficial in terms of QALYs gained (+0.05) and time without visual impairment (0.031 and 0.034 years), thereby dominating aflibercept. Moreover, ranibizumab used as PRN or T&E resulted in a net monetary benefit of €3984 and €1278, respectively. CONCLUSIONS: Both PRN and T&E ranibizumab regimens were more beneficial and less costly compared to aflibercept for the management of DME. Hence, ranibizumab seems to be a dominant option for the treatment of visual impairment due to DME in the Greek setting.

A Real-World, Multicenter, 6-Month Prospective Study in Greece of the Effectiveness and Safety of Ranibizumab in Patients with Age-Related Macular Degeneration Who Have Inadequately Responded to Aflibercept: The "ELEVATE" Study.

Purpose: Real-world evidence on short-term outcomes of ranibizumab in wet age-related macular degeneration (wAMD) following inadequate response to aflibercept is scarce. This study aimed to evaluate the functional and anatomic effects of switching to ranibizumab in cases of wAMD previously treated with aflibercept with inadequate response. Patients and Methods: Prospective, observational study performed in eight ophthalmology hospital/private clinics in Greece, enrolling consented patients with active wAMD, ≥50 years-old, who had initiated ranibizumab ≥28 days and <2 months after their last aflibercept injection. Data were collected at enrollment, and at 1, 3 and 6 months post-treatment onset (post-baseline). Results: Between September-2015 and November-2017, 103 eligible patients (56.3% females; mean age: 74.8±8.6 years) were consecutively enrolled. The age at AMD diagnosis in the study eye was 71.3±8.8 years. Aflibercept (median of 5 injections received over 11.3 months) had been discontinued for anatomical (in 69.9%) and/or functional (38.8%) reasons. At baseline (median: 24.3 months after wAMD diagnosis), choroidal neovascularization was occult in 69.1% of evaluable study eyes; 60.2% of the study eyes had pigment epithelial detachment (PED); 42.7% cysts; 21.4% fibrosis; 66.0% subretinal, and 59.2% intraretinal fluid. At 6 months post-baseline: a median of 3 ranibizumab injections (range: 1-6) had been received; the best-corrected visual acuity (BCVA)≥0 letter gain rate was 81.8%; the BCVA ≥15 letter gain rate was 17.0%; BCVA gain was 3.2 letters [mean increase: 3.2±10.0 letters; median: 0.0; p = 0.002]; PED greatest basal diameter (GBD; median: 1470.5 µm) also decreased (median decrease: 114.0 µm; p = 0.019). Baseline central retinal thickness (CRT; median: 312.0 µm) remained unchanged. One patient permanently discontinued ranibizumab due to adverse event occurrence, assessed as not causally related to ranibizumab. There were no ranibizumab-related adverse reactions. Conclusion: Six-month treatment with ranibizumab in aflibercept inadequate responders led to visual acuity and PED GBD improvements, with no statistically significant CRT change.

Recurrence-free Survival and Safety of Imatinib in Patients With Gastrointestinal Stromal Tumour (GIST) in Greece.

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.

A Multicenter, Cross-Sectional Study of the Incidence of Major Macular Diseases That Cause Visual Impairment and Require Therapeutic Intervention in Greece: The ADVICE Study.

PURPOSE: This multicenter, epidemiological, cross-sectional study aimed to estimate the annual cumulative incidence of major macular diseases that cause visual impairment and require therapeutic intervention in the routine care of Greece. METHODS: The study was carried out between December 2012 and May 2015 in 20 ophthalmology clinics. Over a one-year recruitment period per study site, all treatment naïve adult patients newly diagnosed with wet age-related macular degeneration, visual impairment due to diabetic macular edema or macular edema secondary to retinal vein occlusion requiring therapeutic management and who had not been diagnosed or treated for the same disease in the past were enrolled after providing informed consent. Study data were collected during the single study visit. RESULTS: A total of 1532 incident cases were enrolled. The estimated annual cumulative incidence of wet age-related macular degeneration, diabetic macular edema and macular edema secondary to retinal vein occlusion requiring therapeutic management was 0.82 [95% confidence interval (CI): 0.76, 0.88; n=723], 0.63 (95% CI: 0.58, 0.69; n=559), and 0.29 (95% CI: 0.25, 0.32; n=250) per 10,000 cases, respectively. CONCLUSION: The study provides estimates of the incidence of major macular diseases causing visual impairment and requiring treatment in outpatient hospital settings in Greece, indicating a considerable socioeconomic burden to the healthcare system.

Small tyrosine kinase inhibitors as key molecules in the expression of metalloproteinases by solid tumors.

Critical steps for cancer cell growth, migration, invasion, and metastasis are the interactions of extracellular matrix (ECM) molecules with cells, the disconnection of intercellular adhesion, and the degradation of ECM. The latter is mediated mainly by metalloproteinases (MMPs), the expression and activation of which is related to various tyrosine kinase receptors (RTKs). The aberrant RTK activity is associated with the development and progress of various human cancers. Tyrosine kinase inhibitors (TKIs) are small molecules which compete with ATP for binding to the kinase domain of the RTKs and have been used for the treatment of solid tumors. In this review, the recent advances of the effects of TKIs on MMPs expressed by solid tumors are presented.

Design, synthesis and cell growth inhibitory activity of a series of novel aminosubstituted xantheno[1,2-d]imidazoles in breast cancer cells.

A series of novel aminosubstituted xantheno[1,2-d]imidazole derivatives have been designed and synthesized and their antiproliferative activity has been evaluated against human breast MDA-MB-231 cell line. Among the tested compounds those bearing two basic side chains at 2- and 5-positions exhibited a strong dose-dependent antiproliferative activity. Increase of the size and basicity of the N-alkyl substituent resulted in amplification of the inhibitory activity.

Design, synthesis, and evaluation of the antiproliferative activity of a series of novel fused xanthenone aminoderivatives in human breast cancer cells.

Derivatives of two novel, structurally related heterocyclic ring systems, xantheno[3,4-d]imidazole and chromeno[4,3,2-c,d]imidazo[4,5-f]indazole, bearing aminoalkyl side chains, have been synthesized, and their antiproliferative activity has been studied against the aggressive human breast MDA-MB-231 cell line. The pyrazole-fused analogue 27a possesses a pronounced antiproliferative effect on the tested cell line, evident at 1 muM, and achieves an IC50 of 6.5 microM.

Design and synthesis of new pyranoxanthenones bearing a nitro group or an aminosubstituted side chain on the pyran ring. Evaluation of their growth inhibitory activity in breast cancer cells.

Some new 2,6-disubstituted pyrano- and 1,2-dihydropyrano[2,3-c]xanthen-7-ones have been synthesized and their antiproliferative activity has been evaluated against MDA-MB-231 breast cancer cells. The antiproliferative activity evaluation of the compounds provided evidence that a dimethylamino substituted side chain and the presence of 1,2 double bond play a key role in cell growth inhibition. Among the tested derivatives the 6-dimethylaminoethylamino-2-nitropyranoxanthenone analogue possessed a significant inhibitory effect in a wide range of concentrations.

Gonadotropin-releasing hormone analogues alter gene expression of metalloproteinases and their tissue inhibitors in human breast cancer epithelial cells.

Luteinizing hormone-releasing hormone (LHRH or GnRH) is not only produced by hypothalamus, but also by other normal and cancer tissues. GnRH peptide agonists and antagonists inhibit the proliferation of breast cancer cells, but their effect on the expression of metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) has not been studied despite the fact that growth and invasiveness of breast cancer cells in adjacent and distant sites is associated with the expression of MMPs. In the present study, the effects of [D-Leu6, desGly10]GnRH-NHEt (commercially available) and [D-Tic3, Deg6, desGlyl0]GnRH-NHEt on gene expression of MMPs and TIMPs in the breast cancer cell line MCF-7 were examined with semi-quantitative RT-PCR. Results showed that incubation of MCF-7 cells with 30 microM of the synthetic GnRH analogues for 48 h in serum-containing medium resulted in a decrease of MMP-9 expression and increase in MT1- and MT2-MMP mRNA levels. Furthermore, both synthetic analogues induced a significant decrease in TIMP-1 and TIMP-3 mRNA levels and increase in TIMP-2 mRNA levels. The impact of the observed changes on the expression of MMPs and TIMPs warrants further investigation on the effects of GnRH analogues on the invasiveness and metastatic potential of breast cancer cells.

Estradiol-estrogen receptor: a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cells.

Estrogens are related with the growth and development of target tissues and play a critical role in breast cancer progression. The effects of estrogens are mediated by the estrogen receptors ERalpha and ERbeta, which are members of the nuclear steroid receptor superfamily. To date, it is not known how these hormones elicit many of their effects on extracellular matrix molecules and how these effects can be connected with ER expression. For this purpose, the effect of estradiol on ER expression as well as on proteoglycan and metalloproteinase expression was studied. The effect of E2 on extracellular matrix molecule expression has been studied using ERalpha suppression in breast cancer cells. Our studies using ERalpha-positive MCF-7 cells show that estradiol affects the expression of syndecan-2, but not of syndecan-4, through ERalpha. Furthermore, the ability of estradiol to affect MMP-9 and TIMP-1 expression is connected with ERalpha status. Together, these data demonstrate the significant role of ERalpha on mediating the effect of estradiol on extracellular matrix molecules.