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Current Therapeutic Approaches for Graves' Orbitopathy - are Targeted Therapies the Future?

Graves' orbitopathy is an autoimmune disease of the orbit that most frequently occurs with Graves' hyperthyroidism. The occurrence of autoantibodies directed against the TSH receptor (TRAb) is of central importance for the diagnosis and pathogenesis. These autoantibodies are mostly stimulating, and induce uncontrolled hyperthyroidism and tissue remodelling in the orbit and more or less pronounced inflammation. Consequently, patients suffer to a variable extent from periocular swelling, exophthalmos, and fibrosis of the eye muscles and thus restrictive motility impairment with double vision. In recent decades, therapeutic approaches have mainly comprised immunosuppressive treatments and antithyroid drug therapy for hyperthyroidism to inhibit thyroid hormone production. With the recognition that TRAb also activates an important growth factor receptor, IGF1R (insulin-like growth factor 1 receptor), biological agents have been developed. Teprotumumab (an inhibitory IGF1R antibody) has already been approved in the USA and the therapeutic effects are enormous, especially with regard to the reduction of exophthalmos. Side effects are to be considered, especially hyperglycaemia and hearing loss. It is not yet clear whether the autoimmune reaction (development of the TRAb/attraction of immunocompetent cells) is also influenced by anti-IGF1R inhibiting agents. Recurrences after therapy show that the inhibition of antibody development must be included in the therapeutic concept, especially in severe cases.

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Real-world experience with trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer and HER2-positive gastric cancer: A retrospective study

Aim. To evaluate the effectiveness of trastuzumab deruxtecan in real-world practice in the Russian Federation.
 Materials and methods. We performed a retrospective analysis of clinical case series related to the use of trastuzumab deruxtecan (N=15) in the setting of a single clinical center, University Headache Clinic (Dr. Laskov's Clinic), as part of the program for the import of an unapproved drug as a life-saving measure. The overall survival, progression-free survival, and objective response rate were assessed, and individual real-world cases of drug efficacy were presented.
 Results. Objective response rates are comparable to those shown in large randomized trials. The median follow-up was 67 days; the 6-month overall survival was 70.1% (95% confidence interval [CI] 49.4–99.6%), and the 6-month progression-free survival was 52.1% (95% CI 29.9–90.6%). There were no significant complications associated with therapy; in particular, no events of interstitial lung disease were reported.
 Discussion. The real-world efficacy of trastuzumab deruxtecan was comparable to that in randomized clinical trials. However, at the level of individual clinical cases, slightly lower efficacy was noted in initially frailer patients (ECOG score 3). Also, it should be noted that the study included patients who had the opportunity to purchase an expensive drug and, therefore, had a social status different from the general population, which could affect the results of this study.
 Conclusion. The use of trastuzumab deruxtecan in real-world settings has demonstrated high efficacy and a good safety profile.

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Open Access
Unilateral intraindividual comparison and bilateral performance of a monofocal spherical and diffractive extended depth of field intraocular lens mix-and-match approach.

To evaluate the intraindividual visual performance of a spherical and extended depth of field (EDOF) IOL used in a mix-and-match approach. Single centre (tertiary care centre), retrospective consecutive case series. Included patients had uneventful cataract surgery with implantation of a spherical monofocal IOL (CT Spheris 204) in the dominant eye and a diffractive EDOF IOL (AT LARA 829) in the non-dominant eye. Monocular and binocular defocus curves and visual acuity at various distances were assessed. In addition, binocular reading speed, contrast sensitivity, and patient satisfaction using QOV, Catquest 9SF, and glare/halo questionnaires are reported. A total of 29 patients (58 eyes) were included. We observed significant intra-individual differences for monocular DCIVA, DCNVA, UIVA, and UNVA. There were no differences in monocular BCDVA or UDVA. The monocular defocus curves for the two IOLs significantly differed at defocus steps between -1.0 and -3.5 D. 93.10% of patients reported they would opt for the same combination of IOLs. Excellent uncorrected and corrected distance visual acuity was demonstrated in both groups. The mix-and-match approach described in this study yielded good intermediate vision and improved near vision with high-patient satisfaction.

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Neurofibromin 1 mutations impair the function of human induced pluripotent stem cell-derived microglia.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human microglia-like (hiMGL) cells heterozygous for three different NF1 gene mutations found in patients with NF1. Whereas all NF1-mutant and isogenic control hiMGL cells expressed classical microglia markers and exhibited similar transcriptomes and cytokine/chemokine release profiles, only NF1-mutant hiMGL cells had defects in P2X receptor activation, phagocytosis and motility. Taken together, these findings indicate that heterozygous NF1 mutations impair a subset of the functional properties of human microglia, which could contribute to the neurological abnormalities seen in children with NF1.

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Open Access
Needs and Satisfaction Analysis of Patients and Referring Physicians in an Outpatient Cataract Service.

To ensure efficient use of resources within outpatient services, constant patient flow is vital. This can be achieved by addressing the wishes and needs of all relevant stakeholders. The present study aims to show how the needs and present satisfaction of patients and referring physicians can be determined in the context of an outpatient cataract service. It presents the conclusions that can be drawn for the design of the service. To assess needs and satisfaction, we developed a patient questionnaire and a referring physician questionnaire. Promoters and detractors for referral were identified following the concept of the net promoter score, a market research instrument. 339 (38%) patients and 26 (45%) referring physicians of the main referring group answered the questionnaires. The most important characteristics for referring physicians were quality of treatment, patient satisfaction, and communication in case of queries as well as speed of sending the doctor's letter. When making their decision on a cataract centre, the patients prioritised professional reputation, previous experience with the clinic, and recommendation of their ophthalmologist as well as customary appointment scheduling. The two groups influence each other's recommendation or choice. Simultaneous analysis of patients and referring physicians is therefore essential. Overall, patients and referring physicians are highly satisfied with the cataract service of the university medical centre. Beyond that, however, various potentials for improvement could be identified. In summary, this report describes a comprehensive approach to assess needs and satisfaction of patients and referring physicians in an outpatient clinic trying to sustainably improve patient care.

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Radial peripapillary capillary density as a predictive factor for glaucoma in eyes with ocular hypertension. An observational, comparative, single-centred study.

Background: Ocular hypertension (OH) is a condition characterized by elevated intraocular pressure (IOP) exceeding the normal range, without any evident damage to the optic nerve or visual field defects characteristic of glaucoma. It constitutes a significant precursor to the development of glaucoma, a leading cause of irreversible vision loss worldwide. Emerging evidence has shown that microcirculation alterations in eyes with OH could serve as predicting factors to identify eyes at high risk for progression to glaucoma. In view of the above, the purpose of our study is to investigate microcirculation alterations of the radial peripapillary capillary plexus using optical coherence tomography angiography (OCT-A) in patients with ocular hypertension (OH). Methods: A total of 192 eyes were included in this observational, comparative, single-centre study and were divided in two groups: OH eyes and healthy controls. OCT-A was performed to analyze microcirculation characteristics at the peripapillary area. Radial peripapillary capillary density was measured at the total area of the optic disc and at each separate region (superior, inferior, inside). The parameters of age, medical treatment for ocular hypertension, sex and retinal fiber layer thickness were evaluated. Results: Total radial peripapillary capillary density was significantly lower in patients with OH than in healthy controls Concerning the microcirculation characteristics at each separate region of the peripapillary area, the results were as follows: inferior radial peripapillary capillary density was significantly decreased in individuals with OH than in controls, while measurements in the superior peripapillary area and internal optic disc were similar in both groups. Conclusions: Our study indicates decreased radial peripapillary capillary density in eyes with OH. Microcirculation alterations in the inferior peripapillary area could potentially comprise biomarkers for OH progression to glaucoma.

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Open Access