Combined WNT-activated deep-penetrating/plexiform melanocytoma: insights into clinicopathological and molecular characterization.

BACKGROUND: A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses. OBJECTIVES: To review the clinicopathological characteristics of combined DPMs and characterize the molecular profile of atypical and malignant forms. METHODS: The study included 51 patients with combined DPMs diagnosed at the Hospital Clinic of Barcelona and the University of Florence between 2012 and 2020. Clinical data, dermoscopy images (when available) and histological characteristics were reviewed. Immunohistochemistry for ß-catenin, LEF1, HMB45, Ki67, p16 and PRAME (preferentially expressed antigen in melanoma) was performed. Atypical forms underwent next-generation sequencing (NGS) panel analysis, including driver genes implicated in DPMs, TERT-promoter (p) mutations and the investigation of the 9p21 locus via fluorescence in situ hybridization. RESULTS: Among the 51 patients (32 females and 19 males, age range 4-74 years), 68% with available clinical data (15/22) were initially suspected of having melanoma. Except for one patient, complete excision resulted in no recurrences or metastases. One patient who had an incompletely excised combined DPM developed a lymph node melanoma metastasis 10 years later. In the 51 patients, 10 samples (20%) showed atypical histological features; 7 (14%) exhibited a significant loss of p16 expression; and 2 (4%) showed a high-proliferative index (Ki67 over 5%). NGS analysis in 11 patients revealed a double mutation BRAFV600E and exon 3 CTNNB1; no TERTp mutations were detected. CONCLUSIONS: Clinical suspicion of melanoma is common in combined DPMs, but malignant progression is infrequent in tumours lacking high-grade atypia or proliferation. These findings are congruent with the consideration of these lesions as intermediate-grade tumours or melanocytomas.

Transorbital Route to Intracranial Space.

The endoscopic superior eyelid transorbital approach has emerged as a notable and increasingly utilized surgical technique in recent years. This chapter presents an overview of the approach, tracing its historical development and highlighting its growing acceptance within the skull base community.Beginning with an introduction and historical perspective, the chapter outlines the evolution of the transorbital approach, shedding light on its origins and the factors driving its adoption. Subsequently, a comprehensive exploration of the anatomic bone pillars and intracranial spaces accessible via this approach is provided. Hence, five bone pillars of the transorbital approach were identified, namely the lesser sphenoid wing, the anterior clinoid, the sagittal crest, the middle cranial fossa, and the petrous apex. A detailed correlation of those bone targets with respective intracranial areas has been reported.Furthermore, the chapter delves into the practical application of the technique through a case example, offering insights into its clinical utility, indications, and limitations.

Endoscopic transorbital approach bone pillars: a comprehensive stepwise anatomical appraisal.

OBJECTIVE: The endoscopic superior eyelid transorbital approach has garnered significant consideration and gained popularity in recent years. Detailed anatomical knowledge along with clinical experience has allowed refinement of the technique as well as expansion of its indications. Using bone as a consistent reference, the authors identified five main bone pillars that offer access to the different intracranial targeted areas for different pathologies of the skull base, with the aim of enhancing the understanding of the intracranial areas accessible through this corridor. METHODS: The authors present a bone-oriented review of the anatomy of the transorbital approach in which they conducted a 3D analysis using Brainlab software and performed dry skull and subsequent cadaveric dissections. RESULTS: Five bone pillars of the transorbital approach were identified: the lesser sphenoid wing, the sagittal crest (medial aspect of the greater sphenoid wing), the anterior clinoid, the middle cranial fossa, and the petrous apex. The associations of these bone targets with their respective intracranial areas are reported in detail. CONCLUSIONS: Identification of consistent bone references after the skin incision has been made and the working space is determined allows a comprehensive understanding of the anatomy of the approach in order to safely and effectively perform transorbital endoscopic surgery in the skull base.

Systemic contribution of inflammatory mediators to the severity of diabetic and uveitic macular edema.

PURPOSE: To assess whether serum cytokine and growth factor levels are associated with diabetic macular edema (DME) and uveitic macular edema (UME) objective severity. METHODS: Cross-sectional observational study of 81 patients (1 eye/patient) with DME (n=48) and UME (n=33). Macular edema (ME) was defined upon central macular thickness (CMT) ≥ 300 µm on spectral domain optical coherence tomography (OCT). Serum samples were obtained from peripheral blood and IL-1ß, IL-6, IL-8, IL-10, MCP-1, TNF-α, and VEGF levels were determined by Luminex analysis. Main outcome measure was the correlation between mediators' levels and CMT and macular volume (MV) on OCT for ME cases. RESULTS: In DME, IL-6 levels were found to significantly correlate with MV (r=0.324; p=0.028) whereas in UME, IL-8 was significantly associated with both CMT (r=0.401; p=0.021) and MV (r=0.391; p=0.024). IL-8 independently correlated with CMT (ß=177.2; p=0.033) and MV (ß=3.17; p=0.008) in UME multivariate model. CONCLUSION: Peripheral blood IL-6 and IL-8 levels could play a role in the severity of DME and UME, respectively. IL-8 even seems to be independently associated with CMT and MV in UME cases. Such systemic implications could enforce DME and UME personalized diagnostic and therapeutic approaches.

Orbital TFE3-Rearranged Perivascular Epithelioid Cell Tumor: A Case Report and Review of the Literature.

ABSTRACT: Perivascular epithelioid cell tumors (PEComas) are infrequent mesenchymal neoplasms that have particular histological and immunohistochemical features. Only a few cases have been described in the eye and orbit. This report presents a 28-year-old man who consulted for a painless left orbital mass. With the presumptive diagnosis of cavernous hemangioma, a surgical excisional biopsy was performed. Histopathological examination showed a well-delimited tumor composed of epithelioid cells with an eosinophilic cytoplasm and oval nucleus. The tumor cells stained diffusely for HMB-45 and transcription factor E3 (TFE3) and were focally positive for actin. There was no reactivity to S100 or desmin. Genetic testing revealed a TFE3 rearrangement. Based on these results, an extremely rare orbital TFE3-rearranged PEComa was diagnosed. Although no recurrence was seen at last follow-up, a review of the literature shows experience is limited regarding orbital PEComas and their malignant potential. Further research is needed to establish management guidelines, their association with the tuberous sclerosis complex, and the role of genetic mutations such as TFE3 rearrangement.

Behavior of hyperreflective foci in non-infectious uveitic macular edema, a 12-month follow-up prospective study.

BACKGROUND: Hyperreflective foci have been described in OCT imaging of patients with retinal vascular diseases. It has been suggested that they may play a role as a prognostic factor of visual outcomes in these diseases. The purpose of this study is to describe the presence of hyperreflective foci in patients with non-infectious uveitic macular edema and evaluate their behavior after treatment. METHODS: We conducted a multicenter, prospective, observational, 12-month follow-up study. Inclusion criteria were age > 18 years and a diagnosis of non-infectious uveitic macular edema, defined as central macular thickness of > 300 µm as measured by OCT and fluid in the macula. Collected data included best corrected visual acuity, central macular thickness and the presence, number and distribution (inner or outer retinal layers) of hyperreflective foci. Evaluations were performed at baseline, and at 1, 3, 6, and 12 months after starting treatment. RESULTS: We included 24 eyes of 24 patients. The frequency of patients with ≥11 hyperreflective foci was 58.4% at baseline, falling to 20.8% at 12 months. Further, hyperreflective foci were observed in the outer retinal layers in 50% of patients at baseline and just 28.6% at 12 months. Mean LogMAR visual acuity improved from 0.55 (95% CI 0.4-0.71) at baseline to 0.22 (95% CI 0.08-0.35) at 12 months (p < 0.001). Mean central macular thickness decreased from 453.83 µm (95% CI 396.6-511) at baseline to 269.32 µm (95% CI 227.7-310.9) at 12 months (P < 0.001). Central macular thickness was associated with number (p = 0.017) and distribution (p = 0.004) of hyperreflective foci. CONCLUSIONS: We have observed hyperreflective foci in most of our patients with non-infectious uveitic macular edema. During follow-up and after treatment, the number of foci diminished and they tended to be located in the inner layers of the retina.

Endoscopic transorbital approach to the petrous apex: is orbital rim removal worthwhile for the exposure? An anatomical study with illustrative case.

OBJECTIVE: The endoscopic transorbital approach (ETOA) has been demonstrated to be a feasible ventral route to the petrous apex. Yet, it has been pointed to as a deep and narrow corridor for anterior petrosectomy; particularly, medialization of the instruments can become an issue when targeting the petroclival area. To overcome this limitation, an ETOA with orbital rim removal (ETOA-OR) has been suggested, but not de facto compared, with a transorbital approach without removal of the rim. This addition could augment the surgical exposure and freedom of movement when accessing the petrous apex area. METHODS: Five human cadaveric heads (10 sides) were dissected. First, anterior petrosectomy was performed via a conventional ETOA (without orbital rim removal). Second, en bloc removal of the orbital rim was performed, with enlargement of the orbital craniectomy and, subsequently, further drilling of the medial petrous apex. Qualitative and quantitative comparisons are provided. An illustrative surgical case is also shown. RESULTS: The transorbital route allowed the authors to perform an anterior petrosectomy in all specimens. The landmarks of bone removal are superposed onto those in the transcranial route. The ETOA-OR increased the volume of craniectomy (from 4.0 mL to 5.5 mL), the lateromedial angulation, and superoinferior angulation of the instruments within the petrous area. Thus, this approach improved the exposure of the medial petroclival area, allowing for an augmented petrosectomy (from 1.4 mL to 2.0 mL, 39.5% increase) and for increased maneuverability, both in the petrous area (from 44.1 cm2 to 76.5 cm2, 73.3% increase) and in the posterior fossa (from 20.2 cm2 to 52.0 cm2, 158% increase). The ETOA-OR was also pragmatically applied to treat a recurrent petroclival meningioma. Complete removal was achieved, the abducens nerve palsy improved, and the trigeminal neuralgia decreased in severity, yet still required medication. CONCLUSIONS: The authors provide the first formal anatomical comparison between the transorbital approach with preservation of the orbital rim and a transorbital approach with removal of the rim to access the petrous apex. In addition, an illustrative case is used as a proof of concept and feasibility. According to the authors' data, the ETOA-OR significantly improves surgical exposure and the surgeon's comfort in this deep region. The bony defect can be reconstructed to avoid cosmetic deformities, maintaining the minimally disruptive concept of transorbital surgery.

Neurophysiologic Monitoring of Oculomotor Nerves During Transorbital Surgery: Proof of Concept and Anatomic Demonstration.

BACKGROUND AND OBJECTIVES: Transorbital neuroendoscopic surgery (TONES) is continuously evolving and gaining terrain in approaching different skull base pathologies. The objective of this study was to present our methodology for introducing recording electrodes, which includes a new transconjunctival pathway, to monitor the extraocular muscle function during TONES. METHODS: A translational observational study was performed from an anatomic demonstration focused on the transconjunctival electrode placement technique to a descriptive analysis in our series of 6 patients operated using TONES in association with intraoperative neurophysiologic monitoring of the oculomotor nerves from 2017 to 2023. The stepwise anatomic demonstration for the electrode placement and correct positioning in the target muscle was realized through cadaveric dissection. The descriptive analysis evaluated viability (obtention of the electromyography in each cranial nerve [CN] monitored), security (complications), and compatibility (interference with TONES). RESULTS: In our series of 6 patients, 16 CNs were correctly monitored: 6 (100%) CNs III, 5 (83.3%) CNs VI, and 5 (83.3%) CNs IV. Spontaneous electromyography was registered correctly, and compound muscle action potential using triggered electromyography was obtained for anatomic confirmation of structures (1 CN III and VI). No complications nor interference with the surgical procedure were detected. CONCLUSION: The methodology for introducing the recording electrodes was viable, secure, and compatible with TONES.

Endoscopic Transorbital Approach to the Middle Fossa: Qualitative and Quantitative Anatomic Study.

BACKGROUND: The endoscopic superior eyelid transorbital route to the skull base is gaining progressive popularity in the neurosurgical community. OBJECTIVE: To evaluate the anatomy of the middle cranial fossa from this novel ventral perspective to reach the skull base through the transorbital route and to show limits for possible safe middle fossa drilling from the transorbital route. METHODS: Anatomic study was performed; 5 cadaveric specimens (ie, 10 sides) and 2 dry skulls (ie, 4 sides) were dissected. RESULTS: To obtain a functional result, there are boundaries that correspond to neurovascular structures that traverse, enter, or leave the middle fossa that must be respected: inferiorly, the lateral pterygoid muscle; medially, the Gasserian ganglion and the lateral border of the foramen rotundum; laterally, the foramen spinosum with the middle meningeal artery; superiorly, the lesser sphenoid wing; posteriorly, the anterior border of the foramen ovale. Average bone resected was 6.49 ± 0.80 cm3 which is the 63% of total middle fossa floor. The mean axial surgical length calculated was 3.85 cm (3.18-5.19 cm) while the mean sagittal surgical length was 5.23 cm (4.87-6.55 cm). The mean horizontal angle of approach was 38.14° (32.87°-45.63°), while the mean vertical angle of approach was 18.56° (10.81°-26.76°). CONCLUSION: Detailed anatomy of the middle cranial fossa is presented, and herewith we demonstrated that from the endoscopic superior eyelid transorbital approach removal of middle cranial fossa floor is possible when anatomic landmarks are respected.

Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema.

Purpose: To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME). Methods: Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) > 300 µm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1ß, IL-6, IL-8, IL-17, MCP-1, TNF-α, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3+CD4+FoxP3+ in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels. Results: Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67, 95% CI (0.45-1.00), P = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, 95% CI: 1.12-2.56, P = 0.049). Conclusions: Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.

Predictors for functional and anatomic outcomes in macular edema secondary to non-infectious uveitis.

AIMS: We aimed to investigate predictive factors for visual and anatomic outcomes in patients with macular edema secondary to non-infectious uveitis. MATERIAL AND METHODS: We conducted a multicenter, prospective, observational, 12-month follow-up study. Participants included in the study were adults with non-infectious uveitic macular edema (UME), defined as central subfoveal thickness (CST) of >300 µm as measured by spectral domain optical coherence tomography (SD-OCT) and fluid in the macula. Demographic, clinical and tomographic data was recorded at baseline, 1, 3, 6 and 12 months. Foveal-centered SD-OCT exploration was set as the gold-standard determination of UME using a standard Macular Cube 512x128 A-scan, within a 6 x 6 mm2 area, and the Enhanced High Definition Single-Line Raster. To assess favorable prognosis, the main outcomes analyzed were the best-corrected visual acuity (BCVA) and the CST. Favorable prognosis was defined as sustained improvement of BCVA (2 lines of gain of the Snellen scale) and CST (decrease of 20% of the initial value or <300 µm) within a 12 month period. RESULTS: Fifty-six eyes were analyzed. The number of eyes with sustained improvement in the CST was 48 (86.2%), against 23 (41.1%) eyes with sustained improvement in BCVA. Favorable prognosis, as defined above, was observed in 18 (32.1%) eyes. UME prognosis was negatively correlated with baseline foveal thickening, alteration in the vitreo-macular interface and cystoid macular edema. In contrast, bilaterally, systemic disease and the presence of anterior chamber cells were predictive of favorable prognosis. CONCLUSION: Available treatment modalities in UME may avoid chronic UME and improve anatomic outcome. However, the proportion of functional amelioration observed during 12 months of follow-up is lower. Thicker CST, alteration in the vitreo-macular interface and cystoid macular edema may denote less favorable prognosis. Conversely, bilaterally, systemic disease and anterior chamber cells may be associated with favorable prognosis in UME.

Peripheral blood metabolic and inflammatory factors as biomarkers to ocular findings in diabetic macular edema.

AIMS: To study the association between peripheral blood metabolic and inflammatory factors and presence of diabetic macular edema (DME) and its related anatomic features in type 2 diabetic mellitus (T2DM) patients. MATERIAL AND METHODS: Observational cross-sectional study on a proof of concept basis. Seventy-six T2DM included patients were divided based on the presence (n = 58) or absence of DME (n = 18) according to optical coherence tomography (OCT). Ultra-widefield fluorescein angiography (UWFA) was performed in DME patients. Fasting peripheral blood sample testing included glycemia, glycated hemoglobin, creatinin and lipid levels among others. Serum levels of a broad panel of cytokines and inflammatory mediators were also analysed. OCT findings included central subfoveal thickness, diffuse retinal thickness (DRT), cystoid macular edema (CME), serous retinal detachment and epirretinal membrane. UWFA items included pattern of DME, presence of peripheral retinal ischemia and enlarged foveal avascular zone (FAZ). RESULTS: Metabolic and inflammatory factors did not statistically differ between groups. However, several inflammatory mediators did associate to certain ocular items of DME cases: IL-6 was significantly higher in patients with DRT (p = 0.044), IL-10 was decreased in patients with CME (p = 0.012), and higher IL-8 (p = 0.031) and VEGF levels (p = 0.031) were observed in patients with enlarged FAZ. CONCLUSION: Inflammatory and metabolic peripheral blood factors in T2DM may not be differentially associated to DME when compared to non-DME cases. However, some OCT and UWFA features of DME such as DRT, CME and enlarged FAZ may be associated to certain systemic inflammatory mediators.

Interleukin-22 serum levels are elevated in active scleritis.

PURPOSE: To evaluate serum cytokine profile from patients with active scleritis in a two-centre prospective case-control study. METHODS: The serum of 20 active scleritis patients not treated with any local, periocular, or systemic immunomodulatory therapy (IMT) was analysed with multiplex assay to determine the levels of 11 cytokines interleukin (IL)-1ß, IL-6, IL-2, IFN-γ, IL-10, IL-12p40, IL-13, IL-17A, IL-5, TNF-α, and TNF-ß, and with ELISA to determine the levels of TGF-ß1, IL-22, and IL-23. Twenty-five age-matched healthy volunteers were used as controls. In a subgroup of 13 patients with active disease, a second serum sample was obtained when the disease was inactive and levels of IL-22 were determined. Serum IL-22 levels from patients with active scleritis were correlated with type of scleritis (non-necrotizing and necrotizing), degree of inflammation (0-4+ :≤2+ and >2+), and associated systemic disease. RESULTS: Serum levels of IL-22 were elevated in active scleritis patients compared to controls (6.41 ± 1.52 pg/ml versus 1.93 ± 0.39 pg/ml, p = 0.012) and significantly decreased after scleritis remission with the use of IMT (p = 0.005). There was no statistical association with scleritis type, degree of inflammation, or associated systemic disease. The serum levels of other cytokines were not significantly different from controls. CONCLUSION: In our study cohort, IL-22 serum levels were significantly elevated in active scleritis patients compared to controls and decreased significantly after remission. Our results suggest that IL-22, a T helper (Th) 17- and Th22- derived cytokine, may play a critical role in the physiopathology of scleritis.

Nonpenetrating deep sclerectomy as an effective treatment of glaucoma related to familial amyloid polyneuropathy.

PURPOSE: To present the clinical course and treatment by nonpenetrating deep sclerectomy (NPDS) of open-angle glaucoma secondary to familial amyloid polyneuropathy (FAP). PATIENTS AND METHODS: In a series of 10 patients with FAP in a tertiary ophthalmology center, 4 eyes of 3 patients required glaucoma filtration surgery and NPDS with implant, and local intraoperative mitomycin C application was performed. Intraocular pressure and anatomic bleb functionality were measured. We performed a retrospective review of data from medical charts of the 10 FAP patients, which included demographics, incidence and treatment of glaucoma, and previous vitrectomy. RESULTS: NPDS resulted in normalization of intraocular pressure in all 4 eyes. Ten eyes (6 patients) of the studied group underwent vitrectomy because of amyloid opacities, 7 eyes (4 patients) had glaucoma, 6 of the eyes with glaucoma were previously vitrectomized, and 4 of them subsequently required glaucoma surgery. CONCLUSIONS: NPDS is an effective treatment of FAP glaucoma. Previously vitrectomized eyes have a more severe course of glaucoma and more frequently require filtration surgery.