Unravelling the mosaic: Epigenetic diversity in glioblastoma.

Glioblastoma is the most common primary malignant brain tumour. Despite decades of intensive research in the disease, its prognosis remains poor, with an average survival of only 14 months after diagnosis. The remarkable level of intra- and interpatient heterogeneity is certainly contributing to the lack of progress in tackling this tumour. Epigenetic dysregulation plays an important role in glioblastoma biology and significantly contributes to intratumour heterogeneity. However, it is becoming increasingly clear that it also contributes to intertumour heterogeneity, which historically had mainly been linked to diverse genetic events occurring in different patients. In this review, we explore how DNA methylation, chromatin remodelling, microRNA (miRNA) dysregulation, and long noncoding RNA (lncRNA) alterations contribute to intertumour heterogeneity in glioblastoma, including its implications for advanced tumour stratification, which is the essential first step for developing more effective patient-specific therapeutic approaches.

EN FACE OPTICAL COHERENCE TOMOGRAPHY MORPHOLOGY OF MACULAR PUCKER CORRELATES WITH METAMORPHOPSIA: Possible Role of the Henle Fiber Layer.

PURPOSE: To describe macular pucker contraction patterns with en face optical coherence tomography (OCT), to provide a correlation with metamorphopsia scores, and to discuss the protective role of the Henle fiber layer (HFL) against tangential traction. METHODS: Retrospective, institutional, observational, and consecutive case series. Clinical charts, M-charts scores, and structural and en face OCT imaging of patients diagnosed with macular pucker were reviewed. RESULTS: A 120 eyes of 114 consecutive patients diagnosed with macular pucker were included. En face OCT patterns of macular pucker contraction were foveal in 51 of 120 eyes (42.5%) and extrafoveal in 69 of 120 eyes (57.5%). Foveal macular puckers had regular, a concentric, circle morphology in the HFL (46/51 eyes, 90.2%), whereas extrafoveal membranes had irregular, distorted, circular HFL morphology (62/69 eyes, 89.8%; P < 0.001). Foveal contraction morphology and regular HFL pattern, as well as extrafoveal contraction morphology and an irregular HFL pattern, highly correlated one with another (P < 0.001 in both cases). Foveal macular puckers with regular HFL patterns had significantly less vertical and horizontal M-charts scores as compared with extrafoveal membranes with irregular HFL (P < 0.001 in both cases). Ellipsoid zone and external limiting membrane defects were rare in the parafoveal region (5/120 eyes, 4.2%). Visual acuity did not correlate with metamorphopsia scores (P = 0.903). CONCLUSION: En face OCT imaging identifies macular pucker contraction patterns that correlate with metamorphopsia scores and that can be used alongside the current structural OCT staging system to guide clinicians in the surgical decision-making process.

Lineage specification in glioblastoma is regulated by METTL7B.

Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.

IMAGING RHEGMATOGENOUS RETINAL LESIONS AND PERIPHERAL VITREORETINAL INTERFACE WITH WIDEFIELD OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Analyze the peripheral vitreoretinal interface with widefield optical coherence tomography. METHODS: Retrospective chart analysis and widefield optical coherence tomography in 120 consecutive cases of rhegmatogenous pathology. RESULTS: There were 166 lesions in 120 eyes, including 106 horseshoe tears, 22 operculated holes, 30 nonoperculated holes, six giant tears, and two peripheral lamellar defects followed for 6.1 ± 1.2 months. Posterior vitreous detachment was present in all eyes (101/101, 100%) with tears and operculated holes, but only in 5/19 eyes (26.3%) with nonoperculated holes ( P < 0.001). Axial vitreous traction was evident at the anterior edge of horseshoe tears (106/106, 100%), but not the posterior border (18/106, 17%, P < 0.001). Operculated holes located posterior to the vitreous base were free from vitreous traction, displaying a morphology similar to the macular hole. Nonoperculated holes were farther anterior with signs of tangential traction in 23/30 (76.7%) cases. Peripheral vitreoschisis was more often associated with nonoperculated holes (25/30, 83.3%), than horseshoe tears (17/106, 16%; P < 0.001). Horseshoe tears and nonoperculated holes were more often associated with retinal detachment (58/106 [54.7%] and 15/30 [50%], respectively) than operculated holes (5/22, 22.7%), P = 0.023. CONCLUSION: Peripheral vitreoretinal interactions are similar to vitreomaculopathies, with axial and vitreoschisis-related tangential traction playing different roles in different rhegmatogenous pathologies. Peripheral optical coherence tomography improves understanding of pathophysiology and risks of retinal detachment.

Recovery of bacillary layer detachment associated with macula-off rhegmatogenous retinal detachment: Evidence of foveation mechanisms?

Purpose: To describe the mechanisms of postoperative foveal restoration in three patients with bacillary layer detachment (BALAD) associated with macula-off rhegmatogenous retinal detachment. Observations: BALAD associated with macula-off rhegmatogenous retinal detachment presented with two different morphologies: with an intact foveal roof (case 1) and lamellar, with an open foveal roof (cases 2 and 3). In case 1 visual acuity significantly improved and foveal morphology completely restored at postoperative month 6, with a marked increase in foveal thickness. Case 2 presented with a lamellar BALAD in a long-standing retinal detachment, and it was treated with scleral buckling with an unfavourable evolution into a full-thickness hole in the early postoperative period. It was then addressed with internal limiting membrane peeling and inverted flap, which resulted in the resolution of the lesion, but with limited postoperative visual and anatomical recovery. Case 3 lamellar BALAD was directly addressed with pars plana vitrectomy, ILM peeling and inverted flap, with a remarkable foveal anatomical restoration and visual acuity improvement over the follow-up period. Conclusions and importance: The process of foveation may play a key role in the healing process of BALAD associated with rhegmatogenous retinal detachment. Lamellar BALAD should be considered and treated as a FTMH associated with retinal detachment. The two BALAD subtypes may represent different clinical stages of the BALAD spectrum.

Early clonal extinction in glioblastoma progression revealed by genetic barcoding.

Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field.

Peripheral Intravascular Catheter-Assisted Sutureless Scleral Fixation of Three-Piece Intraocular Lenses: A Novel Technique.

PURPOSE: To describe and report the anatomical and functional outcomes of a novel sutureless peripheral intravascular catheter (PIVC)-assisted scleral fixation of three-piece IOL. METHODS: A retrospective chart review of all patients who underwent scleral fixation surgery performed by a single surgeon was conducted. In all cases, a novel scleral fixation technique of three-piece IOL was performed with the aid of a 24-gauge PIVC cannula. Patients were followed up at postoperative months 1, 3, and 6. RESULTS: Thirteen eyes of 12 patients were included in the analysis. Preoperatively, mean best-corrected visual acuity was 1.26 ± 0.82 LogMar (20/364 Snellen Equivalent), and it improved significantly at all follow-up endpoints being of 0.52 ± 0.25 LogMar at 1 month (20/66 Snellen Equivalent, P = 0.02), 0.4 ± 0.22 LogMar at 3 months (20/50 Snellen Equivalent, P = 0.007) and 0.37 ± 0.2 LogMar (20/47 Snellen Equivalent, P = 0.008) at 6 months postoperatively. No serious intraoperative or postoperative complications were registered. Postoperatively, there were no cases of conjunctival erosions. Over the follow-up period, in all the included cases, the IOL remained centered and stable. CONCLUSION: The PIVC-assisted scleral fixation technique may be a safe and reliable surgical option for secondary IOL placement in cases of insufficient capsular support.

Full-Thickness Macular Hole: Are Supra-RPE Granular Deposits Remnants of Photoreceptors Outer Segments? Clinical Implications.

PURPOSE: To describe the presence of specific morphological characteristics of idiopathic, full-thickness macular hole (MH) potentially influencing postoperative best corrected visual acuity (BCVA) and surgical outcomes. DESIGN: Retrospective, multicenter and interventional case series. METHODS: Clinical charts and multimodal imaging pictures of 149 eyes of 143 consecutive patients diagnosed with MH, treated surgically and with a minimum follow-up of 12 months, were reviewed. RESULTS: Supra-retinal pigment epithelium (RPE) granular deposits were diagnosed in 121 of 149 eyes (81.2%). A smooth morphology was identified in 58 of 149 eyes (38.9%), whereas a bumpy border was present 91 of 149 eyes (61.1%). Photoreceptor disruption was mainly located close to the MH aperture. In 8% of the included cases, preoperative anatomical progression from smooth to bumpy morphology was noted. The presence of supra-RPE granular deposits was a significant predictor of lower postoperative BCVA only in univariate analysis (P < .001). The presence of a bumpy border was significantly correlated with lower postoperative BCVA in both univariate and multivariate analysis (P < .001). BCVA gain was significantly lower in MH with bumpy borders (P < .001). A bumpy border was also significantly associated with poor postoperative anatomical restoration (P < .001). CONCLUSIONS: Supra RPE-granular deposits and a bumpy morphology may be indicators of photoreceptor disruption in MH. A bumpy morphology may suggest deeper and potentially irreversible photoreceptor damage, and may negatively influence both functional and anatomical recovery.

Presumed sympathetic ophthalmia following scleral buckling surgery: A case report and review of the literature.

PURPOSE: To report a case of presumed sympathetic ophthalmia (SO) following scleral buckling (SB) surgery and to discuss the possible pathogenesis of this condition by reviewing the current evidence on this subject. METHODS: Case report and narrative review of the literature; our case was imaged with spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA), fundus autofluorescence (FAF), fluorescein angiography (FFA) and indocyanine green angiography (ICGA). RESULTS: A 55-year-old man presented with a macula on rhegmatogenous retinal detachment which was treated with 360° SB surgery, subretinal fluid drain (SRFD), cryopexy and pneumoretinopexy. Due to failure of the primary surgery, a second procedure was performed the day after with the explant of the prior buckle and the implant of a wider circumferential element. At three months from surgery, the patient complained of severe bilateral vision loss. Multimodal imaging revealed bilateral, multi-focal exudative retinal detachments and choroidal swelling. A diagnosis of presumed SO was made and the patient was treated with a combination of steroid and immunosuppressive drugs. The clinical picture completely resolved at postoperative month 12. CONCLUSION: SO may be a rare complication of SB surgery. In our case, early recognition and prompt immunosuppressive treatment achieved good long-term clinical results.

The relation between violence exposure and conduct problems among adolescents: a prospective study.

This study tested the hypothesis that exposure to community violence, intimate partner violence, and child maltreatment independently contribute to the prediction of conduct problems over a 2-year period. Participants were a subsample of youth ages 12 to 17 years (N = 423) from the Patterns of Care study, which drew a stratified random sample of high-risk youth receiving services from public service sectors. Exposure to community violence significantly predicted conduct disorder and externalizing problems 2 years later when potential confounds were controlled. Child maltreatment predicted conduct disorder but not externalizing symptoms. Exposure to intimate partner violence was not related to either outcome. Exposure to community violence contributed to the development of conduct disorder and externalizing symptoms, even when exposure to child maltreatment or intimate partner violence was controlled. Results are discussed in terms of implications for treatment and prevention of youth conduct problems.