Systemic Arterial and Venous Thrombotic Events Associated With Anti-Vascular Endothelial Growth Factor Injections: A Meta-Analysis.

PURPOSE: To compare the risk of systemic arteriovenous thrombotic events between intravitreal anti-vascular endothelial growth factor (anti-VEGF) and sham injections. DESIGN: Random-effects meta-analysis. METHODS: A systematic search was performed on OVID MEDLINE, Embase, and Cochrane Library from January 2005 to August 2023. Our inclusion criteria were randomized controlled trials (RCTs) reporting on systemic arteriovenous events for standard dose intravitreal anti-VEGF agents for any indication. RESULTS: A total of 20 RCTs reporting on 12,833 eyes were included. There was no significant difference in the risk of any thrombotic event between bevacizumab 1.25 mg and ranibizumab 0.5 mg (Risk ratio (RR) = 0.96, 95% CI = 0.52-1.75, P = .89). There was no significant difference between bevacizumab and ranibizumab when restricting to arterial thrombotic events (RR= 0.88, 95% CI = 0.60-1.30, P = .53) or venous thrombotic events (RR = 1.99, 95% CI =86 0.68-5.82], P = .21). The risk of arterial thrombotic events was similar between aflibercept and bevacizumab (RR = 1.11, 95% CI = 0.60-2.07, P = .74), between aflibercept and ranibizumab (RR= 0.77, 95% CI = 0.49-1.21, P = .26), between brolucizumab and aflibercept (RR= 0.67, 95% CI = 0.32-1.38, P = .27), and between aflibercept and faricimab (RR = 0.96, 95% CI = 0.43-2.17, P = .93). Compared to sham, neither dose of ranibizumab (0.5 mg or 0.3 mg) showed a higher risk of arterial thrombotic events. CONCLUSIONS: There was a similar risk of systemic arteriovenous thrombotic adverse events between anti-VEGF agents and between ranibizumab and sham injections.

The Leading Causes of Optic Disc Edema Seen in Tertiary Care, Academic Neuro-Ophthalmology Clinics.

BACKGROUND: Optic disc edema (ODE) is one of the most common reasons for referral to a neuro-ophthalmologist. There are various causes that require vastly different workup. Thus, differentiating among each cause is important. Our goal was to determine the causes of ODE and various clinical characteristics of consecutive patients with ODE presenting to neuro-ophthalmology clinics. METHODS: A retrospective review of consecutive patients with ODE over a period of 5 years were included. Fundus photographs were routinely obtained as part of clinical care. Clinical data including retinal nerve fiber layer thickness, best-corrected visual acuity, and visual field mean deviation were retrieved, and patients were grouped by etiology. RESULTS: A total of 654 patients (n = 462 or 70.6% women and 192 or 29.4% men) with ODE were included with a mean age of 41.2 ± 17.9 years. Female patients were significantly younger than male patients (mean age female participants: 38.7 years, male participants: 47.6; P < 0.001). The top 5 most common causes of ODE in our clinics were idiopathic intracranial hypertension (IIH; 351/654 or 53.7%), nonarteritic anterior ischemic optic neuropathy (NAION; 116/654 or 17.4%), non-IIH papilledema (71/654 or 10.9%), optic neuritis (ON; 46/654 or 7.0%), and uveitis (17/654 or 2.6%). When considering female-only patients, the top 3 causes of ODE were IIH, non-IIH papilledema, and NAION. Among male-only patients, the top 3 causes were NAION, IIH, and non-IIH. Among the top 5 causes of ODE, visual acuity was the worst at presentation in the ON group and the best in the patients with IIH. The Humphrey mean deviation was the worst in ON/NAION groups and best in IIH group. The ODE was most severe in patients with non-IIH papilledema and least severe in ON group. Non-IIH patients with papilledema were not significantly different in visual acuity and visual field parameters at presentation compared with patients with IIH papilledema. Patients with papilledema (both IIH and non-IIH etiologies) had significantly better visual function at presentation compared with other top causes of disc edema (P < 0.001). CONCLUSIONS: The most common cause of ODE seen in neuro-ophthalmology clinics was IIH, and these patients were more likely to present with preserved visual function. The higher prevalence of IIH was likely why most patients with ODE were women. Visual function at presentation was not able to differentiate the specific cause of papilledema; however, it was an important differentiating factor for all papilledema cases compared with all other causes of ODE including ON and NAION.

Current Status of Cancer Genomics and Imaging Phenotypes: What Radiologists Need to Know.

Ongoing discoveries in cancer genomics and epigenomics have revolutionized clinical oncology and precision health care. This knowledge provides unprecedented insights into tumor biology and heterogeneity within a single tumor, among primary and metastatic lesions, and among patients with the same histologic type of cancer. Large-scale genomic sequencing studies also sparked the development of new tumor classifications, biomarkers, and targeted therapies. Because of the central role of imaging in cancer diagnosis and therapy, radiologists need to be familiar with the basic concepts of genomics, which are now becoming the new norm in oncologic clinical practice. By incorporating these concepts into clinical practice, radiologists can make their imaging interpretations more meaningful and specific, facilitate multidisciplinary clinical dialogue and interventions, and provide better patient-centric care. This review article highlights basic concepts of genomics and epigenomics, reviews the most common genetic alterations in cancer, and discusses the implications of these concepts on imaging by organ system in a case-based manner. This information will help stimulate new innovations in imaging research, accelerate the development and validation of new imaging biomarkers, and motivate efforts to bring new molecular and functional imaging methods to clinical radiology. Keywords: Oncology, Cancer Genomics, Epignomics, Radiogenomics, Imaging Markers Supplemental material is available for this article. © RSNA, 2023.

The Causes of Optic Disc Edema in Patients Presenting With Significantly Compromised Vision.

BACKGROUND: To evaluate the most common causes of optic disc edema (ODE) in patients with significantly compromised vision (initial best-corrected visual acuity [BCVA] of 20/400 or worse) at presentation. METHODS: Retrospective chart review over a 5-year period of consecutive patients presenting to tertiary neuro-ophthalmology clinics at the University of Toronto. RESULTS: A total of 656 patients with ODE were included, and 49 patients (7.47%) had an initial BCVA of 20/400 or worse. There were 54 eyes included at baseline and 49 eyes at final follow-up. There were 29 female and 20 male patients. The mean age at first visit across patients was 55.9 years. Female patients (n = 29) were significantly older than male patients (n = 20) (P < 0.05). The causes of ODE were optic neuritis (ON) (n = 22; 40.7%), nonarteritic anterior ischemic optic neuropathy (NAION) (n = 22; 40.7%), arteritic anterior ischemic optic neuropathy (AAION) (n = 5; 9.26%), uveitis-related (n = 3; 5.56%), papilledema from idiopathic intracranial hypertension (IIH) (n = 1; 1.85%), and Vogt-Koyanagi-Harada disease (n = 1; 1.85%). Initial BCVA was not significantly different between ON and NAION groups (P = 0.52); however, final BCVA was significantly better in the ON group (P < 0.0001). The mean initial BCVA was worst in the AAION group (2.62 ± 0.54 logarithm of the minimum angle of resolution). The most common cause of ODE in patients <40 years old was ON (83.3%), whereas the 2 most common causes in patients >80 were NAION (60%) and AAION (40%). In patients between the ages of 60-80, NAION (100%) was the only cause. CONCLUSIONS: Patients with ODE and poor vision at presentation represent a minority of cases seen in neuro-ophthalmology clinics (<10%). Optic neuritis and NAION are the 2 most common causes of ODE with poor vision at presentation. These findings are limited by a small sample size and potential sampling bias.

Pathophysiology of Secondary Macular Hole in Rhegmatogenous Retinal Detachment.

Purpose: To describe the pathophysiology of secondary macular hole (MH) in rhegmatogenous retinal detachment (RRD). Methods: A retrospective cohort of 360 consecutive primary fovea-off RRDs presenting to St. Michael's Hospital, Toronto, from January 2012 to September 2022 were included. Preoperative OCT was assessed for bacillary layer detachment (BALAD) abnormalities. Histological sections of normal eyes were assessed to inform OCT interpretations. Primary outcome measure was the progression of BALAD to full-thickness MH (FTMH). Results: Of the 360 patients, 22.5% (n = 81) had BALAD abnormalities at presentation. Eight percent (29/360) had associated MH, of which 79.3% (23/29) were a BALAD-lamellar hole and 20.7% (6/29) were FTMH. After reattachment, 62% of MHs persisted (18/29), of which 83% (15/18) had BALAD-lamellar holes that subsequently progressed to FTMH in a mean of 8.1 ± 3.2 days. BALAD-lamellar holes had significantly worse postoperative visual acuity (P < 0.001) when compared with other BALAD abnormalities (58/81) or with the rest of the cohort (279/360). OCT spectrum from BALAD to FTMH includes (1) cleavage planes extending from Henle fiber layer into the BALAD; (2) central outer nuclear layer thinning; (3) Müller cell cone loss with tissue remnants at the foveal walls; (4) retinal tissue operculum close to BALAD-MH; and (5) progressive thinning or degradation of the posterior band of BALAD-lamellar hole leading to FTMH. Histological specimens identified foveal regions of low mechanical stability. Conclusions: BALAD plays a crucial role in the pathophysiology of MH in RRDs, which forms owing to sequential changes in four critical areas: RPE-photoreceptor interface, myoid zone, Henle fiber layer, and Müller cell cone with surrounding tissue. Timely management of fovea-off RRD with BALAD may be prudent to avoid the progression to BALAD-lamellar hole, subsequent FTMH, and worse functional outcomes.

Outer Retinal Hyperreflective Dots: A Potential Imaging Biomarker in Rhegmatogenous Retinal Detachment.

PURPOSE: To investigate hyperreflective dots (HRDs) on baseline OCT in rhegmatogenous retinal detachment (RRD). DESIGN: Retrospective cohort study. SUBJECTS: Consecutive primary fovea-off RRDs presenting between January 2012 and September 2022. METHODS: Visual acuity (VA) was obtained at baseline, 3, 6, and 12 months. Baseline foveal OCT scans were graded for the presence of HRDs in the outer retina, morphologic stage of RRD in the parafovea, and foveal photoreceptor integrity (intact, patchy or complete loss of the bacillary layer). Epiretinal membrane (ERM) and cystoid macular edema (CME) were graded after surgery. MAIN OUTCOME MEASURES: The primary outcome was the proportion of patients in each morphologic stage with HRDs present on OCT and their association with postoperative VA. Secondary outcomes included association with the height of foveal detachment, duration of central vision loss, RRD extent, and development of ERM/CME. RESULTS: A total of 351 patients were included. The presence of HRDs by morphologic stage of RRD was 0% in stage 1, 4.5% (2/42) in stage 2, 13% (7/54) in stage 3a, 16% (20/126) in stage 3b, 48% (40/83) in stage 4, and 85% (35/41) in stage 5. Hyperreflective dots were associated with increasing stage of RRD (P < 0.001), reduced integrity of foveal photoreceptors (P < 0.001), and reduced postoperative VA at 3, 6, and 12 months (P < 0.001), after excluding visually significant cataracts and adjusting for covariates. There was also a significant association between HRDs and height of foveal detachment, duration of central vision loss, and RRD extent (P < 0.001). Hyperreflective dots were neither associated with postoperative ERM formation nor with its severity (P = 0.27). Nevertheless, they were associated with the occurrence of CME at 3 and 6 months after surgery (P = 0.01; P = 0.006). CONCLUSIONS: Hyperreflective dots have been hypothesized to consist of intraretinal inflammatory cells. We found that HRDs were significantly associated with the morphologic stage, extent, duration, and height of the RRD before surgery and with reduced VA and CME after surgery. Our results suggest that HRDs are associated with photoreceptor degeneration, as longstanding and extensive RRDs are more likely to present with HRDs. The association of HRDs with CME provides insight into the possible importance of inflammatory processes in RRD before and after surgery. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A Rare ND5 Mutation Causing Leber's Hereditary Optic Neuropathy.

Mutations to the ND5 gene are uncommonly associated with Leber's hereditary optic neuropathy (LHON). Herein, we describe a 57-year-old man with the m. 13528A>G, p. (Thr398Ala) mutation at the ND5 gene who presented with progressive bilateral vision loss over the course of 3 months. He had a significant history of smoking and alcohol consumption. Visual field testing demonstrated bilateral central scotomas. At 2-year follow-up, his visual acuity improved relative to baseline and temporal optic disc pallor was observed in both eyes. There are scarce reports of this mutation in the literature, and this case report further expands the clinical presentation of the m. 13528A>G mutation at the ND5 gene in patients with LHON phenotype.

Prophylactic intraocular pressure lowering measures in anti-vascular endothelial growth factor therapy: A systematic review and meta-analysis.

Acute intraocular pressure (IOP) elevation following repeat intravitreal anti-vascular endothelial growth factor (VEGF) injections (IVI) may pose a risk to the integrity of the retinal nerve fiber (RNFL). This meta-analysis investigates the role of IOP-lowering interventions such as an anterior chamber paracentesis (ACP) and IOP-lowering medications on the IOP in patients undergoing IVIs. MEDLINE, EMBASE, and the Cochrane Library were searched up to February, 2021. Studies investigating IOP-lowering interventions in patients undergoing IVI versus controls were included. The primary outcome was the IOP in the short- and long-term post-IVI. Secondary outcomes were changes in the RNFL thickness and best corrected visual acuity (BCVA). ACP at time of anti-VEGF injection significantly lowered IOP immediately post anti-VEGF (WMD: -27.98 mm Hg, P < 0.001). Patients in the ACP group also had significantly thicker RNFL compared to control (WMD: 2.07 um, P < 0.00001) at median follow-up of 16.5 months. IOP-lowering medications (on the day of injection or in the long-term) significantly reduced IOP up to 30 minutes after injection (WMD: -3.31 mm Hg, P = 0.003). This effect was statistically significant between the 2 arms up to 1 month follow-up. There was no difference in BCVA in intervention versus controls. ACP reduces immediate IOP spikes post-IVI and preserves the RNFL in the short- and longterms IOP-lowering medications also reduce IOP spike, with limited data on RNFL thickness.

Idiopathic intracranial hypertension in atypical demographics.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition that most often occurs in women of reproductive age with elevated body mass index (BMI) (typical patients). Individuals outside of this demographic group (atypical patients) may have a different pathophysiology underlying raised intracranial pressure (ICP) leading to unique clinical presentations and prognosis. METHODS: Retrospective chart review of patients with IIH in typical and atypical demographic groups: men, those diagnosed at age 40 or older and those with BMI <26.0 kg/m2. RESULTS: 193 typical and 50 atypical patients with IIH were included. Age at diagnosis was higher in men and patients with normal BMI (37.2 ± 11.8 and 32.3 ± 9.8 years versus 27.3 ± 5.6 years). Older patients presented with headache less often than typical patients (42.9% versus 77.2%). Opening pressure on lumbar puncture (LP) and degree of optic disc edema were not significantly different between groups, though men had worse mean deviation (MD) on visual fields (VFs) (10.16 ± 10.40 dB versus 4.52 ± 5.53 dB in typical group). There was no significant difference between the typical and atypical groups in visual outcomes including number of patients requiring surgical treatment, development of optic atrophy and presence of persistent papilledema, though a trend toward worse VF MD was seen in men. In a pooled analysis of all patients, MD on VF at presentation was the only significant predictor of final visual outcome. CONCLUSION: Men and patients with normal BMI are diagnosed with IIH later in life. Clinical presentations of typical and atypical groups are similar, although older patients report headaches less frequently. Final visual outcomes were not significantly different between typical and atypical patients and VF loss at presentation is the most consistent predictor of final visual outcome in all patients.

Empty Sella in Neuro-Ophthalmology Patients Without Raised Intracranial Pressure.

BACKGROUND: Empty sella often supports a diagnosis of raised intracranial pressure (ICP) but is also seen in normal individuals. This study's objective was to determine the prevalence of empty and partially empty sella in neuro-ophthalmology patients undergoing MRI for indications other than papilledema or raised ICP. METHODS: Consecutive patients without papilledema or suspected raised ICP who underwent brain MRI between August 2017 and May 2021 were included in this study. Sagittal T1 images were evaluated by 2 independent, blinded neuroradiologists who graded the sella using the published criteria (Categories 1-5, with 1 being normal and 5 showing no visible pituitary tissue). Clinical parameters were also collected. RESULTS: A total of 613 patients (309 men; average age 56.69 ± 18.06 years) were included in this study with optic neuropathy as the most common MRI indication. A total of 176 patients had moderate concavity of the pituitary gland (Category 3), 81 had severe concavity (Category 4), and 26 had no visible pituitary tissue (Category 5). Sella appearance was mentioned in 92 patients' radiology reports (15%). There was a statistically significant difference in age between composite Categories 1 and 2 (mean 52.89 ± 18.91; P < 0.001) and composite Categories 4 and 5 (mean 63.41 ± 15.44), but not the other clinical parameters. CONCLUSION: Empty sella is common in neuro-ophthalmology patients without raised ICP; 17.4% of patients have severe concavity or no pituitary tissue visible. An isolated finding of empty or partially empty sella on imaging is therefore of questionable clinical value in this patient population.

A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer.

PURPOSE: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC. EXPERIMENTAL DESIGN: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing. RESULTS: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this "4-chemokine signature" positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell-inflamed phenotype across primary PDAC and PDAC liver metastases. CONCLUSIONS: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

Extramural venous invasion in rectal cancer: overview of imaging, histopathology, and clinical implications.

OBJECTIVE: Extramural venous invasion (EMVI) is an independent prognostic factor for prediction of overall unfavorable outcomes in rectal cancer. While EMVI has traditionally been detected in postoperative pathologic specimens, MRI can provide this important piece of information preoperatively. This article reviews the methods of EMVI detection and their clinical implications for treatment and outcomes of rectal cancer. CONCLUSION: EMVI has fundamental implications for rectal cancer prognosis and long-term outcomes. Since MRI has the advantage of preoperative detection of EMVI, it has been suggested that MRI-detected EMVI be incorporated for preoperative chemoradiotherapy (CRT) treatment stratification of rectal cancer for better patient triage and outcomes.