Hypoxia-inducible factor-1 (HIF-1) plays an important role in retinal and subretinal neovascularization (NV). Increased levels of HIF-1 cause increased expression of vascular endothelial growth ...factor (VEGF-A) and current therapies for ocular NV focus on neutralizing VEGF-A, but there is mounting evidence that other HIF-1-responsive gene products may also participate. In this study, we tested the effect of a designed ankyrin repeat protein (DARPin) that selectively binds and antagonizes the hypoxia-regulated gene product PDGF-BB in three models of subretinal NV (relevant to neovascular age-related macular degeneration) and compared its effects to a DARPin that selectively antagonizes VEGF-A. Daily intraperitoneal injections of 10 mg/kg of the anti-PDGF-BB DARPin or 1 mg/kg of the anti-VEGF DARPin significantly suppressed subretinal NV from laser-induced rupture of Bruch’s membrane. Injections of 1 mg/kg/day of the anti-PDGF-BB DARPin had no significant effect, but when combined with 1 mg/kg/day of the anti-VEGF-A DARPin there was greater suppression than injection of the anti-VEGF-A DARPin alone. In
Vldlr
−
/
−
mice which spontaneously develop subretinal NV, intraocular injection of 1.85 μg of anti-PDGF-BB or anti-VEGF-A DARPin caused significant suppression of NV and when combined there was greater suppression than with either alone. The two DARPins also showed an additive effect in
Tet/opsin/VEGF
double transgenic mice, a particularly severe model of subretinal NV and exudative retinal detachment. In addition, intraocular injection of 1.85 μg of anti-PDGF-BB DARPin strongly suppressed ischemia-induced retinal NV, which is relevant to proliferative diabetic retinopathy and retinopathy of prematurity. These data demonstrate that PDGF-BB is another hypoxia-regulated gene product that along with VEGF-A contributes to ocular NV and suppression of both provides an additive effect.
The radiologic diagnosis of adrenal disease can be challenging in settings of atypical presentations, mimics of benign and malignant adrenal masses, and rare adrenal anomalies. Misdiagnosis may lead ...to suboptimal management and adverse outcomes. Adrenal adenoma is the most common benign adrenal tumor that arises from the cortex, whereas adrenocortical carcinoma (ACC) is a rare malignant tumor of the cortex. Adrenal cyst and myelolipoma are other benign adrenal lesions and are characterized by their fluid and fat content, respectively. Pheochromocytoma is a rare neuroendocrine tumor of the adrenal medulla. Metastases to the adrenal glands are the most common malignant adrenal tumors. While many of these masses have classic imaging appearances, considerable overlap exists between benign and malignant lesions and can pose a diagnostic challenge. Atypical adrenal adenomas include those that are lipid poor; contain macroscopic fat, hemorrhage, and/or iron; are heterogeneous and/or large; and demonstrate growth. Heterogeneous adrenal adenomas may mimic ACC, metastasis, or pheochromocytoma, particularly when they are 4 cm or larger, whereas smaller versions of ACC, metastasis, and pheochromocytoma and those with washout greater than 60% may mimic adenoma. Because of its nonenhanced CT attenuation of less than or equal to 10 HU, a lipid-rich adrenal adenoma may be mimicked by a benign adrenal cyst, or it may be mimicked by a tumor with central cystic and/or necrotic change such as ACC, pheochromocytoma, or metastasis. Rare adrenal tumors such as hemangioma, ganglioneuroma, and oncocytoma also may mimic adrenal adenoma, ACC, metastasis, and pheochromocytoma. The authors describe cases of adrenal neoplasms that they have encountered in clinical practice and presented to adrenal multidisciplinary tumor boards. Key lessons to aid in diagnosis and further guide appropriate management are provided.
RSNA, 2023
Quiz questions for this article are available through the Online Learning Center.
Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of ...BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/β-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression.
Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.
The PHASES (Population, Hypertension, Age, Size, Earlier subarachnoid hemorrhage, Site) score was developed to facilitate risk stratification for management of unruptured intracranial aneurysms ...(UIAs). This study aimed to identify the optimal PHASES score cutoff for predicting neurologic outcomes in patients with surgically treated aneurysms.
All patients who underwent microneurosurgical treatment for UIA at a large quaternary center from January 1, 2014, to December 31, 2020, were retrospectively reviewed. Inclusion criteria included a modified Rankin Scale (mRS) score of ≤2 at admission. The primary outcome was 1-year mRS score, with a “poor” neurologic outcome defined as an mRS score >2.
In total, 375 patients were included in the analysis. The mean (SD) PHASES score for the entire study population was 4.47 (2.67). Of 375 patients, 116 (31%) had a PHASES score ≥6, which was found to maximize prediction of poor neurologic outcome. Patients with PHASES scores ≥6 had significantly higher rates of poor neurologic outcome than patients with PHASES scores <6 at discharge (58 50% vs. 90 35%, P = 0.005) and follow-up (20 17% vs. 18 6.9%, P = 0.002). After adjusting for age, Charlson Comorbidity Index score, nonsaccular aneurysm, and aneurysm size, PHASES score ≥6 remained a significant predictor of poor neurologic outcome at follow-up (odds ratio, 2.75; 95% confidence interval, 1.42–5.36, P = 0.003).
In this retrospective analysis, a PHASES score ≥6 was associated with significantly greater proportions of poor outcome, suggesting that awareness of this threshold in PHASES scoring could be useful in risk stratification and UIA management.
Approximately 3.2%-6% of the general population harbor an unruptured intracranial aneurysm (UIA). Ruptured aneurysms represent a significant healthcare burden, and preventing rupture relies on early ...detection and treatment. Most patients with UIAs are asymptomatic, and many of the symptoms associated with UIAs are nonspecific, which makes diagnosis challenging. This study explored symptoms associated with UIAs, the rate of resolution of such symptoms after microsurgical treatment, and the likely pathophysiology.
A retrospective review of patients with UIAs who underwent microsurgical treatment from January 1, 2014, to December 31, 2020, at a single quaternary center were identified. Analyses included the prevalence of nonspecific symptoms upon clinical presentation and postoperative follow-up; comparisons of symptomatology by aneurysmal location; and comparisons of patient demographics, aneurysmal characteristics, and poor neurologic outcome at postoperative follow-up stratified by symptomatic versus asymptomatic presentation.
The analysis included 454 patients; 350 (77%) were symptomatic. The most common presenting symptom among all 454 patients was headache (
= 211 46%), followed by vertigo (
= 94 21%), cognitive disturbance (
= 6815%), and visual disturbance (
= 64 14%). Among 328 patients assessed for postoperative symptoms, 258 (79%) experienced symptom resolution or improvement.
This cohort demonstrates that the clinical presentation of patients with UIAs can be associated with vague and nonspecific symptoms. Early detection is crucial to prevent aneurysmal subarachnoid hemorrhage. It is imperative that physicians not rule out aneurysms in the setting of nonspecific neurologic symptoms.
Posterior inferior cerebellar artery (PICA) aneurysms account for 0.3% of all intracranial aneurysms, and they commonly present with a complex fusiform morphology that necessitates unique bypass ...strategies.1-5 An adolescent boy with a familial predisposition to aneurysmal subarachnoid hemorrhage was identified as harboring a fusiform aneurysm of the right distal PICA, characterized by 2 outflow branches. Our recommended treatment strategy involved a right far lateral craniotomy, followed by P1 PICA reanastomosis and P2 PICA reimplantation. Informed written consent was obtained. On exposure, the aneurysm was trapped, and the inflow and 2 outflow PICA branches were excised. Revascularization was established through a P1 PICA end-to-end reanastomosis using running continuous suturing techniques, followed by P2 PICA end-to-side reimplantation into a more distal portion of PICA. Subsequent indocyanine green videoangiography confirmed patency of the P2 PICA reimplantation; however, the initial P1 PICA reanastomosis was noted to be thrombosed. After several unsuccessful attempts to dissolve the thrombus, the decision was made to proceed with a P2 PICA side-to-side in situ reimplantation into the V4 segment of the vertebral artery. Indocyanine green videoangiography and postoperative digital subtraction angiography confirmed patency of the PICA double reimplantation bypass. The patient tolerated the procedure well and was discharged home at his neurological baseline. This video showcases the microsurgical treatment of a complex dolichoectatic, distal PICA aneurysm using a double reimplantation technique, in addition to highlighting bypass decision-making processes for managing complex PICA aneurysms.
The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) ...Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.
: Patients with supratentorial cavernous malformations (SCMs) commonly present with seizures. First-line treatments for cavernoma-related epilepsy (CRE) include conservative management (antiepileptic ...drugs (AEDs)) and surgery. We compared seizure outcomes of CRE patients after early (≤6 months) vs. delayed (>6 months) surgery.
: We compared outcomes of CRE patients with SCMs surgically treated at our large-volume cerebrovascular center (1 January 2010-31 July 2020). Patients with 1 sporadic SCM and ≥1-year follow-up were included. Primary outcomes were International League Against Epilepsy (ILAE) class 1 seizure freedom and AED independence.
: Of 63 CRE patients (26 women, 37 men; mean ± SD age, 36.1 ± 14.6 years), 48 (76%) vs. 15 (24%) underwent early (mean ± SD, 2.1 ± 1.7 months) vs. delayed (mean ± SD, 6.2 ± 7.1 years) surgery. Most (32 (67%)) with early surgery presented after 1 seizure; all with delayed surgery had ≥2 seizures. Seven (47%) with delayed surgery had drug-resistant epilepsy. At follow-up (mean ± SD, 5.4 ± 3.3 years), CRE patients with early surgery were more likely to have ILAE class 1 seizure freedom and AED independence than those with delayed surgery (92% (44/48) vs. 53% (8/15),
= 0.002; and 65% (31/48) vs. 33% (5/15),
= 0.03, respectively).
: Early CRE surgery demonstrated better seizure outcomes than delayed surgery. Multicenter prospective studies are needed to validate these findings.
Racial and socioeconomic health disparities are well documented in the literature. This study examined patient demographics, including socioeconomic status (SES), among individuals presenting with ...aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (UIA) to identify factors associated with aSAH presentation. A retrospective assessment was conducted of all patients with aSAH and UIA who presented to a large-volume cerebrovascular center and underwent microsurgical treatment from January 2014 through July 2019. Race and ethnicity, insurance type, and SES data were collected for each patient. Comparative analysis of the aSAH and UIA groups was conducted. Logistic regression models were also employed to predict the likelihood of aSAH presentation based on demographic and socioeconomic factors. A total of 640 patients were included (aSAH group, 251; UIA group, 389). Significant associations were observed between race and ethnicity, SES, insurance type, and aneurysm rupture. Non-White race or ethnicity, lower SES, and having public or no insurance were associated with increased odds of aSAH presentation. The aSAH group had poorer functional outcomes and higher mortality rates than the UIA group. Patients who are non-White, have low SES, and have public or no insurance were disproportionately affected by aSAH, which is historically associated with poorer functional outcomes.
PDF
