RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta-analysis.

RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty-six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non-isolated. Thirty-six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty-four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.

Diagnostic yield from prenatal exome sequencing for non-immune hydrops fetalis: A systematic review and meta-analysis.

Non-immune hydrops fetalis (NIHF) has multiple genetic etiologies diagnosable by exome sequencing (ES). We evaluated the yield of prenatal ES for NIHF, and the contribution of additional clinical findings and history. Systematic review was performed with PROSPERO tag 232951 using CINAHL, PubMed, and Ovid MEDLINE from January 1, 2000 through December 1, 2021. Selected studies performed ES to augment standard prenatal diagnostic approaches. Cases meeting a strict NIHF phenotype were tabulated with structured data imputed from papers or requested from authors. Genetic variants and diagnostic outcomes were harmonized across studies using current ACMG and ClinGen variant classification guidelines. Thirty-one studies reporting 445 NIHF cases had a 37% (95% CI: 32%-41%) diagnostic rate. There was no significant difference between isolated NIHF and NIHF with fetal malformations or between recurrent and simplex cases. Diagnostic rate was higher for consanguineous than non-consanguineous cases. Disease categories included RASopathies (24%), neuromuscular (21%), metabolic (17%), lymphatic (13%), other syndromes (9%), cardiovascular (5%), hematologic (2%), skeletal (2%), and other categories (7%). Inheritance patterns included recessive (55%), dominant (41%), and X-linked (4%). ES should be considered in the diagnostic workup of NIHF with and without associated ultrasound findings regardless of history of recurrence or consanguinity.

PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.

OBJECTIVE: To clarify the relevance of PIEZO1 variants detected by prenatal exome in the context of non-immune hydrops fetalis (NIHF). METHODS: A systematic review of prenatal exome studies from 1/1/2000-8/1/2022 was performed. Thirty-six studies met the inclusion criteria. PIEZO1 variants were categorized by disease mode (dominant (AD) versus recessive (AR)) and classified by the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Twenty-two pregnancies with 35 distinct PIEZO1 variants were included. We deemed PIEZO1 variants to be "likely diagnostic" in 12/22 pregnancies, "possibly diagnostic" in 7/22, and "unlikely diagnostic" in 3/22. In total, 19 of 191 NIHF cases diagnosed by prenatal exome were attributed to PIEZO1. Among likely diagnosed cases, the disease mode was AR in eight and AD in four. PIEZO1 variants causing AR NIHF were characterized by loss of function and isolated NIHF phenotype. PIEZO1 variants causing AD NIHF were characterized by gain of function in red blood cells, scarcity in databases, and sporadic inheritance. Missense variants associated with NIHF were clustered in three domains: transmembrane helical unit 4 (THU4), THU5, and the Cap. CONCLUSION: PIEZO1 variants were reported in 10% of NIHF cases diagnosed by prenatal exome, making PIEZO1 the most common single gene reported in NIHF.

An assessment of oncofertility content on reproductive endocrinology and infertility clinic websites.

PURPOSE: To assess oncofertility content on fertility clinic websites as indicated by eight relevant keywords. Additionally, we sought to describe the relationship between oncofertility content and five predetermined clinic characteristics. METHODS: We examined 381 fertility clinic websites that are members of the Society for Associated Reproductive Technology (SART). Extracted data included clinic location, practice type (private vs academic), size (cycles/year), type of NCI designated center (cancer center vs comprehensive cancer center), and distance from the nearest NCI center. Additionally, we documented whether the clinic was located in a state mandating reproductive and infertility services and/or included fertility preservation for "iatrogenic infertility" as reported by the American Society for Reproductive Medicine (ASRM). Data were summarized using descriptive statistics and compared using chi-squared or t-test as appropriate. RESULTS: Of the 381 fertility clinic websites analyzed, 322 (85%) contained at least one oncofertility-related keyword. Most frequently used terms included cancer (79%) and fertility preservation (78%), while less frequently used terms included suppression (9.4%) and shielding (5.0%). Practices that initiated ≥ 501 cycles per year were more likely to mention one of the oncofertility keywords (OR 1.2; 95% CI 1.1-1.3). The associations of oncofertility website content with practice type, state-mandated fertility insurance coverage, and distance from an NCI-designated cancer center were not statistically significant. Large clinic size was the only predictive factor for inclusion of oncofertility website content. Further studies are required to evaluate whether inclusion of oncofertility content on clinic websites impacts the use of these services by patients with cancer. CONCLUSION: This is the first study correlating availability of oncofertility content on SART fertility clinic websites with consideration of geographic proximity to NCI designated cancer centers. Large clinic size was the only predictive factor for inclusion of oncofertility website content.

Radial Artery Catheterization for Neuroendovascular Procedures.

Background and Purpose- Radial artery catheterization is an alternate route of access that has started to gain more widespread use for neuroendovascular procedures, and there have been few studies that describe its safety and efficacy. We present our institution's experience in performing neuroendovascular interventions via a transradial approach, with excellent clinical outcomes and patient satisfaction measures. Methods- We conducted a retrospective analysis and identified 223 patients who underwent 233 consecutive neuroendovascular interventions via radial artery access at our institution. The incidence of perioperative and postprocedural complications was investigated. We identified a subset of 98 patients who have undergone both transradial and transfemoral cerebral angiograms and compared clinical outcomes and patient satisfaction measures between the 2 groups. Results- The overall incidence of complications was low across all procedures performed via transradial access. Peri-procedurally, only 2 patients had symptomatic radial artery spasm, and there were no instances of iatrogenic complications (vessel dissection, stroke, and hemorrhage). In 10 cases (4.3%), the intended procedure could not be completed via a transradial approach, and, thus, femoral artery access had to be pursued instead. Ten patients complained of minor postprocedural complications, although none required therapeutic intervention. The mean procedure time was shorter for diagnostic angiograms performed via transradial versus transfemoral access (18.8±15.8 versus 39.5±31.1 minutes; P=0.025). Patients overall reported shorter recovery times with transradial access, and the majority of patients (94%) would elect to have subsequent procedures performed via this route. Conclusions- Radial artery catheterization is a safe and durable alternative to perform a wide range of neuroendovascular procedures, with a low rate of complications. On the whole, patients prefer transradial compared with transfemoral access.

Rescue stenting for acute ischemic stroke with refractory emergent large vessel occlusion in the modern thrombectomy era.

BACKGROUND AND PURPOSE: Rescue stenting is used as a bailout technique during mechanical thrombectomy for stroke. We performed a retrospective study analyzing outcomes of patients that received a stent as a bailout measure and compared results to a control group. METHODS: We identified all patients who underwent a mechanical thrombectomy for a large vessel occlusion between January 2010 and October 2019. Subjects with mTICI 0-2 A after at least three passes were defined as failed MT and constituted the control group (NSG-controls). Patients that received a rescue stent (RSG) formed the study group. RESULTS: Comparative analysis of patient demographics between NSG-controls and SRG was performed. Baseline characteristics and comorbidities were not significantly different between both groups. NIHSS at admission and IV t-PA were not significantly different among both groups (16.5 vs. 14.2, p = 0.19) and (39.4% vs. 29.4%, p = 0.30), respectively. There was no significant difference in procedural and post-procedural complications between both the groups. In the RSG, 24 patients (82.4%) achieved favorable revascularization outcomes. NIHSS at discharge (p = 0.01) was higher in the NSG-controls, while favorable functional outcome at three months (12% vs. 39.2%, p = 0.01) was observed at a higher proportion in the RSG. There was also a significant mortality difference, with 15.2% mortality in the RSG compared to 35.1% mortality in the NSG-controls (p = 0.03). In multivariate analysis, stenting was an independent predictor of favorable outcome (OR: 10.0, p = 0.009). CONCLUSION: Herein, we demonstrated that rescue stenting is a feasible, safe, and effective procedure to improve stroke outcomes and should be seriously considered if the primary mechanical thrombectomy is not successful.

Mechanical Thrombectomy in Acute Ischemic Stroke Patients Greater than 90 Years of Age: Experience in 26 Patients in a Large Tertiary Care Center and Outcome Comparison with Younger Patients.

BACKGROUND: Several independent randomized controlled trials have shown superior efficacy of mechanical thrombectomy (MT) for management of acute ischemic stroke (AIS). However, elderly patients have been underrepresented or excluded in these trials. The aim of this study was to investigate the feasibility and safety of MT in patients with AIS ≥90 years old. METHODS: A retrospective review was performed of patients ≥90 years old presenting with AIS who underwent MT between 2010 and 2018. RESULTS: Of 453 patients with AIS, 5.74% (n = 26) were ≥90 years old, and 69.32% (n = 314) were 60-89 years old. Of baseline characteristics between both groups, there was a significant difference in age, sex, body mass index, smoking, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Mean National Institutes of Health Stroke Scale score on admission was higher in the nonagenarians (17 vs. 15). Similar proportions of both groups received tissue plasminogen activator, 57.69% (n = 15) versus 42.68% (n = 134), P = 0.14). There was no difference in periprocedural and postprocedural complications, good Thrombolysis In Cerebral Infarction scores (88.46% [n = 23] vs. 87.58% [n = 275], P = 1.00), good modified Rankin Scale scores (34.62% [n = 4] vs. 49.36% [n = 155], P = 0.40), or mortality (11.54% [n = 3] vs. 13.06% [n = 41], P = 0.82). CONCLUSIONS: Age is a factor that affects functional outcome following MT. Advancements in catheter techniques, technical experience, and great outcomes with MT allow for pushing the boundaries to consider age as one factor, rather than an exclusion criterion. Our results show that MT is safe and feasible in nonagenarians.

The Use of Alternative Routes for the Delivery of Intra-Arterial Chemotherapy for Retinoblastoma.

BACKGROUND: The introduction of intra-arterial chemotherapy (IAC) for treatment of retinoblastoma considerably changed the paradigm by which this disease is managed, with event-free survival rates being above 70%. OBJECTIVE: To analyze efficacy of IAC treatment using alternative approaches to ophthalmic artery catheterization (OAC), such as external carotid artery approach or balloon-assisted drug delivery. METHODS: This is a retrospective chart review for subjects receiving IAC for retinoblastoma. The primary approach was OAC. In cases in which selective OAC was not feasible, alternative routes including catheterization of the external carotid artery or use of a balloon-assisted drug infusion were used. RESULTS: This study included 197 consecutive patients with 207 retinoblastomas who underwent 658 IAC procedures overall. The mean age at diagnosis was 24 mo, and 54.5% of the study population was male. Success rate with IAC was 97% (639). Alternative approaches to OAC were, in total, 42 cases (6.4%)-external carotid artery catheterization and use of ICA balloon were performed in 22 (3.3%) and 20 (3%) cases, respectively. A mean of 3.1 IAC cycles were performed for each patient. In total, there were 23 technical failures of the primary OAC technique (3.4%). Periprocedural adverse events occurred in 4 procedures (0.6%). Use of an alternative technique for chemotherapy delivery other than selective OAC in at least one IAC cycle was not a predictor of enucleation. CONCLUSION: IAC is a safe and effective treatment option for retinoblastoma. Chemotherapy delivery using alternative techniques is as effective as selective OAC.

Ophthalmic artery catheterization for retinoblastoma treatment: does reflux affect tumor response?

BACKGROUND: Intra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has been established as a primary treatment for the disease. To determine whether the presence of reflux into the ICA is associated with tumor response or with any other adverse events in pediatric retinoblastoma patients. METHODS: A retrospective chart review was performed for patients diagnosed with Rb and managed with ophthalmic artery catheterization (OAC). RESULTS: The total study cohort included 205 Rb tumors of 205 eyes in 194 consecutive patients who underwent 624 successful intra-arterial chemotherapy infusions using OAC. Of the 205 eyes, 65 eyes (32.7%) underwent 157 OAC procedures constituted group A (no reflux), 64 eyes (31.2%) underwent 236 OAC procedures constituted group B (variable pattern), and 74 eyes (36.1%) underwent 231 OAC procedures constituted group C (reflux). There was no significant difference in baseline characteristics between the three cohorts. Also, there was no significant difference in tumor characteristics between the three groups, except for genetic status. There was no significant difference between the three groups in terms of tumor response at completion of the treatment regimen. Complete tumor response was achieved at 70.2% in Group A, at 83.3% in Group B, and at 78.5% in group C (P=0.39). Similarly, eye enucleation occurred at 38.5% in group A, 31.8% in group B, and 31.5% in group C. None of the patients in both groups had any neurological adverse events or new onset of seizures. CONCLUSIONS: The presence of reflux, which may complicate the procedure and prolong it, was not associated with poor outcomes in our analysis.

Mechanical Thrombectomy in Distal Vessels: Revascularization Rates, Complications, and Functional Outcome.

INTRODUCTION: Pivotal trials have shown the tremendous efficacy of mechanical thrombectomy in proximal occlusions. However distal occlusions involving second-order branches of the middle cerebral artery and beyond, anterior cerebral and posterior cerebral arteries were not represented. In this study, we investigated the feasibility and safety of distal circulation mechanical thrombectomy. METHODS: A retrospective review of patients presenting with distal circulation acute ischemic stroke who underwent mechanical thrombectomy 2010 and 2018. RESULTS: Of 453 patients who underwent mechanical thrombectomy for acute ischemic stroke, 76 had a distal occlusion. The mean National Institute Health Stroke Scale on admission was 12. Vessels involved included second-order branches of the middle cerebral artery (89%), third- and fourth-order branches of the middle cerebral artery (5%), second-order branch of the anterior cerebral artery (3%), and posterior cerebral artery (3%). Most procedures required 1 pass to recanalize the vessel (55%, n = 42). Thrombolysis in Cerebral Infarction score ≥IIb was achieved in 89% of subjects. Mortality rate was 8% and independent functional outcome of m Rankin score ≤2 at 3 months was seen in 64.7% with clinical follow-up. On multivariate analysis, distal circulation had a significantly shorter length of stay by about 2 days, compared with proximal circulation. Subjects with proximal occlusion were more than 5 times more likely to have a good Thrombolysis in Cerebral Infarction score compared with the distal group. There was no significant difference in periprocedural and postprocedural complications, good functional outcome at 3 months, and mortality between both groups. CONCLUSIONS: Mechanical thrombectomy procedure for distal circulation strokes is as effective and safe as a proximal group. Though distal vessels supply smaller brain area; however, when symptoms are pronounced, the benefit of the procedure outweighs the risks.

Transradial approach for the treatment of brain aneurysms using flow diversion: feasibility, safety, and outcomes.

BACKGROUND: The aim of this paper is to describe our experience with the transradial approach (TRA) for intracranial aneurysms treatment using the Pipeline Embolization device (PED). We also performed a logistic regression comparing outcomes between TR and transfemoral approach (TFA). METHODS: The clinical and imaging characteristics as well as periprocedural outcomes of patients treated for aneurysms using a TRA with PED were analyzed retrospectively. RESULTS: A total of 598 aneurysms were treated with pipeline during a period extending from 2010-2019 (N.=580 [97%] using TFA vs. N.=18 [3%] using TRA). About 84.28% (N.=504) were females, and the average age was 55.5 years. There was no significant difference between both approaches in procedural duration, complication rate, morbidity, and aneurysms obliteration. We did not encounter any access site complication in the TR group compared to 2% in the TF; however, this did not reach statistical significance. One case was converted to TFA due to the need for more support. Multivariate analysis did not show that the access site was an independent predictor of the complications, morbidity, and aneurysms obliteration. CONCLUSIONS: The results of this study illustrate that the transradial approach is a safe and effective means of treating intracranial aneurysms with PED. The TRA in selected patients offers better safety with high rates of procedural success.