Association of Mutant KRAS Alleles With Morphology and Clinical Outcomes in Pancreatic Ductal Adenocarcinoma.

CONTEXT.­: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. OBJECTIVE.­: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. DESIGN.­: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. RESULTS.­: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively). CONCLUSIONS.­: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies.

Predictors of occlusion, long-term outcomes, and safety in a cohort of 674 aneurysms treated with the Pipeline embolization device.

OBJECTIVE: By providing a more physiological approach to the treatment of intracranial aneurysms, the Pipeline embolization device (PED) has revolutionized the endovascular treatment of aneurysms. Although there are many flow diverters on the market, the authors report their experience with the PED, the first flow diverter to be approved by the Food and Drug Administration. They aimed to assess the efficacy and safety of PED flow diversion for the treatment of a wide range of aneurysms, as well as to look at factors affecting occlusion. METHODS: This is a retrospective study of a prospectively maintained database of patients treated with the PED between January 2011 and December 2019. Charts were reviewed for patient, aneurysm, and procedure characteristics. The primary outcomes of interest were complication rates, occlusion outcomes (O'Kelly-Marotta grading scale), and functional outcomes (modified Rankin Scale [mRS]). Secondary outcomes included predictors of incomplete occlusion at 6 and 24 months of follow-up. RESULTS: The study cohort included 581 patients with 674 aneurysms. Most aneurysms (90.5%) were in the anterior circulation and had a saccular morphology (85.6%). Additionally, 638 aneurysms (94.7%) were unruptured, whereas 36 (5.3%) were acutely ruptured. The largest mean aneurysm diameter was 8.3 ± 6.1 mm. Complications occurred at a rate of 5.5% (n = 32). The complete occlusion rate was 89.3% at 24 months' follow-up, and 94.8% of patients had a favorable neurological outcome (mRS score 0-2) at the last follow-up. On multivariate analysis, predictors of incomplete aneurysm occlusion at 6 months were hypertension (OR 1.7, p = 0.03), previous aneurysm treatment (OR 2.4, p = 0.001), and increasing aneurysm neck diameter (OR 1.2, p = 0.02), whereas a saccular morphology was protective (OR 0.5, p = 0.05). Predictors of incomplete occlusion at 24 months were increasing aneurysm neck diameter (OR 1.2, p = 0.01) and previous aneurysm treatment (OR 2.3, p = 0.01). CONCLUSIONS: The study findings are corroborated by those of previous studies and trials. The complete occlusion rate was 89.3% at 24 months' follow-up, with 94.8% of patients having favorable functional outcomes (mRS score 0-2). Aneurysm treatment before PED deployment and an increasing aneurysm neck diameter increase the risk of incomplete occlusion at 6 and 24 months.

Comparison of PED/PED Flex and PED Shield in the treatment of unruptured intracerebral aneurysms.

OBJECTIVE: The object of this study was to compare the efficacy and safety profile of the Pipeline embolization device (PED)/Pipeline Flex embolization device (PED Flex) with that of the Pipeline Flex embolization device with Shield Technology (PED Shield). After introducing the first-generation PED and the second-generation PED Flex with its updated delivery system, the PED Shield was launched with a synthetic layer of phosphorylcholine surface modification to reduce thrombogenicity. METHODS: This is a retrospective review of unruptured aneurysms treated with PED/PED Flex versus PED Shield between 2017 and 2022 at the authors' institution. Patients with ruptured aneurysms, adjunctive treatment, failed flow diverter deployment, and prior treatment of the target aneurysm were excluded. Baseline characteristics were collected for all patients, including age, sex, past medical history (hypertension, hyperlipidemia, diabetes mellitus), smoking status, aneurysm location, and aneurysm dimensions (neck, width, height) and morphology (saccular, nonsaccular). The primary outcome was procedural and periprocedural complication rates. RESULTS: The study cohort comprised 200 patients with 200 aneurysms, including 150 aneurysms treated with the PED/PED Flex and 50 treated with the PED Shield. With respect to intraprocedural and periprocedural complications, length of stay, length of follow-up, and functional outcome at discharge, there was no significant difference between the two cohorts. At the midterm follow-up, the rate of in-stent stenosis (PED/PED Flex: 14.2% vs PED Shield: 14.6%, p = 0.927), aneurysm occlusion (complete occlusion: 79.5% vs 80.5%, respectively; neck remnant: 4.7% vs 12.2%; dome remnant: 15.7% vs 7.3%; p = 0.119), and the need for retreatment (5.3% vs 0%, p = 0.097) were comparable between the two cohorts. CONCLUSIONS: This study suggests that, as compared to first- and second-generation PED and PED Flex, the third-generation PED Shield offers similar rates of complications, aneurysm occlusion, and in-stent stenosis at the midterm follow-up.

Comparison of 5-Item and 11-Item Modified Frailty Index as Predictors of Functional Independence in Patients With Spinal Cord Injury.

STUDY DESIGN: Retrospective Cohort Study. INTRODUCTION: The 11-item modified Frailty index (mFI-11) by the ACS-NSQIP database was used to predict which patients are high risk for complications and inpatient mortality. ACS-NSQIP now has switched to the 5-item MFI. However, there are no studies on how these frailty indices fare against each other and their prognostic value of functional independence in patients with spinal cord injury (SCI). OBJECTIVE: To compare the mFI-5 and mFI-11 in order to standardize frailty assessment in the SCI population. METHODS: Retrospective analysis of 272,174 patients with SCI from 2010 to 2020 from the Pennsylvania Trauma Systems Foundation (PTSF) registry. Multivariable logistic regression was used to determine the predictive value of mFI for functional independence as determined by locomotion and transfer mobility. RESULTS: A total of 1907 patients were included with a mean age of 46.9 ± 15.1 years. The 3 most common MFI factors were hypertension (32.2%), diabetes mellitus (13.7%) and chronic obstructive pulmonary disease (8.5%). Multivariable logistic regression analyses using MFI-5 and MFI-11 showed that a higher frailty score in MFI-5 (OR 1.375, P < .001) and in MFI-11 (OR 1.366, P < .001) were each predictive of poor functional status at discharge. ROC curves for the MFI-5 (AUC = .818, P < .001) and MFI-11 (AUC = .819, P < .001) demonstrated excellent diagnostic accuracy. CONCLUSION: The new MFI-5 is equivalent to its predecessor, the MFI-11, and predictive of functional outcomes in patients with SCI. MFI-5 can serve as the preferred frailty index at the point of care and in research contexts.

The Rate and Predictors of 30-Day Readmission in Patients Treated for Unruptured Cerebral Aneurysms: A Large Single-Center Study.

BACKGROUND AND OBJECTIVES: Numerous studies of various populations and diseases have shown that unplanned 30-day readmission rates are positively correlated with increased morbidity and all-cause mortality. In this study, we aim to provide the rate and predictors of 30-day readmission in patients undergoing treatment for unruptured intracranial aneurysms. METHODS: This is a retrospective study of 525 patients presenting for aneurysm treatment between 2017 and 2022. All patients who were admitted and underwent a successful treatment of their unruptured intracerebral aneurysms were included in the study. The primary outcome was the rate and predictors of 30-day readmission. RESULTS: The rate of 30-day readmission was 6.3%, and the mean duration to readmission was 7.8 days ± 6.9. On univariate analysis, factors associated with 30-day readmission were antiplatelet use on admission (odds ratio [OR]: 0.4, P = .009), peri-procedural rupture (OR: 15.8, P = .007), surgical treatment of aneurysms (OR: 2.2, P = .035), disposition to rehabilitation (OR: 9.5, P < .001), and increasing length of stay (OR: 1.1, P = .0008). On multivariate analysis, antiplatelet use on admission was inversely correlated with readmission (OR: 0.4, P = .045), whereas peri-procedural rupture (OR: 9.5, P = .04) and discharge to rehabilitation (OR: 4.5, P = .029) were independent predictors of 30-day readmission. CONCLUSION: In our study, risk factors for 30-day readmission were aneurysm rupture during the hospital stay and disposition to rehabilitation, whereas the use of antiplatelet on admission was inversely correlated with 30-day readmission. Although aneurysm rupture is a nonmodifiable risk factor, more studies are encouraged to focus on the correlation of antiplatelet use and rehabilitation disposition with 30-day readmission rates.

Predictors of Transfemoral Access Site Complications in Neuroendovascular Procedures: A large Single-Center Cohort Study.

OBJECTIVE: The transfemoral (TF) route has historically been the preferred access site for endovascular procedures. However, despite its widespread use, TF procedures may confer morbidity as a result of access site complications. The aim of this study is to provide the rate and predictors of TF access site complications for neuroendovascular procedures. METHODS: This is a single center retrospective study of TF neuroendovascular procedures performed between 2017 and 2022. The incidence of complications and associated risk factors were analyzed across a large cohort of patients. RESULTS: The study comprised of 2043 patients undergoing transfemoral neuroendovascular procedures. The composite rate of access site complications was 8.6 % (n = 176). These complications were divided into groin hematoma formation (n = 118, 5.78 %), retroperitoneal hematoma (n = 14, 0.69 %), pseudoaneurysm formation (n = 40, 1.96 %), and femoral artery occlusion (n = 4, 0.19 %). The cross-over to trans radial access rate was 1.1 % (n = 22). On univariate analysis, increasing age (OR=1.0, p = 0.06) coronary artery disease (OR=1.7, p = 0.05) peripheral vascular disease (OR=1.9, p = 0.07), emergent mechanical thrombectomy procedures (OR=2.1, p < 0.001) and increasing sheath size (OR=1.3, p < 0.001) were associated with higher TF access site complications. On multivariate analysis, larger sheath size was an independent risk factor for TF access site complications (OR=1.8, p = 0.02). CONCLUSION: Several pertinent factors contribute towards the incidence of TF access site complications. Factors associated with TF access site complications include patient demographics (older age) and clinical risk factors (vascular disease), as well as periprocedural factors (sheath size).

Ventriculostomy Associated with Reduced Mortality in Severe Traumatic Brain Injury Compared to Parenchymal ICP Monitoring: A Propensity Score-Adjusted Analysis.

BACKGROUND: There is a lack of data on whether intracranial pressure (ICP)-guided therapy with an intraparenchymal fiberoptic monitor (IPM) or an external ventricular drain (EVD) leads to superior outcomes. Our goal is to determine the relationship between ICP-guided therapy with an EVD or IPM and mortality. METHODS: Retrospective analysis of severe traumatic brain injury cases that required IPM or EVD placement for ICP-guided therapy from January 1, 2010 to December 31, 2020. The data were obtained from the Pennsylvania Trauma Systems Foundation registry. RESULTS: A total of 2305 patients met the inclusion criteria, with 1048 (45.5%) IPM and 1257 (54.5%) EVD placed. Inpatient mortality occurred in 337 (32.2%) and 334 (26.6%) patients in the IPM and EVD cohorts, respectively (P = 0.003). Even among those treated medically only, inpatient mortality occurred in 171 (30.8%) of those with an IPM and in 100 (23.4%) of those with an EVD (P = 0.010). Multivariable logistic regression analysis showed that older age (odds ratio [OR] 1.03, P < 0.001), lower Glasgow Coma Scale (GCS) score (OR 1.16, P < 0.001), requiring surgery (OR 1.22, P = 0.049), and an IPM (OR 1.40, P = 0.001) were significant predictors of mortality. Propensity score-adjusted analysis using inverse probability of treatment weighted method revealed a 28% decrease in mortality and a 14% decrease in length of hospital stay with EVD use when adjusting for age, sex, GCS, Injury Severity Score, surgery, and Hispanic ethnicity. CONCLUSIONS: A significant mortality benefit was associated with the use of EVD compared to IPM. This mortality benefit was observed regardless of whether patients required surgery or not.

Clinical Outcomes After Ultra-Early Cranioplasty Using Craniectomy Contour Classification as a Patient Selection Criterion.

BACKGROUND: Although not a technically difficult operation, cranioplasty is associated with high rates of complications. The optimal timing of cranioplasty to mitigate complications remains the subject of debate. OBJECTIVE: To report outcomes between patients undergoing cranioplasty at ultra-early (0-6 weeks), intermediate (6 weeks to 6 months), and late (>6 months) time frames. We report a novel craniectomy contour classification (CCC) as a radiographic parameter to assess readiness for cranioplasty. METHODS: A single-institution retrospective analysis of patients undergoing cranioplasty was performed. Patients were stratified into ultra-early (within 6 weeks of index craniectomy), intermediate (6 weeks to 6 months), and late (>6 months) cranioplasty cohorts. We have devised CCC scores, A, B, and C, based on radiographic criteria, where A represents those with a sunken brain/flap, B with a normal parenchymal contour, and C with "full" parenchyma. RESULTS: A total of 119 patients were included. There was no significant difference in postcranioplasty complications, including return to operating room ( P = .212), seizures ( P = .556), infection ( P = .140), need for shunting ( P = .204), and deep venous thrombosis ( P = .066), between the cohorts. Univariate logistic regression revealed that ultra-early cranioplasty was significantly associated with higher rate of functional independence at >6 months (odds ratio 4.32, 95% CI 1.39-15.13, P = .015) although this did not persist when adjusting for patient selection features (odds ratio 2.90, 95% CI 0.53-19.03, P = .234). CONCLUSION: In appropriately selected patients, ultra-early cranioplasty is not associated with increased rate of postoperative complications and is a viable option. The CCC may help guide decision-making on timing of cranioplasty.

Minimally invasive intracerebral hemorrhage evacuation: A bibliometric analysis of current research trends.

OBJECTIVE: Intracerebral hemorrhage (ICH) is associated with significant morbidity and mortality. Randomized clinical trials focusing on minimally invasive surgery (MIS) for ICH evacuation have suggested a potential benefit regarding mortality but results remain unclear regarding impact on functional outcome. This study presents a bibliometric analysis investigating the current trends in the literature on MIS for ICH. METHODS: Using the Scopus collection database, a search was performed to identify literature that discussed MIS for ICH from 2000 to 2021. Primary research articles were included in this study. Reviews and book chapters were excluded. Analysis and visualization of the included literature were completed with VOSviewer. RESULTS: A total of 278 articles were identified. An upward trend in publications began in 2008, with the most publications in 2021 (36) followed by 2020 (25). The most citations occurred in 2013 (1192). The h-index, i-10 and i-100 were 37, 79 and 6 respectively. For the top 100 most cited studies, the mean citation count was 45.55 with a range of 6-760. The highest-producing institutions of MIS for ICH literature were Johns Hopkins University (31, 15 %), University of Chicago with (21, 10 %), Guiyang Medical College (17, 8 %), and Icahn School of Medicine at Mount Sinai (15, 7 %). Keyword analysis revealed four major avenues: 1) medication enhancement of clot removal, 2) minimally invasive devices such as endoscopes, 3) craniotomy approach, and 4) physiology of clot removal. CONCLUSIONS: The literature on MIS for ICH has been expanding since 2008. Key topics include thrombolysis, device innovation, and surgical approach.

Initial Heart Rate Predicts Functional Independence in Patients With Spinal Cord Injury Requiring Surgery: A Registry-Based Study in a Mature Trauma System Over the Past 10 Years.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: To determine the ability of early vital sign abnormalities to predict functional independence in patients with SCI that required surgery. METHODS: A retrospective analysis of data extracted from the Pennsylvania Trauma Outcome Study database. Inclusion criteria were patients >18 years with a diagnosis of SCI who required urgent spine surgery in Pennsylvania from 1/1/2010-12/31/2020 and had complete records available. RESULTS: A total of 644 patients met the inclusion criteria. The mean age was 47.1 ± 14.9 years old and the mean injury severity score (ISS) was 22.3 ± 12.7 with the SCI occurring in the cervical, thoracic, and lumbar spine in 61.8%, 19.6% and 18.0%, respectively. Multivariable logistic regression analyses for predictors of functional independence at discharge showed that higher HR at the scene (OR 1.016, 95% CI 1.006-1.027, P = .002) and lower ISS score (OR .894, 95% CI .870-.920, P < .001) were significant predictors of functional independence. Similarly, higher admission HR (OR 1.015, 95% CI 1.004-1.027, P = .008) and lower ISS score (OR .880, 95% CI 0.864-.914, P < .001) were significant predictors of functional independence. Peak Youden indices showed that patients with HR at scene >70 and admission HR ≥83 were more likely to achieve functional independence. CONCLUSIONS: Early heart rate is a strong predictor of functional independence in patients with SCI. HR at scene >70 and admission HR ≥83 is associated with improved outcomes, suggesting lack of neurogenic shock.

Social Media and Neurosurgery: Insights from the Top 100 Neurosurgery Influencers on Twitter.

BACKGROUND: The rise in popularity of social media (SoMe) in medicine has created a powerful tool for the professional development and continued education of clinicians. Numerous benefits of SoMe exist; however, significant challenges concerning professionalism, confidentiality, and spread of misinformation may limit its usefulness. To understand the ways the top 100 Twitter influencers interact with SoMe, their views on SoMe, and its future in the medical field. METHODS: Literature was reviewed to obtain common concerns about SoMe in the medical field. A survey with 30 questions was sent to the top 100 Twitter influencers in the Neurosurgical field identified by Riccio et al. The survey assessed participant demographics, SoMe activity, stance toward SoMe, and views on the future of SoMe. RESULTS: Most participants were in the age group of 35-44 years (n = 23, 44.2%), resided in the United States (n = 39, 73.6%), have been in practice for 6-10 years (n = 14, 26.4%), and ranked Twitter as the mostly used platform (n = 37,72.6%). Per participant Reponses, 35 (66%) participants have taken a political stance on SoMe, 0 (0%) have gotten into any legal issues regarding a post shared on SoMe, 45 (84.9%) agreed/strongly agreed that SoMe is essential for networking and mentorship, and 49 (92.3%) agreed/strongly agreed that that SoMe will continue to play a major role in the medical field. CONCLUSIONS: Although SoMe has its advantages, several disadvantages render it a double-edged sword. Maximizing SoMe's benefits and minimizing its misuse will further strengthen its role in the medical field.

The Effect of COVID-19 Vaccines on Stroke Outcomes: A Single-Center Study.

BACKGROUND: One of the defining narratives of the COVID-19 pandemic has been the acceptance and distribution of vaccine. To compare the outcomes of COVID-19 positive vaccinated and unvaccinated stroke patients. METHODS: This is a single-center retrospective study of COVID-19-vaccinated and unvaccinated stroke patients between April 2020 and March 2022. All patients presenting with stroke regardless of treatment modalities were included. National Institutes of Health Stroke Scale was used to assess stroke severity. The primary outcome was functional capacity of the patients at discharge. RESULTS: The study cohort comprised 203 COVID-19 positive stroke patients divided into 139 unvaccinated and 64 fully vaccinated patients. At discharge, the modified Rankin scale score was significantly lower in the vaccinated cohort (3[1-4] vs. 4[2-5], odds ratio = 0.508, P = 0.011). At 3 months of follow-up, the median modified Rankin scale score was comparable between both cohorts. CONCLUSIONS: Although vaccination did not show any significant difference in stroke patient outcomes on follow-up, vaccines were associated with lower rates of morbidity and mortality at discharge among stroke patients during the pandemic.

Euglycemic diabetic ketoacidosis (EDKA) after pancreaticoduodenectomy: An under-recognized metabolic abnormality with outcome implications.

BACKGROUND: Euglycemic diabetic ketoacidosis is a metabolic condition characterized by relative euglycemia, ketonemia, and metabolic acidosis that occurs through mechanisms resembling starvation. Pancreaticoduodenectomy is a complex abdominal operation that subjects patients to a prolonged fasting and an inflammatory state. This study examined the incidence of euglycemic diabetic ketoacidosis and potential opportunities for early diagnosis and management in patients undergoing pancreaticoduodenectomy. METHODS: A single-institution retrospective review of 350 patients who underwent pancreaticoduodenectomy between 2017 and 2020 was performed. Primary endpoints were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits, and urinary output within the first 24 hours, postoperatively. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative hospital length of stay, readmission rates, and changes in insulin regimen at discharge. RESULTS: Of the 350 cases reviewed, 39 (11.1%) patients developed euglycemic diabetic ketoacidosis. Male sex and pancreatic cancer were associated with a risk for euglycemic diabetic ketoacidosis (P < .05). Patients with euglycemic diabetic ketoacidosis had significantly higher peak beta-hydroxybutyrate levels than patients without euglycemic diabetic ketoacidosis (mean difference = 19.8 mg/dL, 95% confidence interval = 14.7-24.9, P < .001), and were nearly four times more likely to require insulin at discharge (odds ratio 3.8, 95% confidence interval = 1.1-13.0, P < .05). CONCLUSION: This is the first large descriptive study that investigates euglycemic diabetic ketoacidosis after pancreaticoduodenectomy. Euglycemic diabetic ketoacidosis after pancreaticoduodenectomy is associated with significantly higher beta-hydroxybutyrate levels and new or increased insulin requirement at discharge. Our study demonstrates potential markers for euglycemic diabetic ketoacidosis after pancreaticoduodenectomy, offering an opportunity to identify and successfully treat this disease in a timely manner.

Comparison of Flow-Redirection Endoluminal Device and Pipeline Embolization Device in the Treatment of Intracerebral Aneurysms.

BACKGROUND: The use of flow diverters for treating intracranial aneurysms has been widely used in the past decade; however, data comparing pipeline embolization device (PED; Medtronic Inc) and flow-redirection endoluminal device (FRED; MicroVention) in the treatment of intracranial aneurysms remain scarce. OBJECTIVE: To compare the outcomes of PED and FRED in the treatment of intracranial aneurysms. METHODS: This is a single-center retrospective review of aneurysms treated with PED and FRED devices. Patients treated with PED or FRED were included. Cases requiring multiple or adjunctive devices were excluded. Primary outcome was complete aneurysm occlusion at 6 months. Secondary outcomes included good functional outcome, need for retreatment, and any complication. RESULTS: The study cohort comprised 150 patients, including 35 aneurysms treated with FRED and 115 treated with PED. Aneurysm characteristics including location and size were comparable between the 2 cohorts. 6-month complete occlusion rate was significantly higher in the PED cohort (74.7% vs 51.5%; P = .017) but lost significance after inverse probability weights. Patients in the PED cohort were associated with higher rates of periprocedural complications (3.5% vs 0%; P = .573), and the rate of in-stent stenosis was approximately double in the FRED cohort (15.2% vs 6.9%; P = .172). CONCLUSION: Compared with PED, FRED offers modest 6-month occlusion rates, which may be due to aneurysmal and baseline patient characteristics differences between both cohorts. Although not significant, FRED was associated with a higher complication rate mostly because of in-stent stenosis. Additional studies with longer follow-up durations should be conducted to further evaluate FRED thrombogenicity.

Safety and efficacy of salvage therapy with laser interstitial thermal therapy for malignant meningioma refractory to cesium-131 brachytherapy: illustrative case.

BACKGROUND: Anaplastic meningioma are rare, cancerous tumors of the central nervous system that often require multimodal therapy for tumor control. Both laser interstitial thermal therapy (LITT) and brachytherapy with implanted cesium-131 metallic seeds have demonstrated efficacy in the treatment of recurrent and resistant anaplastic meningioma; however, their safety as a dual therapy has never been reported. OBSERVATIONS: In this report, the authors present a case of a 53-year-old female who received LITT in combination with brachytherapy after surgical and radiation treatment options had been exhausted. The authors discuss the unique safety concern of thermal injury with this treatment combination and demonstrate their method for the safe administration of these treatments together. Furthermore, the authors provide a review of the literature on LITT as an emerging therapy for anaplastic meningioma. LESSONS: The use of LITT in combination with brachytherapy remains an option for salvage therapy in patients with recurrent meningioma that provides durable local control of tumor.

Radiation of meningioma dural tail may not improve tumor control rates.

Introduction: Dural tails are thickened contrast-enhancing portions of dura associated with some meningiomas. Prior studies have demonstrated the presence of tumor cells within the dural tail, however their inclusion in radiation treatment fields remains controversial. We evaluated the role of including the dural tail when treating a meningioma with stereotactic radiation and the impact on tumor recurrence. Methods: This is a retrospective, single-institution, cohort study of patients with intracranial World Health Organization (WHO) grade 1 meningioma and identified dural tail who were treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) from January 2012 to December 2018. SRS and FSRT subgroups were categorized based on coverage or non-coverage of the dural tail by the radiation fields, as determined independently by a radiation oncologist and a neurosurgeon. Demographics, tumor characteristics, radiation plans, and outcomes were evaluated. High grade tumors were analyzed separately. Results: A total of 187 WHO grade 1 tumors from 177 patients were included in the study (median age: 62 years, median follow-up: 40 months, 78.1% female) with 104 receiving SRS and 83 receiving FSRT. The dural tail was covered in 141 (75.4%) of treatment plans. There was no difference in recurrence rates (RR) or time to recurrence (TTR) between non-coverage or coverage of dural tails (RR: 2.2% vs 3.5%, P = 1.0; TTR: 34 vs 36 months, P = 1.00). There was no difference in the rate of radiation side effects between dural tail coverage or non-coverage groups. These associations remained stable when SRS and FSRT subgroups were considered separately, as well as in a high grade cohort of 16 tumors. Conclusion: Inclusion of the dural tail in the SRS or FSRT volumes for meningioma treatment does not seem to reduce recurrence rate. Improved understanding of dural tail pathophysiology, tumor grade, tumor spread, and radiation response is needed to better predict the response of meningiomas to radiotherapy.

Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10.

Leber congenital amaurosis type 10 is a severe retinal dystrophy caused by mutations in the CEP290 gene1,2. We developed EDIT-101, a candidate genome-editing therapeutic, to remove the aberrant splice donor created by the IVS26 mutation in the CEP290 gene and restore normal CEP290 expression. Key to this therapeutic, we identified a pair of Staphylococcus aureus Cas9 guide RNAs that were highly active and specific to the human CEP290 target sequence. In vitro experiments in human cells and retinal explants demonstrated the molecular mechanism of action and nuclease specificity. Subretinal delivery of EDIT-101 in humanized CEP290 mice showed rapid and sustained CEP290 gene editing. A comparable surrogate non-human primate (NHP) vector also achieved productive editing of the NHP CEP290 gene at levels that met the target therapeutic threshold, and demonstrated the ability of CRISPR/Cas9 to edit somatic primate cells in vivo. These results support further development of EDIT-101 for LCA10 and additional CRISPR-based medicines for other inherited retinal disorders.

Amelioration of Alpha-1 Antitrypsin Deficiency Diseases with Genome Editing in Transgenic Mice.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary liver disease caused by mutations in the SERPINA1 serine protease inhibitor gene. Most severe patients are homozygous for PiZ alleles (PiZZ; amino acid E324K), which lead to protein aggregates in hepatocytes and reduced circulating levels of AAT. The liver aggregates typically lead to fibrosis, cirrhosis, and hepatocellular carcinoma, and the reduced circulating AAT levels can lead to emphysema and chronic obstructive pulmonary diseases. In this study, two CRISPR/Cas9 gene editing approaches were used to decrease liver aggregates and increase systemic AAT-M levels in the PiZ transgenic mouse. In the first approach, AAT expression in hepatocytes was reduced more than 98% following the systemic delivery of AAV8-CRISPR targeting exon 2 of hSERPINA1, leading to reduced aggregates in hepatocytes. In the second approach, a second adeno-associated virus, which provided the donor template to correct the Z mutation, was also administered. These treated mice had reduced AAT expression (> 98%) and a low level (5%) of wildtype AAT-M mRNA. Taken together, this study shows that CRISPR gene editing can efficiently reduce liver expression of AAT-Z and restore modest levels of wildtype AAT-M in a mouse model of AATD, raising the possibility of CRISPR gene editing therapeutic for AATD.