ABSTRACT
Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals1, yet their preparation often relies on low-efficiency multi-step synthesis2. These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein we characterize a multifunctional biocatalyst for amine synthesis, which operates using a mechanism that is, to our knowledge, previously unreported. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,ß-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers bearing up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED, which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.
Subject(s)
Amines , Oxidoreductases , Amination , Amines/chemistry , Biocatalysis , Imines/chemistry , Oxidoreductases/genetics , Oxidoreductases/metabolism , StereoisomerismABSTRACT
BACKGROUND: Surgery remains the only recommended intervention for patients with native aortic regurgitation. A transcatheter therapy to treat patients at high risk for mortality and complications with surgical aortic valve replacement represents an unmet need. Commercial transcatheter heart valves in pure aortic regurgitation are hampered by unacceptable rates of embolisation and paravalvular regurgitation. The Trilogy transcatheter heart valve (JenaValve Technology, Irvine, CA, USA) provides a treatment option for these patients. We report outcomes with transfemoral transcatheter aortic valve implantation (TAVI) in patients with pure aortic regurgitation using this dedicated transcatheter heart valve. METHODS: The ALIGN-AR trial is a prospective, multicentre, single-arm study. We recruited symptomatic patients (aged ≥18 years) with moderate-to-severe or severe aortic regurgitation at high risk for mortality and complications after surgical aortic valve replacement at 20 US sites for treatment with the Trilogy transcatheter heart valve. The 30-day composite primary safety endpoint was compared for non-inferiority with a prespecified performance goal of 40·5%. The primary efficacy endpoint was 1-year all-cause mortality compared for non-inferiority with a performance goal of 25%. This trial is registered with ClinicalTrials.gov, NCT04415047, and is ongoing. FINDINGS: Between June 8, 2018, and Aug 29, 2022, we screened 346 patients. We excluded 166 (48%) patients and enrolled 180 (52%) patients with symptomatic aortic regurgitation deemed high risk by the heart team and independent screening committee assessments. The mean age of the study population was 75·5 years (SD 10·8), and 85 (47%) were female, 95 (53%) were male, and 131 (73%) were White. Technical success was achieved in 171 (95%) patients. At 30 days, four (2%) deaths, two (1%) disabling strokes, and two (1%) non-disabling strokes occurred. Using standard Valve Academic Research Consortium-2 definitions, the primary safety endpoint was achieved, with events occurring in 48 (27% [97·5% CI 19·2-34·0]) patients (pnon-inferiority<0·0001), with new pacemaker implantation in 36 (24%) patients. The primary efficacy endpoint was achieved, with mortality in 14 (7·8% [3·3-12·3]) patients at 1 year (pnon-inferiority<0·0001). INTERPRETATION: This study shows the safety and effectiveness of treating native aortic regurgitation using a dedicated transcatheter heart valve to treat patients with symptomatic moderate-to-severe or severe aortic regurgitation who are at high risk for mortality or complications after surgical aortic valve replacement. The observed short-term clinical and haemodynamic outcomes are promising as are signs of left ventricular remodelling, but long-term follow-up is necessary. FUNDING: JenaValve Technology.
Subject(s)
Aortic Valve Insufficiency , Aortic Valve Stenosis , Heart Valve Prosthesis , Transcatheter Aortic Valve Replacement , Adolescent , Adult , Aged , Female , Humans , Male , Aortic Valve/diagnostic imaging , Aortic Valve/surgery , Aortic Valve Insufficiency/etiology , Aortic Valve Insufficiency/surgery , Aortic Valve Stenosis/surgery , Prospective Studies , Prosthesis Design , Risk Factors , Transcatheter Aortic Valve Replacement/adverse effects , Treatment OutcomeABSTRACT
PURPOSE: We aim to determine whether preoperatively initiated gabapentin for pain control impacts the percentage of rootlets cut during monitored, limited laminectomy selective dorsal rhizotomy (SDR) procedure. METHODS: This retrospective cohort study includes participants with cerebral palsy who had SDR for treatment of spasticity between 2010 and 2019 at a single-institution tertiary care center. One-level laminectomy SDR aimed to evaluate the cauda equina roots from levels L2-S1 with EMG monitoring. Gabapentin titration began 3 weeks prior to SDR. Data was analyzed using simple linear regression. Thirty-one individuals met inclusion criteria. Mean age was 7 years, 4 months. Eighteen participants (58%) identified as male, 12 (39%) female, and one (3%) non-binary. Thirty (97%) had bilateral CP. Sixteen (52%) were GMFCS II, four (13%) GMFCS III, five (16%) GMFCS IV, and six (19%) GMFCS V. RESULTS: Mean percentage of rootlets transected was 50.75% (SD 6.00, range 36.36-60.87). There was no relationship between the dose of gabapentin at time of SDR and percentage of rootlets cut with a linear regression slope of - 0.090 and an R2 of 0.012 (P = 0.56). CONCLUSION: Results indicate that preoperative initiation of gabapentin did not impact the percentage of rootlets transected. Thus, gabapentin can be initiated prior to SDR at moderate dosages without impacting SDR surgical outcomes.
Subject(s)
Cerebral Palsy , Rhizotomy , Humans , Male , Female , Child , Rhizotomy/methods , Gabapentin , Retrospective Studies , Spinal Nerve Roots/surgery , Cerebral Palsy/surgery , Muscle Spasticity/surgery , Pain , Treatment OutcomeABSTRACT
PURPOSE: Choroid plexus tumors (CPT) are relatively rare CNS tumors that primarily occur in children. They are classified as low-grade choroid plexus papilloma, including atypical ones, and high-grade choroid plexus carcinoma based on histological characteristics. There has been extensive academic research regarding these complex tumors. The goal of this work was to identify the 100 most-cited articles pertaining to CPTs in order to better understand the most impactful studies to date. METHODS: In August 2023, Elsevier's Scopus database was searched for the 100 most-cited articles about CPT. To look for trends, articles were classified as either basic science or clinical, and the earliest 50 articles were separated from the latest 50 articles and then were compared. Various bibliometric parameters were summarized and compared using Pearson's chi-square exact test and Wilcoxon rank sum test/Mann-Whitney U test. RESULTS: The 100 most-cited articles were published between 1955 and 2016 in 53 different scientific journals, originating from 16 distinct countries. Over 75% of the articles were clinical in nature, and overall mean (range) values were as follows: citation count 78.5 (42-371), citation rate per year 3.4 (0.9-12), number of authors 6.2 (1-28). Newer articles had statistically higher citation rate (P < 0.01) and number of authors (P < 0.01) compared to their older counterparts. Additionally, while there was no significant difference in article focus (P = 0.64), there was a difference in study design (P < 0.01). CONCLUSION: This study used citation number as a surrogate for article impact and identified the 100 most-cited CPT articles. New mutational analyses have allowed for further subgrouping and positive trends in collaboration shine hope for improvement in treatment outcomes and long-term survival.
Subject(s)
Choroid Plexus Neoplasms , Papilloma, Choroid Plexus , Child , Humans , Bibliometrics , Choroid Plexus Neoplasms/pathology , Papilloma, Choroid Plexus/pathology , Treatment Outcome , Research DesignABSTRACT
Medulloblastoma, the most common malignant brain tumor in children, presents a complex treatment challenge due to its propensity for infiltrative growth within the posterior fossa and its potential attachment to critical anatomical structures. Central to the management of medulloblastoma is the surgical resection of the tumor, which is a key determinant of patient prognosis. However, the extent of surgical resection (EOR), ranging from gross total resection (GTR) to subtotal resection (STR) or even biopsy, has been the subject of extensive debate and investigation within the medical community. Today, the impact of neurosurgical EOR on the prognosis of medulloblastoma patients remains a complex and evolving area of investigation. The conflicting findings in the literature, the challenges posed by critical surrounding anatomical structures, the potential for surgical complications and neurologic morbidity, and the nuanced interactions with molecular subgroups all contribute to the complexity of this issue. As the field continues to advance, the imperative to strike a delicate balance between maximizing resection and preserving quality of life remains central to the management of medulloblastoma patients.
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Brain Neoplasms , Cerebellar Neoplasms , Medulloblastoma , Child , Humans , Medulloblastoma/surgery , Quality of Life , Neurosurgical Procedures , Brain Neoplasms/surgery , Cerebellar Neoplasms/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.
Subject(s)
Bibliometrics , Brain Neoplasms , Glioma , Histones , Mutation , Humans , Glioma/genetics , Glioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Histones/genetics , Epigenesis, GeneticABSTRACT
INTRODUCTION: Congenital hydrocephalus often results in irreversible and severe damage to the brain despite postnatal interventions. The potential for prenatal intervention to mitigate these deleterious effects underscores the importance of a suitable animal model. We aimed assess the results of an ultrasound guided transuterine approach to replicate the BioGlue injection fetal hydrocephalus model. METHODS: Pregnant ewes were anesthetized at 95 days of gestation and BioGlue was injected into the fetal cisterna magna under ultrasound guidance through the uterus. Ventriculomegaly was assessed by MRI and histology. RESULTS: Nine pregnant ewes were included in the study, and their fetuses were divided into the the BioGlue intervention group (n=9 fetuses) or the control group (n=7 fetuses) who were not injected. Although hydrocephalus was noted in 5 of 9 fetuses in the intervention group, the ability to induce hydrocephalus went from 0% to 100% in the last 3 fetuses following technical modifications. None of the controls developed hydrocephalus. Fetal brains with hydrocephalus demonstrated increased IBA1+ compared to control animals. CONCLUSIONS: While technical challenges were noted, the ultrasound guided transuterine approach to replicate the BioGlue fetal hydrocephalus model in sheep showed consistent and reproducible results. This model offers the advantage of directly visualizing the location of the needle tip and injection of the BioGlue. This technique offers an alternative for testing novel approaches for prenatal congenital hydrocephalus treatment.
ABSTRACT
INTRODUCTION: Intracranial cavernous malformations (CMs) are rare vascular malformations of the central nervous system in children. Infantile patients, being a developmentally vulnerable age group, pose a special challenge for management of these lesions. We pooled data from infantile patients diagnosed at our institution and individual cases published in the literature to provide input towards therapeutic decision-making. METHODS: A systematic search of PubMed, MEDLINE, Embase, and Scopus was performed in accordance with PRISMA guidelines to identify all reported cases of intracranial CMs in the literature for infantile patients aged ≤ 2 years. In addition, cases from our institution diagnosed between 2010 and 2020 were also included. Individual cases were pooled and analyzed for clinical presentation, natural history, and outcomes from conservative and surgical management. RESULTS: A total of 36 cases were included, of which 32 were identified from the literature. Median age at presentation was 14 months (range: 2 days to 24 months) months; 53% (n = 19) were females. Most cavernomas (64%, 23/36) were supratentorial, while 30% (n = 11) were located in brainstem and 5.5% (n = 2) in the cerebellum. With the exception of one patient, all cases were reported to be symptomatic; seizures (n = 15/31, 48.3%) and motor deficits (n = 13/31, 42%) were the most common symptom modalities. A total of 13 patients were managed conservatively upon initial presentation. No symptomatic hemorrhages were observed during 26 total person-years of follow-up. A total of 77% (28/36) underwent surgery; either upfront (23/28, 82%) at initial presentation or following conservative management. Among 12 patients who had preoperative seizures, 11/12 (91.6%) achieved seizure freedom post-resection. Among 7 patients who presented with hemiparesis preoperatively, 5 (71%) demonstrated some improvement, while 1 remained unchanged, and another patient with a brainstem cavernous malformation had worsening of motor function postoperatively. Postoperative recurrence was noted in 3 cases (3/27, 11%). CONCLUSION: Annual risk of repeat hemorrhage may be low for infantile patients with intracranial cavernous malformations; however, better follow-up rates and higher number of cases are needed to make a definitive assertion. Surgical resection may be associated with high rates of epilepsy cure and provide improvement in neurological function in a select number of cases.
Subject(s)
Hemangioma, Cavernous, Central Nervous System , Hemangioma, Cavernous , Child , Female , Humans , Infant, Newborn , Male , Hemangioma, Cavernous, Central Nervous System/complications , Hemangioma, Cavernous, Central Nervous System/diagnostic imaging , Hemangioma, Cavernous, Central Nervous System/surgery , Brain Stem/pathology , Seizures/complications , ParesisABSTRACT
INTRODUCTION: Pediatric cerebrovascular lesions are very rare and include aneurysms, arteriovenous malformations (AVM), and vein of Galen malformations (VOGM). OBJECTIVE: To describe and disseminate a validated, reproducible set of 3D models for optimization of neurosurgical training with respect to pediatric cerebrovascular diseases METHODS: All pediatric cerebrovascular lesions treated at our institution with adequate imaging studies during the study period 2015-2020 were reviewed by the study team. Three major diagnostic groups were identified: aneurysm, AVM, and VOGM. For each group, a case deemed highly illustrative of the core diagnostic and therapeutic principles was selected by the lead and senior investigators for printing (CSG/JM). Files for model reproduction and free distribution were prepared for inclusion as Supplemental Materials. RESULTS: Representative cases included a 7-month-old female with a giant left MCA aneurysm; a 3-day-old male with a large, complex, high-flow, choroidal-type VOGM, supplied from bilateral thalamic, choroidal, and pericallosal perforators, with drainage into a large prosencephalic vein; and a 7-year-old male with a left frontal AVM with one feeding arterial vessel from the anterior cerebral artery and one single draining vein into the superior sagittal sinus CONCLUSION: Pediatric cerebrovascular lesions are representative of rare but important neurosurgical diseases that require creative approaches for training optimization. As these lesions are quite rare, 3D-printed models and open source educational materials may provide a meaningful avenue for impactful clinical teaching with respect to a wide swath of uncommon or unusual neurosurgical diseases.
Subject(s)
Arteriovenous Malformations , Intracranial Aneurysm , Intracranial Arteriovenous Malformations , Vein of Galen Malformations , Humans , Child , Male , Female , Infant , Vein of Galen Malformations/surgery , Anterior Cerebral Artery , Intracranial Aneurysm/diagnostic imaging , Intracranial Aneurysm/surgery , Printing, Three-Dimensional , Intracranial Arteriovenous Malformations/diagnostic imaging , Intracranial Arteriovenous Malformations/surgeryABSTRACT
PURPOSE: To create a high-quality, cadaver-based, operatively oriented resource documenting the anterior transcortical and interhemispheric transcallosal approaches as corridors to the third ventricle targeted towards neurosurgical trainees at all levels. METHODS: Two formalin-fixed, latex-injected specimens were dissected under microscopic magnification and endoscopic-assisted visualization. Dissections of the transcortical and transcallosal craniotomies with transforaminal, transchoroidal, and interforniceal transventricular approaches were performed. The dissections were documented in a stepwise fashion using three-dimensional photographic image acquisition techniques and supplemented with representative cases to highlight pertinent surgical principles. RESULTS: The anterior transcortical and interhemispheric corridors afford excellent access to the anterior two-thirds of the third ventricle with varying risks associated with frontal lobe versus corpus callosum disruption, respectively. The transcortical approach offers a more direct, oblique view of the ipsilateral lateral ventricle, whereas the transcallosal approach readily establishes biventricular access through a paramedian corridor. Once inside the lateral ventricle, intraventricular angled endoscopy further enhances access to the extreme poles of the third ventricle from either open transcranial approach. Subsequent selection of either the transforaminal, transchoroidal, or interforniceal routes can be performed through either craniotomy and is ultimately dependent on individual deep venous anatomy, the epicenter of ventricular pathology, and the concomitant presence of hydrocephalus or embryologic cava. Key steps described include positioning and skin incision; scalp dissection; craniotomy flap elevation; durotomy; transcortical versus interhemispheric dissection with callosotomy; the aforementioned transventricular routes; and their relevant intraventricular landmarks. CONCLUSIONS: Approaches to the ventricular system for maximal safe resection of pediatric brain tumors are challenging to master yet represent foundational cranial surgical techniques. We present a comprehensive operatively oriented guide for neurosurgery residents that combines stepwise open and endoscopic cadaveric dissections with representative case studies to optimize familiarity with third ventricle approaches, mastery of relevant microsurgical anatomy, and preparation for operating room participation.
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Brain Neoplasms , Third Ventricle , Humans , Child , Third Ventricle/surgery , Third Ventricle/anatomy & histology , Cerebral Ventricles/surgery , Cerebral Ventricles/anatomy & histology , Neurosurgical Procedures/methods , Lateral Ventricles/surgery , Brain Neoplasms/surgery , Corpus Callosum/surgery , Corpus Callosum/anatomy & histologyABSTRACT
Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma, and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events.Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. SIGNIFICANCE STATEMENT: The CNS penetration of alisertib is limited with uniform distribution in various regions of the brain, and P-gp efflux is an important mechanism limiting that CNS distribution. Alisertib rapidly distributes into the bone marrow, a site of toxicity, with a greater exposure than in the CNS, a possible site of efficacy. These results suggest a need to design localized delivery strategies to improve the CNS exposure of alisertib and limit systemic toxicities in the treatment of brain tumors.
Subject(s)
Aurora Kinase A , Brain Neoplasms , Animals , Mice , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Aurora Kinase A/metabolism , Aurora Kinase A/therapeutic use , Bone Marrow/metabolism , Neoplasm Proteins/metabolism , Azepines/pharmacokinetics , Central Nervous System/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , Protein Kinase Inhibitors/metabolism , Brain Neoplasms/drug therapy , Mice, KnockoutABSTRACT
INTRODUCTION: Diffuse midline gliomas (DMG) with the H3 K27M-mutation are a well-described entity with most DMG harboring this mutation, with notable heterogeneity in adults. No therapy has been proven to improve survival in this tumor type. Panobinostat is a histone deacetylase inhibitor that may have therapeutic benefit. METHODS: We report our retrospective experience with use of panobinostat in adults (> 18 years) with H3 K27M-mutant DMG treated at Mayo Clinic (Rochester) from January 2016 to August 2020, with follow-up until October 2021. Survival was calculated using the Kaplan-Meier method. RESULTS: 4 patients with H3 K27M-mutant glioma were treated with panobinostat as compassionate use. Patients had a median age of 40 years (range 22-62 years) and 2 were female. Tumor location was midline for all patients, spinal cord (n = 2), brainstem (n = 1), and thalamus (n = 1). All tumors were IDH1/IDH2 wildtype. 3 patients received radiotherapy followed by adjuvant panobinostat. All patients had no other pharmacologic therapy utilized prior to or during panobinostat therapy aside from concurrent dexamethasone utilized in 3 patients. No patient experienced a grade 2 or higher (per CTCAE grade) adverse effect. The median overall survival was 42 months, median progression free survival of 19 months, 2 patients were alive at last follow up (both with spinal cord tumors and received radiation). The best response was stable disease in 2 patients and a partial response in 1 patient. CONCLUSIONS: This is the first report of clinical outcomes of panobinostat in adults with H3 K27M-mutant DMG. We showed that it is well-tolerated at the dosage schedule that we describe, with no serious adverse effects throughout the study period.
Subject(s)
Brain Neoplasms , Glioma , Adult , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Female , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Histones/genetics , Humans , Middle Aged , Mutation , Panobinostat/therapeutic use , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Medulloblastoma (MB) and diffuse infiltrative pontine glioma (DIPG) are malignant pediatric tumors. Extracellular vesicles (EVs) and their bioactive cargoes have been implicated in tumorigenesis. Most studies have focused on adult tumors, therefore the role of EVs and the noncoding RNA (ncRNA) landscape in pediatric brain tumors is not fully characterized. The overall aim of this pilot study was to isolate EVs from MB and DIPG patient-derived cell lines and to explore the small ncRNA transcriptome. METHODS: EVs from 3 DIPG and 4 MB patient-derived cell lines were analyzed. High-throughput next generation sequencing interrogated the short non-coding RNA (ncRNA) transcriptome. Known and novel miRNAs were quantified. Differential expression analysis, in silico target prediction, and functional gene enrichment were performed. RESULTS: EV secretomes from MB and DIPG patient-derived cell lines demonstrated discrete ncRNA biotypes. Notably, miRNAs were depleted and Y RNAs were enriched in EV samples. Hierarchical cluster analysis revealed high discrimination in miRNA expression between DIPG and MB cell lines and RNA-Seq identified novel miRNAs not previously implicated in MB or DIPG pathogenesis. Known and putative target genes of dysregulated miRNAs were identified. Functional annotation analysis of the target genes for differentially expressed EV-and parental-derived miRNAs revealed significant cancer-related pathway involvement. CONCLUSIONS: This hypothesis-generating study demonstrated that pediatric brain tumor-derived cell lines secrete EVs comprised of various ncRNA cargoes. Validation of these findings in patient samples may provide new insights into the pediatric brain tumor microenvironment and identification of novel therapeutic candidates.
Subject(s)
Brain Neoplasms , Extracellular Vesicles , MicroRNAs , RNA, Small Untranslated , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Child , Extracellular Vesicles/metabolism , Humans , MicroRNAs/metabolism , Pilot Projects , RNA, Small Untranslated/metabolismABSTRACT
BACKGROUND: Pilocytic astrocytomas are the most common low-grade glioma of the central nervous system that typically occurs in children, and much research has been dedicated to characterizing their molecular features and clinical courses. We provide an overview of the current literature through the use of a bibliometric analysis of the top 100 most cited publications discussing pilocytic astrocytomas. METHODS: We identified the top 100 most cited publications discussing pilocytic astrocytomas. Articles were ranked based on the number of citations. Descriptive statistics and univariate analysis were used to determine any trends or significant differences in the data. RESULTS: Of the top 100 articles, 50 were basic science (50%), 34 were clinical (34%), and 16 were review (16%). The number of citations ranged from 79 to 921, with 123 being the median. The US had the most first authors and principal authors (n = 53 and n = 54, respectively). Years of publication had a left-skewed distribution and peaked during 2011 with 12 articles published in that year. Sixty percent of basic science articles investigated BRAF/MAPK pathways, while 67.6% of clinical articles focused on evaluating treatment options for pilocytic astrocytomas. Compared to basic science and clinical articles, review articles were published more recently (p < 0.001), had fewer authors (p = 0.025) and were published in journals with higher impact factors (p = 0.022). CONCLUSION: Research regarding pilocytic astrocytomas has increased over the past three decades. Future directions of research point towards employing targeted therapies and discovering additional cellular pathways contributing to disease pathogenesis.
Subject(s)
Astrocytoma , Glioma , Astrocytoma/pathology , Astrocytoma/therapy , Bibliometrics , Child , Humans , Research DesignABSTRACT
OBJECTIVE: Chiari I malformation is treated with suboccipital craniectomy with cervical laminectomy, a procedure which has been associated with the possibility of pre-existing or iatrogenic occipitocervical instability. The long-term risk of subsequent spinal deformity and need for occipito cervical fusion after standard Chiari decompression in pediatric patients has not yet been characterized. METHODS: We queried our institutional electronic database for patients aged 18 and under, with at least 5 years of follow-up, that underwent surgical decompression for Chiari I malformation. Occurrence of subsequent occipitocervical fusion at follow-up comprised the primary endpoint. Cases with myelomeningocele, Chiari II, or fusion at time of decompression were excluded. RESULTS: A total of 30 patients (median age 5.5 years, 60% males) were analyzed. Age distribution was as follows: n = 3 for 0-1 years, n = 11 for 1-5 years, n = 4 for 5-10 years, and n = 12 for 10-18 years. Median tonsillar descent below the foramen magnum was 12.5 mm (interquartile range [IQR]: 10.8-19.5 mm). Syringomyelia was observed in 43%, retroflexion of the dens in 55%, basilar invagination in 6.7%, and medullary kinking in 27%. The median clivo-axial angle was 142° (132-150°). The majority of patients underwent C1 laminectomy (n = 24, 80%), followed by C1-C2 laminectomy (n = 4, 13%), while one patient had C1-upper C2 and C1-C3 laminectomy each, respectively. At a median follow-up of 6.3 years, there was only one patient (3.3% of overall cohort) that underwent subsequent occipitocervical fusion. The patient (4-year-old male) initially had a suboccipital craniectomy with C1 laminectomy and duraplasty and presented with recurrence of posterior headaches and neck pain 4 months after original surgery. We proceeded with occiput-C2 fusion with subsequent resolution of his symptoms. CONCLUSION: Current analysis shows that in the absence of clinical or imaging features suggestive of craniocervical instability, Chiari I decompressive surgery is associated with very low long-term risk of requiring occipitocervical fusion. This observance can be used to guide surgical treatment decisions, especially in young children with Chiari I malformations.
Subject(s)
Arnold-Chiari Malformation , Syringomyelia , Arnold-Chiari Malformation/complications , Arnold-Chiari Malformation/diagnostic imaging , Arnold-Chiari Malformation/surgery , Child , Child, Preschool , Decompression, Surgical/adverse effects , Decompression, Surgical/methods , Female , Foramen Magnum/surgery , Humans , Laminectomy/adverse effects , Magnetic Resonance Imaging , Male , Syringomyelia/surgery , Treatment OutcomeABSTRACT
BACKGROUND: The diagnosis of glioblastoma (GBM) in infants aged ≤ 1 year is extremely rare, and its comparability to the more common adult diagnosis is underexplored. Correspondingly, the objective of this study was to interrogate a national cancer database to elucidate the typical survival and clinical profile of this demographic. METHODS: All GBM patients aged ≤ 1 year in the U.S. National Cancer Database (NCDB) between 2005 and 2016 were retrospectively reviewed. Data were summarized, and overall survival (OS) was modeled using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 86 patients satisfied criteria for entry into study, making up 0.08% of all GBM diagnoses in the database. There were 32 (37%) females and 54 (63%) males. Irrespective of treatment, median OS was 67.3 months (95% CI, 46-91), which was distinct from all other ages and pediatric age groups. There were 74 (86%) treated by surgery, 51 (59%) treated by chemotherapy, and 17 (20%) treated by radiation therapy. Multivariable analysis demonstrated that Hispanic status (HR = 3.41, P = 0.02) and the presence of comorbidity (HR = 3.24, P = 0.01) independently predicted shorter OS, whereas treatment with chemotherapy (HR = 0.18, P < 0.01) independently predicted longer OS. Neither extent of surgery nor radiation therapy demonstrated independent statistical significance. CONCLUSION: Infantile GBM should be viewed as a distinct GBM entity with a longer OS than other pediatric and adult patients. Chemotherapy is a statistically significant component in the treatment of this demographic, and the value of surgical treatment is likely universal. Future studies into understanding the biological and genetic profile of infantile GBM are needed to advance both pediatric and adult fields.
Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Aged , Brain Neoplasms/drug therapy , Child , Databases, Factual , Female , Humans , Infant , Kaplan-Meier Estimate , Male , Prognosis , Retrospective StudiesABSTRACT
Pediatric tectal gliomas generally have a benign clinical course with the majority of these observed radiologically. However, patients often need treatment for obstructive hydrocephalus and occasionally require cytotoxic therapy. Given the lack of level I data, there is a need to further characterize management strategies for these rare tumors. We have therefore performed the first systematic review comparing various management strategies. The literature was systematically searched from January 1, 2000, to July 30, 2020, to identify studies reporting treatment strategies for pediatric tectal gliomas. The systematic review included 355 patients from 14 studies. Abnormal ocular findings-including gaze palsies, papilledema, diplopia, and visual field changes-were a common presentation with between 13.6 and 88.9% of patients experiencing such findings. CSF diversion was the most performed procedure, occurring in 317 patients (89.3%). In individual studies, use of CSF diversion ranged from 73.1 to 100.0%. For management options, 232 patients were radiologically monitored (65.4%), 69 received resection (19.4%), 30 received radiotherapy (8.4%), and 19 received chemotherapy (5.4%). When examining frequencies within individual studies, chemotherapy ranged from 2.5 to 29.6% and radiotherapy ranged from 2.5 to 28.6%. Resection was the most variable treatment option between individual studies, ranging from 2.3 to 100.0%. Most tectal gliomas in the pediatric population can be observed through radiographic surveillance and CSF diversion. Other forms of management (i.e., chemotherapy and radiotherapy) are warranted for more aggressive tumors demonstrating radiological progression. Surgical resection should be reserved for large tumors and/or those that are refractory to other treatment modalities.
Subject(s)
Brain Stem Neoplasms , Glioma , Hydrocephalus , Brain Stem Neoplasms/diagnostic imaging , Brain Stem Neoplasms/surgery , Child , Glioma/pathology , Glioma/surgery , Humans , Hydrocephalus/surgery , Radiography , Tectum Mesencephali/pathology , Tectum Mesencephali/surgeryABSTRACT
OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has significantly changed clinical practice across US healthcare. Increased adoption of telemedicine has emerged as an alternative to in-person contact for patient-physician interactions. The aim of this study was to analyze the impact of telemedicine on workflow and care delivery from January 2019 to December 2021 in a neurosurgical department at a quaternary care center. METHODS: Prospectively captured data on clinic appointment utilization, duration, and outcomes were queried. Visits were divided into in-person visits and telemedicine appointments, categorized as follow-up visits of previously surgically treated patients, internal consultations, new patient visits, and early postoperative returns after surgery. Appointment volume was compared pre- and postpandemic using March 2020 as the pandemic onset. Clinical efficiency was measured by time to appointment, rate of on-time appointments, proportion of appointments resulting in surgical intervention (surgical yield), and patient-reported satisfaction, the latter measured as the proportion of patients indicating "high likelihood to recommend practice." RESULTS: A total of 54,562 visits occurred, most commonly for follow-up for previously operated patients (51.8%), internal new patient referrals (24.5%), and external new patient referrals (19.8%). Total visit volume was stable pre- to postpandemic (1521.3 vs 1512, p = 0.917). However, in-person visits significantly decreased (1517/month vs 1220/month, p < 0.001), with a nadir in April 2020, while telemedicine appointment utilization increased significantly (0.3% vs 19.1% of all visits). Telemedicine utilization remained stable throughout the 1st calendar year following the pandemic. Telemedicine appointments were associated with shorter time to appointment than in-person visits both before and after the pandemic onset (0-5 days from appointment request: 60% vs 33% vs 29.8%, p < 0.001). Patients had on-time appointments in 87% of telemedicine encounters. Notably, telemedicine appointments resulted in surgery in 31.8% of internal consultations or new patient visits, a significantly lower rate than that for in-person visits (51.8%). After the widespread integration of telemedicine, patient satisfaction for all visits was higher than before the pandemic onset (85.9% vs 88.5%, p = 0.027). CONCLUSIONS: Telemedicine use significantly increased following the pandemic onset, compensating for observed decreases in face-to-face visits. Utilization rates have remained stable, suggesting effective integration, and delays between referrals and appointments were lower than for in-person visits. Importantly, telemedicine integration was not associated with a decrease in overall patient satisfaction, although telemedicine appointments had a lower surgical yield. These data suggest that telemedicine smoothened the impact of the pandemic on clinical workflow and helped to maintain continuity and quality of outpatient care.
Subject(s)
COVID-19 , Telemedicine , Ambulatory Care , COVID-19/epidemiology , Humans , Pandemics , Patient Satisfaction , Telemedicine/methodsABSTRACT
Neurosurgical education is a continually developing field with an aim of training competent and compassionate surgeons who can care for the needs of their patients. The Mayo Clinic utilizes a unique mentorship model for neurosurgical training. In this paper, the authors detail the historical roots as well as the logistical and experiential characteristics of this teaching model. This model was first established in the late 1890s by the Mayo brothers and then adopted by the Mayo Clinic Department of Neurological Surgery at its inception in 1919. It has since been implemented enterprise-wide at the Minnesota, Florida, and Arizona residency programs. The mentorship model is focused on honing resident skills through individualized attention and guidance from an attending physician. Each resident is closely mentored by a consultant during a 2- or 3-month rotation, which allows for exposure to more complex cases early in their training. In this model, residents take ownership of their patients' care, following them longitudinally during their hospital course with guided oversight from their mentors. During the chief year, residents have their own clinic, operating room (OR) schedule, and OR team and service nurse. In this model, chief residents conduct themselves more in the manner of an attending physician than a trainee but continue to have oversight from staff to provide a "safety net." The longitudinal care of patients provided by the residents under the mentorship model is not only beneficial for the trainee and the hospital, but also has a positive impact on patient satisfaction and safety. The Mayo Clinic Mentorship Model is one of many educational models that has demonstrated itself to be an excellent approach for resident education.
Subject(s)
Internship and Residency , Neurosurgery , Surgeons , Humans , Male , MentorsABSTRACT
INTRODUCTION: Germ cell tumors (GCTs) are uncommon neoplasms predominantly arising in midline tissues. The prognostic significance of histopathology in predicting metastatic GCT behavior is poorly understood. METHODS: Multicenter international cohort study including 29 patients with GCTs metastatic to brain were retrospectively investigated (18 patients from Mayo Clinic and 11 patients from the intracranial germ cell tumor genome analysis consortium in Japan). Clinical characteristics were analyzed using the Chi-square test (two-tailed) for categorical variables and using the log-rank test for survival data. RESULTS: Median age at treatment was 31 years (range 14-58). Primary disease sites were testis (71%), mediastinum (18%), and female reproductive organs (11%). Median metastatic interval was 223 days (range, 6-6124). Median follow-up was 346 days (range, 1-5356), with 16 deaths (57%) occurring after the median overall survival of 455 days. Actuarial one-year survival was 51%; 12-of-16 deaths (75%) were attributed to intracranial disease. Appearance of the same GCT subtype at the metastatic site as the primary was high for non-seminomatous GCT (NSGCT, 64-100%), but low for seminoma/dysgerminoma and mature teratoma (MT, 14, 17%, respectively). Gain of a new component was seen in 4 (20%)-3 of which included embryonal carcinoma (EC) at the primary site (75%). Incidence of cases without seminoma/dysgerminoma increased significantly after metastasis (p = 0.02). Metastatic interval was shorter in cases with histological change (199 vs 454 days, p = 0.009). Overall survival was associated with MT primary histopathology (p = 0.02). CONCLUSION: Histological differentiation at the primary GCT site influences metastatic prognosis. Aggressive behavior is associated with NSGCT, while EC frequently demonstrates multi-directional histological differentiation after brain metastasis, and such histological dynamism is associated with shorter metastatic interval. Most metastases occurred within one year of diagnosis, emphasizing the need for close surveillance in newly diagnosed extra-cranial GCT.