Publications by authors named "David J Daniels"

101 Publications

A multicenter analysis of the prognostic value of histone H3 K27M mutation in adult high-grade spinal glioma.

J Neurosurg Spine 2021 Aug 20:1-10. Epub 2021 Aug 20.

1Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida.

Objective: High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic.

Methods: The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS).

Results: Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19-76) years were included in the analysis. Eighteen patients had H3 K27M mutation-positive tumors, and 12 had H3 K27M mutation-negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation-positive tumors (p = 0.017).

Conclusions: Although H3 K27M mutant-positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant-positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant-negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.
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http://dx.doi.org/10.3171/2021.2.SPINE201675DOI Listing
August 2021

Antibody-drug conjugates for H3K27M-mutant diffuse midline gliomas: prospects and challenges.

Ther Deliv 2021 08 21;12(8):553-557. Epub 2021 Jul 21.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.

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http://dx.doi.org/10.4155/tde-2021-0045DOI Listing
August 2021

Histopathology and prognosis of germ cell tumors metastatic to brain: cohort study.

J Neurooncol 2021 Aug 16;154(1):121-130. Epub 2021 Jul 16.

Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

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.
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http://dx.doi.org/10.1007/s11060-021-03810-xDOI Listing
August 2021

Extradural decompression versus duraplasty in Chiari malformation type I with syrinx: outcomes on scoliosis from the Park-Reeves Syringomyelia Research Consortium.

J Neurosurg Pediatr 2021 Jun 18:1-9. Epub 2021 Jun 18.

25Division of Pediatric Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA.

Objective: Scoliosis is common in patients with Chiari malformation type I (CM-I)-associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression.

Methods: A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty.

Results: In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion.

Conclusions: In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD.
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http://dx.doi.org/10.3171/2020.12.PEDS20552DOI Listing
June 2021

The emerging role of nanotechnology in pursuit of successful drug delivery to H3K27M diffuse midline gliomas.

Nanomedicine (Lond) 2021 07 17;16(16):1343-1346. Epub 2021 May 17.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.

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http://dx.doi.org/10.2217/nnm-2021-0067DOI Listing
July 2021

Convection-enhanced delivery for H3K27M diffuse midline glioma: how can we efficaciously modulate the blood-brain barrier?

Ther Deliv 2021 06 5;12(6):419-422. Epub 2021 May 5.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.

Graphical abstract [Formula: see text].
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http://dx.doi.org/10.4155/tde-2021-0026DOI Listing
June 2021

Precision Medicine in Pediatric Bithalamic Glioma: Significance of the EGFR exon 20 Insertion Mutation.

World Neurosurg 2021 05;149:271-273

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

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http://dx.doi.org/10.1016/j.wneu.2021.03.009DOI Listing
May 2021

Pediatric Gliomas: Molecular Landscape and Emerging Targets.

Neurosurg Clin N Am 2021 Apr 18;32(2):181-190. Epub 2021 Feb 18.

Department of Neurosurgery, University of California Los Angeles, 300 Stein Plaza, Suite #520, Los Angeles, CA 90095, USA. Electronic address:

Next-generation sequencing of pediatric gliomas has revealed the importance of molecular genetic characterization in understanding the biology underlying these tumors and a breadth of potential therapeutic targets. Promising targeted therapies include mTOR inhibitors for subependymal giant cell astrocytomas in tuberous sclerosis, BRAF and MEK inhibitors mainly for low-grade gliomas, and MEK inhibitors for NF1-deficient BRAF:KIAA fusion tumors. Challenges in developing targeted molecular therapies include significant intratumoral and intertumoral heterogeneity, highly varied mechanisms of treatment resistance and immune escape, adequacy of tumor penetrance, and sensitivity of brain to treatment-related toxicities.
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http://dx.doi.org/10.1016/j.nec.2020.12.001DOI Listing
April 2021

The Third Eye Sees Double: Cohort Study of Clinical Presentation, Histology, Surgical Approaches, and Ophthalmic Outcomes in Pineal Region Germ Cell Tumors.

World Neurosurg 2021 06 17;150:e482-e490. Epub 2021 Mar 17.

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Background: Intracranial germ cell tumors (GCTs) predominantly occur in the adolescent and young adult population and are most frequently located at the pineal gland. Tumor masses in the pineal region may cause ophthalmic symptoms due to compression to the midbrain, frequently presenting with Parinaud syndrome and hydrocephalus due to aqueductal compression.

Methods: We conducted a single-institution cohort study of primary, pineal region GCTs to characterize the clinical presentation, as well as associated ophthalmic and hydrocephalus outcomes.

Results: Fifty-six primary pineal GCTs were identified. Among the 40 isolated pineal region GCTs, 15 were germinomas while 25 were nongerminomatous GCTs. Among 43 cases of hydrocephalus, endoscopic third ventriculostomy was the primary treatment in 27 cases, which was successful in 23 but failed and required additional treatment for the rest. Pineal tumor mass was significantly larger in cases with hydrocephalus compared with those without, and the 20-mm diameter of the tumor was the crucial point for obstructive hydrocephalus. Ophthalmic symptoms were commonly observed at presentation, which included diplopia (74.3%), upward-gaze palsy (69.7%), and Argyll Robertson pupil (40%). These symptoms tended to remain, and the existence of these symptoms at presentation predicted the remaining symptoms in the follow-up.

Conclusions: Intracranial GCTs presenting with ophthalmic abnormalities appear to be at increased risk of residual posttreatment symptoms, while second-look surgery presents a significant risk factor for the development of new deficits. Hydrocephalus often accompanies pineal region GCTs, and in most cases both cerebrospinal fluid diversion and tissue diagnosis can be successfully achieved via endoscopic third ventriculostomy.
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http://dx.doi.org/10.1016/j.wneu.2021.03.030DOI Listing
June 2021

Early Recurrence of an Infantile Endodermal Oculomotor Nerve Cyst following Surgical Fenestration: A Case Report.

Pediatr Neurosurg 2021 12;56(2):157-162. Epub 2021 Mar 12.

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Infantile endodermal oculomotor nerve cyst (EONC) is an extremely rare entity. There are very few pediatric cases reported in the literature, and as expected, oculomotor palsy is the most common presenting symptom. To date however, the risk of recurrence of these lesions following surgical intervention is unclear due to a lack of long-term radiological follow-up.

Case Presentation: We present a case of a 13-month-old male patient with an EONC and detail his surgical fenestration and postoperative course. Somewhat surprisingly, re-expansion occurred within 6 months and remained stable 2 years later.

Discussion: A surgical approach to fenestration of an EONC in an infant is possible and should be performed by an expert neurosurgeon. Early recurrence is underreported in the current literature, and we encourage longer term radiological surveillance of these lesions after surgery to optimize primary and recurrent management in the future.
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http://dx.doi.org/10.1159/000511774DOI Listing
March 2021

Diffuse Gliomas of the Brainstem and Cerebellum in Adults Show Molecular Heterogeneity.

Am J Surg Pathol 2021 08;45(8):1082-1090

Departments of Laboratory Medicine and Pathology.

Posterior fossa (PF) diffuse gliomas in pediatric patients frequently harbor the H3 K27M mutation. Among adults, PF diffuse gliomas are rare, with limited data regarding molecular features and clinical outcomes. We identified 28 adult PF diffuse glioma patients (17 males; median: 50 y, range: 19 to 78 y), with surgery performed at our institution (13 brainstem; 15 cerebellum). Histologic subtypes included anaplastic astrocytoma (n=21), glioblastoma (n=6), and diffuse astrocytoma (n=1). Immunohistochemistry was performed for H3 K27M (n=26), IDH1-R132H (n=28), and ATRX (n=28). A 150-gene neuro-oncology-targeted next-generation sequencing panel was attempted in 24/28, with sufficient informative material in 15 (51.7%). Tumors comprised 4 distinct groups: driver mutations in H3F3A (brainstem=4; cerebellum=2), IDH1 (brainstem=4; cerebellum=4), TERT promotor mutation (brainstem=0; cerebellum=3), and none of these (n=5), with the latter harboring mutations of TP53, PDGFRA, ATRX, NF1, and RB1. All TERT promoter-mutant cases were IDH-wild-type and arose within the cerebellum. To date, 20 patients have died of disease, with a median survival of 16.3 months, 1-year survival of 67.5%. Median survival within the subgroups included: H3F3A=16.4 months, IDH mutant=113.4 months, and TERT promoter mutant=12.9 months. These findings suggest that PF diffuse gliomas affecting adults show molecular heterogeneity, which may be associated with patient outcomes and possible response to therapy, and supports the utility of molecular testing in these tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001690DOI Listing
August 2021

Dural augmentation approaches and complication rates after posterior fossa decompression for Chiari I malformation and syringomyelia: a Park-Reeves Syringomyelia Research Consortium study.

J Neurosurg Pediatr 2021 Feb 12:1-10. Epub 2021 Feb 12.

3Division of Pediatric Neurosurgery, University of Alabama at Birmingham, AL.

Objective: Posterior fossa decompression with duraplasty (PFDD) is commonly performed for Chiari I malformation (CM-I) with syringomyelia (SM). However, complication rates associated with various dural graft types are not well established. The objective of this study was to elucidate complication rates within 6 months of surgery among autograft and commonly used nonautologous grafts for pediatric patients who underwent PFDD for CM-I/SM.

Methods: The Park-Reeves Syringomyelia Research Consortium database was queried for pediatric patients who had undergone PFDD for CM-I with SM. All patients had tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and ≥ 6 months of postoperative follow-up after PFDD. Complications (e.g., pseudomeningocele, CSF leak, meningitis, and hydrocephalus) and postoperative changes in syrinx size, headaches, and neck pain were compared for autograft versus nonautologous graft.

Results: A total of 781 PFDD cases were analyzed (359 autograft, 422 nonautologous graft). Nonautologous grafts included bovine pericardium (n = 63), bovine collagen (n = 225), synthetic (n = 99), and human cadaveric allograft (n = 35). Autograft (103/359, 28.7%) had a similar overall complication rate compared to nonautologous graft (143/422, 33.9%) (p = 0.12). However, nonautologous graft was associated with significantly higher rates of pseudomeningocele (p = 0.04) and meningitis (p < 0.001). The higher rate of meningitis was influenced particularly by the higher rate of chemical meningitis (p = 0.002) versus infectious meningitis (p = 0.132). Among 4 types of nonautologous grafts, there were differences in complication rates (p = 0.02), including chemical meningitis (p = 0.01) and postoperative nausea/vomiting (p = 0.03). Allograft demonstrated the lowest complication rates overall (14.3%) and yielded significantly fewer complications compared to bovine collagen (p = 0.02) and synthetic (p = 0.003) grafts. Synthetic graft yielded higher complication rates than autograft (p = 0.01). Autograft and nonautologous graft resulted in equal improvements in syrinx size (p < 0.0001). No differences were found for postoperative changes in headaches or neck pain.

Conclusions: In the largest multicenter cohort to date, complication rates for dural autograft and nonautologous graft are similar after PFDD for CM-I/SM, although nonautologous graft results in higher rates of pseudomeningocele and meningitis. Rates of meningitis differ among nonautologous graft types. Autograft and nonautologous graft are equivalent for reducing syrinx size, headaches, and neck pain.
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http://dx.doi.org/10.3171/2020.8.PEDS2087DOI Listing
February 2021

Pediatric Myxopapillary Ependymomas: A Clinicopathologic Evaluation.

J Pediatr Hematol Oncol 2020 Dec 29;Publish Ahead of Print. Epub 2020 Dec 29.

Departments of Laboratory Medicine and Pathology Neurologic Surgery Diagnostic Radiology Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Myxopapillary ependymomas (MPEs) have an indolent clinical course, corresponding to World Health Organization Grade I. A total of 13 pediatric MPEs have been reported in the literature with "anaplastic features," including elevated proliferative activity (≥5 mitoses/10 high-power fields), necrosis, and microvascular proliferation. No consensus exists regarding the prognostic significance of such features. A retrospective clinicopathologic review of pediatric MPEs diagnosed between 1996 and 2018 at Mayo Clinic was performed. Totally, 8 pediatric MPEs (6 male; age: 7.52 to 16.88 y) were identified. Totally, 3 had disseminated disease at presentation. All patients underwent surgical resection (7 gross total; 1 subtotal). Totally, 5 cases harbored ≥5 mitoses/10 high-power fields (range: 5 to 9), 3 of which showed necrosis (2 with disseminated disease). Postsurgery, 2 patients received radiation; one with disseminated disease and another with increased mitotic activity/necrosis; neither has recurred (follow-up: 1.18 and 3.19 y). In all, 2 patients with disseminated disease, elevated mitotic activity, and necrosis had new metastatic disease/progression of nonresected metastatic foci (2.6 and 26.8 mo), received radiation therapy, and remain progression free (3.01 and 9.34 y). All patients are alive (median follow-up 1.31 y, range: 0.66 to 11.75). Among pediatric MPEs, the concurrent presence of elevated mitotic activity and necrosis may be associated with an aggressive clinical course, warranting closer surveillance and consideration of adjuvant therapies.
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http://dx.doi.org/10.1097/MPH.0000000000002041DOI Listing
December 2020

Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data From the Park-Reeves Syringomyelia Research Consortium.

Neurosurgery 2021 01;88(2):332-341

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, Minnesota.

Background: Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology.

Objective: To examine factors influencing the use of OCF and OCF/VD in a multicenter cohort of pediatric CM-1 and SM subjects treated with PFD.

Methods: The Park-Reeves Syringomyelia Research Consortium registry was used to examine 637 subjects with cerebellar tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and at least 1 yr of follow-up after their index PFD. Comparisons were made between subjects who received PFD alone and those with PFD + OCF or PFD + OCF/VD.

Results: All 637 patients underwent PFD, 505 (79.2%) with and 132 (20.8%) without duraplasty. A total of 12 subjects went on to have OCF at some point in their management (PFD + OCF), whereas 4 had OCF and VD (PFD + OCF/VD). Of those with complete data, a history of platybasia (3/10, P = .011), Klippel-Feil (2/10, P = .015), and basilar invagination (3/12, P < .001) were increased within the OCF group, whereas only basilar invagination (1/4, P < .001) was increased in the OCF/VD group. Clivo-axial angle (CXA) was significantly lower for both OCF (128.8 ± 15.3°, P = .008) and OCF/VD (115.0 ± 11.6°, P = .025) groups when compared to PFD-only group (145.3 ± 12.7°). pB-C2 did not differ among groups.

Conclusion: Although PFD alone is adequate for treating the vast majority of CM-1/SM patients, OCF or OCF/VD may be occasionally utilized. Cranial base and spine pathologies and CXA may provide insight into the need for OCF and/or OCF/VD.
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http://dx.doi.org/10.1093/neuros/nyaa460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803430PMC
January 2021

Efficacy and safety of bevacizumab in progressive pediatric low-grade glioma: a systematic review and meta-analysis of outcome rates.

Neurooncol Pract 2020 Jul 3;7(4):359-368. Epub 2020 Feb 3.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States.

Background: Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression.

Methods: A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions.

Results: Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%).

Conclusions: Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.
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http://dx.doi.org/10.1093/nop/npz076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690362PMC
July 2020

Age of diagnosis clinically differentiates atypical teratoid/rhabdoid tumors diagnosed below age of 3 years: a database study.

Childs Nerv Syst 2021 04 24;37(4):1077-1085. Epub 2020 Nov 24.

Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL, 33136, USA.

Background: Atypical teratoid/rhabdoid tumor (ATRT) is a rare and largely pediatric diagnosis, with poor survival. Diagnosis below the age of 3 years is characteristically seen as a poor prognostic sign. However, elucidating if clinical differences exist within this niche age group has never been attempted before. Correspondingly, we sought to characterize clinical profile of ATRT diagnoses before the age of 3 years based on separate ages of diagnosis.

Methods: All pediatric ATRT patients aged < 3 years in the US National Cancer Database (NCDB) between 2005 and 2016 were retrospectively reviewed. Age groups were divided based on diagnoses at ages 0-1 years in group 1, 1-2 years in group 2, and 2-3 years in group 3. Data were summarized, and overall survival (OS) was modeled using Kaplan-Meier and Cox regression analyses.

Results: A total of 354 ATRT diagnoses were made before the age of 3 years, with surgery used in 316 (89%) cases, chemotherapy in 242 (68%) cases, and radiation therapy in 118 (33%) cases. In terms of diagnosis age, there were 153 (43%) in group 1, 137 (39%) in group 2, and 64 (18%) in group 3. With respect to OS, median value was 9.9 months in group 1, 28.4 months in group 2, and 15.9 months in group 3. Upon multivariate analysis, receiving radiation therapy was the only parameter shared amongst all three groups as independently prognostic of longer OS (HR 0.53, P = 0.01 in group 1; HR 0.34, P < 0.01 in group 2; HR 0.31, P < 0.01 in group 3). In group 1, surgery (HR 0.47, P < 0.01) and chemotherapy (HR 0.44, P < 0.01) were also independently prognostic of longer OS. In group 3, multiple socioeconomic parameters were identified to independently predict longer OS. There were no additional predictive parameters identified in group 2.

Conclusion: Although ATRT diagnosed before the age of 3 is typically viewed a poor prognostic age category, our findings demonstrate that the clinical profile of this pediatric niche is highly heterogeneous based on age of diagnosis. Survival of only those diagnosed between 0 and 1 years is independently prognosticated by all three treatment modalities; patients diagnosed between 1 and 2 years trend towards longest survival, and socioeconomic parameters are most influential in those diagnosed between 2 and 3 years.
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http://dx.doi.org/10.1007/s00381-020-04972-1DOI Listing
April 2021

Epigenetic-Targeted Treatments for H3K27M-Mutant Midline Gliomas.

Adv Exp Med Biol 2021 ;1283:73-84

Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA.

Diffuse intrinsic pontine glioma (DIPG) is a lethal midline brainstem tumor that most commonly occurs in children and is genetically defined by substitution of methionine for lysine at site 27 of histone 3 (H3K27M) in the majority of cases. This mutation has since been shown to exert an influence on the posttranslational epigenetic landscape of this disease, with the loss of trimethylation at lysine 27 (H3K27me3) the most common alteration. Based on these findings, a number of drugs targeting these epigenetic changes have been proposed, specifically that alter histone trimethylation, acetylation, or phosphorylation. Various mechanisms have been explored, including inhibition of H327 demethylase and methyltransferase to target trimethylation, inhibition of histone deacetylase (HDAC) and bromodomain and extraterminal (BET) to target acetylation, and inhibition of phosphatase-related enzymes to target phosphorylation. This chapter reviews the current rationales and progress made to date in epigenetically targeting DIPG via these mechanisms.
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http://dx.doi.org/10.1007/978-981-15-8104-5_6DOI Listing
January 2021

Atypical teratoid rhabdoid tumor: molecular insights and translation to novel therapeutics.

J Neurooncol 2020 Oct 6;150(1):47-56. Epub 2020 Oct 6.

Department of Neurological Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT.

Methods: Seminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics.

Results: In this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor.

Conclusions: SMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements that drive tumorigenesis.
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http://dx.doi.org/10.1007/s11060-020-03639-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230985PMC
October 2020

Effects of intraoperative liposomal bupivacaine on pain control and opioid use after pediatric Chiari I malformation surgery: an initial experience.

J Neurosurg Pediatr 2020 Oct 2:1-7. Epub 2020 Oct 2.

Departments of1Neurologic Surgery and.

Objective: Pediatric Chiari I malformation decompression is a common neurosurgical procedure. Liposomal bupivacaine (LB) is a novel formulation that can have an impact on postoperative recovery for particular procedures, but its potential role in pediatric neurosurgery is largely unexplored. The authors sought to describe and assess their initial experience with LB in pediatric Chiari I malformation decompression to better define its potential role as an analgesic agent in a procedure for which the postoperative course is often remarkably painful.

Methods: A retrospective review of all pediatric Chiari procedures performed at the authors' institution between 2018 and 2020 was conducted. Patients were divided into those who were treated with a single intraoperative dose of LB (LB group) and those who were not (control group). Comparisons of total opioid use and pain control were made using chi-square and Wilcoxon rank-sum tests.

Results: A total of 18 patients were identified, 9 (50%) in the LB group and 9 (50%) in the control group. Overall, there were 13 (72%) female and 5 (28%) male patients with a mean age of 15.9 years. No surgical complications were observed over a mean length of stay of 2.7 days. Within the first 24 hours after surgery, the LB group had significantly lower total opioid use than the control group (17.5 vs 47.9 morphine milligram equivalents, respectively; p = 0.03) as well as lower mean pain scores reported by patients using a 10-point visual analog scale (3.6 vs 5.5 for the LB vs control groups, p = 0.04). However, from the first 24 postoperative hours to discharge, total opioid use (p = 0.51) and mean pain scores (p = 0.09) were statistically comparable between the two groups. There were 2/9 (22%) LB patients versus 0/9 (0%) control patients who did not require opioid analgesia at any point during hospitalization.

Conclusions: The use of a single intraoperative dose of LB in pediatric Chiari I malformation surgery appears to be safe and has the potential to reduce pain scores and opioid use when administered during the first 24 postoperative hours. From that time period to discharge, however, there may be no significant difference in total opioid use or pain scores.
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http://dx.doi.org/10.3171/2020.6.PEDS20370DOI Listing
October 2020

Understanding the trajectory of research efforts in atypical teratoid rhabdoid tumors: a bibliometric analysis of the 50 most impactful studies to date.

Childs Nerv Syst 2021 02 17;37(2):419-425. Epub 2020 Aug 17.

Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant embryonal tumor of the central nervous system (CNS) that occurs predominantly in children. More is being discovered about this disease to improve understanding and outcomes. The aim of this analysis was to evaluate citation and other bibliometric characteristics of the 50 most cited articles in the contemporary literature in order to better model the trajectory of our current efforts.

Methods: Elsevier's Scopus database was searched for the 50 most cited articles about ATRT. To look for trends, earliest 25 articles were separated from the latest 25 articles and then were compared. Various bibliometric parameters were summarized and compared using Pearson's chi-square and Mann-Whitney U tests.

Results: The 50 most cited articles were published between 1990 and 2016, from 5 unique countries in 29 unique journals, with genetic and retrospective observational cohort studies the most common design (n = 11 each). Overall median values were as follows: citation count, 145.4 citations (range, 67-626); citation rate per year, 11.7 (range, 3.5-51.4); number of authors 12 (range, 1-95); with 32 (64%) originating from the USA. Compared with older articles, newer articles had statistically lower citation counts (101.8 vs 189.0; P < 0.01), higher number of authors (17.3 vs 6.6; P < 0.01), and were less likely published from the USA (40% vs 88%; P < 0.01) CONCLUSIONS: The 50 most cited articles about ATRT were characterized in this analysis. There was a distinct focus in these studies on the genetic composition and consequences of these tumors. Trends over time suggest greater impact will be had in highly collaborative efforts worldwide. Moving forward, it will be of great interest to see how the findings of these basic science finding will translate into future clinical studies.
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http://dx.doi.org/10.1007/s00381-020-04863-5DOI Listing
February 2021

Effect of surgery and chemotherapy on long-term survival in infants with congenital glioblastoma: an integrated survival analysis.

J Neurosurg Pediatr 2020 Aug 14:1-9. Epub 2020 Aug 14.

1Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.

Objective: Glioblastoma (GBM) during infancy is rare, and the clinical outcomes of congenital GBM are not well understood. Correspondingly, the aim of this study was to present a long-term survivor case from the authors' institution, and establish an integrated cohort of cases across the published literature to better understand the clinical course of this disease in this setting.

Methods: The authors report the outcomes of an institutional case of congenital GBM diagnosed within the first 3 months of life, and performed a comprehensive literature search for published cases from 2000 onward for an integrated survival analysis. All cases were integrated into 1 cohort, and Kaplan-Meier estimations, Fisher's exact test, and logistic regression were used to interrogate the data.

Results: The integrated cohort of 40 congenital GBM cases consisted of 23 (58%) females and 17 (42%) males born at a median gestational age of 38 weeks (range 22-40 weeks). Estimates of overall survival (OS) at 1 month was 67%, at 1 year it was 59%, and at 10 years it was 45%, with statistically superior outcomes for subgroups in which patients survived to be treated by resection and chemotherapy. In the overall cohort, multivariable analysis confirmed resection (p < 0.01) and chemotherapy (p < 0.01) as independent predictors of superior OS. Gestational age > 38 weeks (p < 0.01), Apgar scores ≥ 7 at 5 minutes (p < 0.01), absence of prenatal hydrocephalus (p < 0.01), and vaginal delivery (p < 0.01) were associated with greater odds of surgical diagnosis versus autopsy diagnosis.

Conclusions: Congenital GBM can deviate from the expected poor prognosis of adult GBM in terms of OS. Both resection and chemotherapy confer statistically superior prognostic advantages in those patients who survive within the immediate postnatal period, and should be first-line considerations in the initial management of this rare disease.
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http://dx.doi.org/10.3171/2020.5.PEDS20226DOI Listing
August 2020

An arrow that missed the mark: a pediatric case report of remarkable neurologic improvement following penetrating spinal cord injury.

Childs Nerv Syst 2021 05 5;37(5):1771-1778. Epub 2020 Aug 5.

Department of Neurological Surgery, Pediatric Neurosurgery, Mayo Clinic, Rochester, MN, 55905, USA.

Penetrating spinal cord injuries are rare in children but result in devastating impacts on long-term morbidity and mortality-with little known about the recovery capacity in this age group. We present the case of an eight-year-old child who sustained a penetrating injury through the right anterior thorax. Thoracic CT showed the arrow tip extending through the spinal canal at T6. Neurologic examination revealed no motor or sensory function below T6. The arrow was surgically removed without complications through an anterior-only approach. MRI on post-operative day (POD) 4 showed focal T2 hyperintensity at the T6 spinal cord. Patient was discharged on POD33 with an American Spinal Injury Association (ASIA)-D score and trace voluntary control over bowel and bladder function. Remarkably, four months later, he had near normal bowel and bladder function, with near-intact lower extremity strength and self-sustained ambulation. Follow-up imaging revealed hemicord formation at the level of injury. We review our case of penetrating spinal cord injury in a child and similar reports in the literature. Penetrating thoracic spinal cord trauma portends poor clinical outcomes, particularly when employing available adult prognostic spinal cord injury scoring metrics. Incomplete spinal cord injury, and often-associated spinal shock, can mimic a complete injury-as in our patient, which improved to near-complete motor and sensory restoration of function and resulted in the formation of a split hemicord. This case represents a unique penetrating spinal cord injury with remarkable neurologic recovery, which would advocate against definitive early prognostication in the pediatric population.
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http://dx.doi.org/10.1007/s00381-020-04842-wDOI Listing
May 2021

Recurring pediatric anaplastic ependymoma with rare peritoneal carcinomatosis: a case report and hypothesis of mechanism.

Childs Nerv Syst 2021 03 17;37(3):1021-1024. Epub 2020 Jul 17.

Department of Pediatric Oncology, Mayo Clinic Children's Center, 200 First St. SW, Rochester, MN, USA.

Background: Although recurrent anaplastic ependymoma in pediatric patients is not uncommon, recurrent disease leading to widespread metastases to the peritoneum is extremely rare.

Case Report: We present a case of an 18-month old male who initially presented with posterior fossa anaplastic ependymoma, who then proceeded to present 1 year later with spinal recurrence, and then 2 years after that with widespread disease involving the intracranial ventricular system and peritoneum.

Conclusion: We posit that surgical interventions to treat primary and recurrent presentations in combination with a conduit to the peritoneum via a ventriculoperitoneal shunt contributed to the mechanisms of this complex case.
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http://dx.doi.org/10.1007/s00381-020-04814-0DOI Listing
March 2021

Teaching NeuroImages: Diffuse intrinsic pontine glioma in white matter.

Neurology 2020 08 13;95(5):e608-e609. Epub 2020 Jul 13.

From the Department of Neurologic Surgery (V.M.L., D.A.B., D.J.D.), Mayo Clinic, Rochester, MN; and Department of Neurologic Surgery (A.Q.-H., K.L.C.), Mayo Clinic, Jacksonville, FL.

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http://dx.doi.org/10.1212/WNL.0000000000009927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455345PMC
August 2020

Surgical treatment of chiasmal glioma in neurofibromatosis 1.

Neurology 2020 07 11;95(1):40-41. Epub 2020 Jun 11.

From the Departments of Ophthalmology (M.C.B., A.M.F.), Neurology (M.C.B.), and Neurosurgery (D.J.D.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000009732DOI Listing
July 2020

Safety of immediate use of nonsteroidal antiinflammatory drugs after pediatric craniotomy for tumor.

J Neurosurg Pediatr 2020 Jun 5:1-7. Epub 2020 Jun 5.

Objective: Postoperative pain can limit the recovery of children undergoing craniotomy for tumor resection, and pain management is highly variable between institutions and practitioners. Nonsteroidal antiinflammatory drugs (NSAIDs) are effective in treating postoperative pain following craniotomy, but their use has been limited by concerns about postoperative hemorrhage. The risk of postoperative hemorrhage is not insignificant in patients undergoing craniotomy for tumor resection. No study has specifically addressed the safety of NSAIDs in the immediate postoperative setting following craniotomy for tumor resection in pediatric patients.

Methods: The authors performed a retrospective cohort study in patients younger than 18 years of age who underwent craniotomy for tumor resection at a single tertiary referral center between 2009 and 2019. The study outcomes were 1) postoperative hemorrhage requiring return to the operating room for decompression, evacuation, or CSF diversion for hemorrhage-associated hydrocephalus; and 2) more-than-minimal hemorrhage on routine postoperative imaging. Patients receiving any NSAID in the hospital formulary on the same day as surgery (postoperative day zero [POD0]) were designated as such.

Results: Two hundred seventy-six children underwent 308 craniotomies for tumor resection over the study period. One hundred fifty-four patients (50.0%) received at least one dose of an NSAID on POD0. Six patients (1.9%) required a return to the operating room for a hemorrhagic complication, including 3 who received an NSAID on POD0 (OR 1.00, 95% CI 0.20-5.03). Seventeen patients (6.3% of patients imaged) had more-than-minimal hemorrhage on routine postoperative imaging, 9 of whom received an NSAID on POD0 (OR 1.08, 95% CI 0.40-2.89).

Conclusions: Use of NSAIDs on POD0 was not associated with either an increased risk of hemorrhage requiring a return to the operating room or asymptomatic hemorrhage on routine postoperative imaging. The overall incidence of clinically significant postoperative intracranial hemorrhage is low. These data support the use of NSAIDs as a safe measure for pain control in the postoperative setting for children undergoing craniotomy for tumor resection.
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http://dx.doi.org/10.3171/2020.4.PEDS2055DOI Listing
June 2020

Shaping Our Understanding of Medulloblastoma: A Bibliometric Analysis of the 100 Most Cited Articles.

Clin Neurol Neurosurg 2020 07 23;194:105895. Epub 2020 May 23.

Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States. Electronic address:

The clinical management of medulloblastoma has undergone significant transformation since the recent dawn of the molecular era. The aim of this analysis was to evaluate citation and other bibliometric characteristics of the 100 most cited medulloblastoma articles in the literature to better understand the current state of our research efforts into this diagnosis. Elsevier's Scopus database was searched for the 100 most cited articles that focused on medulloblastoma. Articles were dichotomized as either primarily basic science (BSc) or clinical (CL) articles. Various bibliometric parameters were summarized and compared between BSc and CL articles using Pearson's Chi-square and Mann Whitney U tests. Of the 100 most cited articles, 52 were characterized as BSc articles and 48 as CL articles. Overall median (range) values were as follows: citation count 252 (164-1,270); citation rate per year 17.5 (2.5-110); number of authors 11 (1-135); and publication year 2005 (1925-2014). Articles were published in a total of 40 different journals, and the majority originated in the US (n = 60). When compared to CL articles, BSc articles reported significantly greater citation rates per year (P < 0.01), and more recent years of publication (P < 0.01). In summary, although similar in overall proportion, BSc articles demonstrated significantly increased bibliometric parameters of impact in this field by the successful clustering molecular subtypes. Moving forward, it will be of great interest to see how the findings from these impactful BSc articles will translate into future clinical initiatives and subsequently high-impact CL articles.
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http://dx.doi.org/10.1016/j.clineuro.2020.105895DOI Listing
July 2020

Rare Diffuse Intrinsic Pontine Glioma Metastasis Throughout the Brain and Spine.

World Neurosurg 2020 08 28;140:301-302. Epub 2020 May 28.

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Diffuse intrinsic pontine glioma with H3 K27M mutation is a rare brain tumor that primarily affects children. It is extremely lethal, and our understanding of the natural course of this disease, and how it progresses, is lacking. We have presented a case that demonstrates how aggressive this disease can be after progression, with remarkable spread throughout the brain and spine despite upfront radiotherapy. Although rarely reported, widespread dissemination of metastatic diffuse intrinsic pontine glioma throughout the brain and spine is possible.
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http://dx.doi.org/10.1016/j.wneu.2020.05.205DOI Listing
August 2020
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