Publications by authors named "Omar N Pathmanaban"

22 Publications

  • Page 1 of 1

Comment on: SMARCB1 Gene Mutation Predisposes to Earlier Development of Glioblastoma: A Case Report of Familial GBM.

J Neuropathol Exp Neurol 2021 Feb;80(3):289-290

Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Division of Evolution and Genomic Medicine, University of Manchester, St. Mary's Hospital, Manchester Universities NHS Foundation Trust, Manchester, United Kingdom.

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http://dx.doi.org/10.1093/jnen/nlaa105DOI Listing
February 2021

Endoscopic sublabial transmaxillary approach to the inferior orbit: pearls and pitfalls-A comparative anatomical study.

Neurosurg Rev 2021 Feb 10. Epub 2021 Feb 10.

Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Objective: Although orbital surgery has always represented a challenge for neurosurgeons, keyhole and endoscopic techniques are gradually surging in popularity maximizing functional and esthetic outcomes. This quantitative anatomical study first compared the surgical operability achieved through three endoscopic approaches within the inferior orbit: the endoscopic sublabial transmaxillary (ESTMax), the endoscopic endonasal transethmoidal (EETEth), and the endoscope-assisted lateral orbitotomy (ELO).

Methods: Each of these approaches was performed bilaterally on five specimens. We described the ESTMax step-by-step, underlining its advantages and pitfalls in comparison with EETEth and ELO. Then, we assessed surgical measurements and operability in ESTMax, EETEth, and ELO.

Results: The ESTMax provided the most favorable operative window (278.9 ± 43.8 mm; EETEth: 240.8 ± 21.5 mm, p < 0.001; ELO: 263.1 ± 19.8 mm, p = 0.006), the broadest surgical field area (415.9 ± 26.4 mm; EETEth: 386.7 ± 30.1 mm, p = 0.041; ELO: 305.2 ± 26.3 mm, p < 0.001), surgical field depths significantly shorter than EETEth (p < 0.001) but similar to ELO, the widest surgical angles of attack (45°-65°; EETEth: 20°-30°, p < 0.001; ELO: 25°-50°, p < 0.001), and the greatest surgical mobility areas (EETEth: p < 0.001; ELO: p < 0.001). Furthermore, the ESTMax allowed multi-angled exposure and handy maneuverability around all the inferior intraorbital targets. Small anterior antrostomy, blunt intraorbital dissections, direct targets' approach, orbital floor reconstruction, and maxillary bone flap replacement may limit the ESTMax morbidity rates.

Conclusions: The ESTMax is a minimally invasive "head-on" orbital approach that exploits endoscopic surgery advantages avoiding the cranio-orbital and trans-nasal approach limitations and possible complications. It represents a promising alternative to EETEth and ELO because of its optimal operability for resecting lesions extending into the entire inferior orbit.
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http://dx.doi.org/10.1007/s10143-021-01494-5DOI Listing
February 2021

Disease course of Neurofibromatosis Type 2; a 30-year follow-up study of 353 patients seen at a single institution.

Neuro Oncol 2020 Dec 18. Epub 2020 Dec 18.

Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Division of Evolution and Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester Universities NHS Foundation Trust, Manchester, UK.

Background: Limited data exists on the disease course of Neurofibromatosis Type 2 (NF2) to guide clinical trial design.

Methods: A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990-2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred and inheritance type. Interventions for NF2-related tumours were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death.

Results: Three-hundred-and-fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65 respectively per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P=0.03 and P=0.02 respectively) but those presenting between 16-39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P=0.004).

Conclusion: Understanding disease course improves prognostication, allowing for better informed decisions about care.
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http://dx.doi.org/10.1093/neuonc/noaa284DOI Listing
December 2020

The spatial phenotype of genotypically distinct meningiomas demonstrate potential implications of the embryology of the meninges.

Oncogene 2021 Feb 1;40(5):875-884. Epub 2020 Dec 1.

Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St Mary's Hospital, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.

Meningiomas are the most common primary brain tumor and their incidence and prevalence is increasing. This review summarizes current evidence regarding the embryogenesis of the human meninges in the context of meningioma pathogenesis and anatomical distribution. Though not mutually exclusive, chromosomal instability and pathogenic variants affecting the long arm of chromosome 22 (22q) result in meningiomas in neural-crest cell-derived meninges, while variants affecting Hedgehog signaling, PI3K signaling, TRAF7, KLF4, and POLR2A result in meningiomas in the mesodermal-derived meninges of the midline and paramedian anterior, central, and ventral posterior skull base. Current evidence regarding the common pathways for genetic pathogenesis and the anatomical distribution of meningiomas is presented alongside existing understanding of the embryological origins for the meninges prior to proposing next steps for this work.
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http://dx.doi.org/10.1038/s41388-020-01568-6DOI Listing
February 2021

Primary glomus tumour of the pituitary gland: diagnostic challenges of a rare and potentially aggressive neoplasm.

Virchows Arch 2020 Sep 12. Epub 2020 Sep 12.

Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.
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http://dx.doi.org/10.1007/s00428-020-02923-4DOI Listing
September 2020

Sporadic vestibular schwannoma: a molecular testing summary.

J Med Genet 2021 Apr 23;58(4):227-233. Epub 2020 Jun 23.

Clinical Genetics, Manchester University NHS Foundation Trust, Manchester, UK

Objectives: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.

Methods: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in on blood samples for all patients, and tumour DNA samples when available. and screening was also performed in patient subgroups.

Results: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline variants were confirmed in 2% of patients. Pathogenic germline variants in were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic variants, including those with germline pathogenic variants.

Conclusions: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of -associated VS tumourigenesis.
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http://dx.doi.org/10.1136/jmedgenet-2020-107022DOI Listing
April 2021

The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

J Neurosurg 2020 May 29:1-11. Epub 2020 May 29.

1Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre.

Objective: Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)-related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach.

Methods: Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI-derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence.

Results: Imaging data demonstrated that DCE-MRI-derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages.

Conclusions: The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.
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http://dx.doi.org/10.3171/2020.3.JNS193230DOI Listing
May 2020

Hampering brain tumor proliferation and migration using peptide nanofiber:si/ complexes.

Nanomedicine (Lond) 2019 12;14(24):3127-3142

Nanomedicine Lab, Faculty of Biology, Medicine & Health, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK.

To develop a nonviral tool for the delivery of siRNA to brain tumor cells using peptide nanofibers (PNFs). Uptake of PNFs was evaluated by confocal microscopy and flow cytometry. Gene silencing was determined by RT-qPCR and cell invasion assay. PNFs enter phagocytic (BV-2) and nonphagocytic (U-87 MG) cells via endocytosis and passive translocation. si delivered using PNFs reduced the expression of polo-like kinase 1 mRNA and induced cell death in a panel of immortalized and glioblastoma-derived stem cells. Moreover, targeting MMP2 using PNF:si reduced the invasion capacity of U-87 MG cells. We show that stereotactic intra-tumoral administration of PNF:si significantly extends the survival of tumor bearing mice comparing with the untreated tumor bearing animals. Our results suggest that this nanomedicine-based RNA interference approach deserves further investigation as a potential brain tumor therapeutic tool.
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http://dx.doi.org/10.2217/nnm-2019-0298DOI Listing
December 2019

Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

Genet Med 2020 01 5;22(1):53-59. Epub 2019 Jul 5.

NW Genomic Laboratory hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.

Purpose: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).

Methods: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.

Results: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant.

Conclusion: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.
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http://dx.doi.org/10.1038/s41436-019-0598-7DOI Listing
January 2020

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing.

Genet Med 2019 07 7;21(7):1525-1533. Epub 2018 Dec 7.

Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.

Purpose: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2).

Methods: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis.

Results: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%.

Conclusions: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.
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http://dx.doi.org/10.1038/s41436-018-0384-yDOI Listing
July 2019

Schwannomatosis: a genetic and epidemiological study.

J Neurol Neurosurg Psychiatry 2018 11 16;89(11):1215-1219. Epub 2018 Jun 16.

Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.

Objectives: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.

Methods: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on , and on blood and tumour DNA samples when available.

Results: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. -associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).

Conclusions: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.
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http://dx.doi.org/10.1136/jnnp-2018-318538DOI Listing
November 2018

High content screening of patient-derived cell lines highlights the potential of non-standard chemotherapeutic agents for the treatment of glioblastoma.

PLoS One 2018 2;13(3):e0193694. Epub 2018 Mar 2.

Brain Tumour Research Group, Stem Cell and Neurotherapies Laboratory, Division of Cell Matrix Biology & Regenerative Medicine, University of Manchester, Manchester, United Kingdom.

Background: Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation.

Methods: Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis.

Results: Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines.

Conclusion: The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834163PMC
June 2018

Malignant Peripheral Nerve Sheath Tumors are not a Feature of Neurofibromatosis Type 2 in the Unirradiated Patient.

Neurosurgery 2018 07;83(1):38-42

Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Central Manchester NHS Foundation Trust, Manchester, United Kingdom.

Background: The published literature suggests that malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in neurofibromatosis type 2 (NF2). A recent review based on incidence data in North America showed that 1 per 1000 cerebellopontine angle nerve sheath tumors were malignant.

Objective: To determine whether MPNST occurred spontaneously in NF2 by reviewing our NF2 database.

Methods: The prospective database consists of 1253 patients with NF2. One thousand and nine are known to be alive at last follow-up. The presence and laterality/pathology of vestibular schwannoma at diagnosis and last follow-up was sought.

Results: There were no cases of spontaneous MPNST with 2114 proven (n = 1150) and presumed benign (n = 964) vestibular schwannomas found. Two patients had developed MPNST (1 presumed) after having previously undergone stereotactic radiosurgery for a vestibular schwannoma.

Conclusion: In this series, and from the literature, malignant transformation of a vestibular schwannoma was not a feature of NF2 in the unirradiated patient. NF2 patients should not be told that they have an increased risk of malignant change in a vestibular schwannoma unless they undergo radiation treatment. However, very much larger datasets are required before it can be determined whether there is any association between NF2 and MPNST in the unirradiated patient.
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http://dx.doi.org/10.1093/neuros/nyx368DOI Listing
July 2018

High-Grade Glioma is not a Feature of Neurofibromatosis Type 2 in the Unirradiated Patient.

Neurosurgery 2018 08;83(2):193-196

Department of Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Central Manchester NHS Foundation Trust, Manchester, United Kingdom.

Background: The Manchester criteria for neurofibromatosis type 2 (NF2) include a range of tumors, and gliomas were incorporated in the original description. The gliomas are now widely accepted to be predominantly spinal cord ependymomas.

Objective: To determine whether these gliomas include any cases of malignant glioma (WHO grade III and IV) through a database review.

Methods: The prospective database consists of 1253 patients with NF2. 1009 are known to be alive at last follow-up.

Results: There was a single case of glioblastoma multiforme (GBM; World Health Organization grade IV) in the series and no WHO grade III gliomas. The GBM was in a patient who had previously undergone stereotactic radiosurgery for a vestibular schwannoma.

Conclusion: High-grade gliomas are not a feature of NF2 in the unirradiated patient and should be excluded from the diagnostic criteria.
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http://dx.doi.org/10.1093/neuros/nyx374DOI Listing
August 2018

Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults.

JAMA Neurol 2017 09;74(9):1123-1129

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, England.

Importance: Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome.

Objective: To determine the frequency of the known heritable meningioma- or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma.

Design, Setting, And Participants: Using the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU.

Main Outcomes And Measures: The type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma- and meningioma-predisposing syndromes.

Results: In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation.

Conclusions And Relevance: A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.
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http://dx.doi.org/10.1001/jamaneurol.2017.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710179PMC
September 2017

Safety of Superior Petrosal Vein Sacrifice During Microvascular Decompression of the Trigeminal Nerve.

World Neurosurg 2017 Jul 2;103:84-87. Epub 2017 Apr 2.

Manchester Skull Base Unit, Department of Neurosurgery, Manchester Centre for Clinical Neuroscience, Salford Royal Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

Background: Microvascular decompression (MVD) is a safe and effective treatment for trigeminal neuralgia. Cerebellar venous infarction is a complication associated with surgical sacrifice of the superior petrosal vein (SPV). The SPV intervenes between the trigeminal nerve and the surgeon. Optimal exposure of the cisternal trigeminal nerve, particularly at the brainstem, can be achieved by sacrificing the SPV. We analyzed a cohort of 224 patients to determine the frequency of cerebellar venous infarction.

Methods: Retrospective analysis of records and neuroradiology for patients undergoing trigeminal MVD at the Manchester Skull Base Unit between August 1st 2008 and July 31st 2015.

Results: A total of 184 of 224 (82%) patients had coagulation and division of the main stem of the SPV. There were no cases of venous infarction. There was one case of mild, transient, cerebellar symptoms and signs, with no radiologic evidence of venous infarction. This patient had SPV sacrifice at surgery but also had postoperative thrombosis of the transverse sinus. Venous sinus thrombosis affected 5 of 184 (2.7%) patients. A total of 208 of 224 (93%) patients had a good outcome with improvement or resolution of their trigeminal neuralgia at 3 months.

Conclusions: The overall rate of venous complications in this study was 2.7%; however, we had no cases of venous infarction in 184 patients who had sacrifice of the SPV. The incidence of venous infarction associated with SPV obliteration during MVD surgery is therefore <0.5%. SPV sacrifice may be used where necessary to optimize visualization of the root entry zone and maximize the chance of effective decompression of the trigeminal nerve.
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http://dx.doi.org/10.1016/j.wneu.2017.03.117DOI Listing
July 2017

Nonsynostotic Posterior Brachycephaly with Hindbrain Herniation.

World Neurosurg 2017 Jan 15;97:755.e11-755.e15. Epub 2016 Oct 15.

Department of Paediatric Neurosurgery, Royal Manchester Children's Hospital, Manchester, United Kingdom.

Background: Positional plagiocephaly is the most common cause of cranial asymmetry. The underlying cause of Chiari-1 malformation has many possible theories, and anecdotally some pediatric neurosurgeons have had experience of severe cases of positional brachycephaly with Chiari-1. However, to date, there have been no published cases linking nonsynostotic plagiocephaly with Chiari-1 malformation.

Case Description: An 18-month-old boy presented with a head injury. On examination he had a Glasgow Coma Score of 15 with no focal neurologic deficits, but he was noted to have marked posterior brachycephaly. A computed tomography scan showed a slim left-sided hemispheric acute subdural hematoma with no mass effect, which was treated conservatively. Of note, all of his cranial vault sutures were open, and a diagnosis of incidental positional plagiocephaly was made. Subsequent magnetic resonance imaging as part of a work-up to exclude nonaccidental injury showed a small posterior fossa with a steep tentorium and herniation of the cerebellar tonsils to the level of the body of the second cervical vertebra.

Conclusions: Chronic hindbrain herniation is well reported in cases of craniosynostosis, but to our knowledge this is the first published case associated with nonsynostotic deformational plagiocephaly. We hypothesize that severe posterior plagiocephaly can cause disproportion of the posterior fossa: hindbrain volume ratio and acquired chronic cerebellar herniation. Nevertheless, positional plagiocephaly and Chiari-1 are common entities, and it is possible that the dual diagnoses were coincidental in this case. This report serves to raise awareness of a putative causal relationship between positional plagiocephaly, reduced posterior fossa volume, and hindbrain herniation.
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http://dx.doi.org/10.1016/j.wneu.2016.10.027DOI Listing
January 2017

Ventricular metastatic dissemination of a paediatric craniopharyngioma: case report and literature review.

Br J Neurosurg 2017 Aug 16;31(4):474-477. Epub 2016 Jun 16.

a Children's Brain Tumour Research Network (CBTRN) , Royal Manchester Children's Hospital , Manchester , UK.

Distant intraventricular metastasis is extremely rare in childhood craniopharyngioma. Here, we report the isolated posterior ventricular recurrence of an adamantinomatous craniopharyngioma, in a child previously treated with surgery and proton beam therapy for local progression. The importance of surveillance imaging is highlighted, while specific surgical approaches and techniques are considered.
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http://dx.doi.org/10.3109/02688697.2016.1139050DOI Listing
August 2017

Intraoperative Supratentorial Extradural Hematoma Complicating Excision of a Giant Vestibular Schwannoma.

World Neurosurg 2016 May 22;89:726.e15-7. Epub 2016 Jan 22.

Department of Neurosurgery, Salford Royal Hospital, Salford, Greater Manchester, United Kingdom.

Background: A man developed a rare and unexpected contralateral intraoperative complication during a translabyrinthine resection of a large cystic vestibular schwannoma.

Case Description: A 29-year-old man presented with progressive, low-level right-sided tinnitus and hearing loss. Magnetic resonance imaging displayed a large multicystic lesion suggestive of a vestibular schwannoma extending into the right cerebellopontine angle and distorting the midbrain. The patient subsequently underwent translabyrinthine excision of the lesion. The operation was complicated by brain swelling that obscured the operative field. Cerebrospinal fluid drainage failed to improve operative conditions, and an urgent computed tomography scan was performed, which showed a large supratentorial extradural hematoma as the cause. This extradural collection was promptly evacuated, and the patient had a good neurologic recovery postoperatively.

Conclusions: Although the development of postoperative extradural hematomas resulting from cerebrospinal fluid overdrainage is reported in the literature, this case is unique in that infratentorial surgery led to the development of a supratentorial hematoma.
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http://dx.doi.org/10.1016/j.wneu.2016.01.030DOI Listing
May 2016

Increased neural progenitors in vascular dementia.

Neurobiol Aging 2011 Dec 5;32(12):2152-61. Epub 2010 Feb 5.

Stem Cell Biology Laboratory, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 IUL, UK.

Since groundbreaking studies demonstrated the presence of progenitor cells in the adult human brain, there have been intense interests in their potential therapeutic application, but to date only limited data has been obtained in man. An immunohistological study was performed in order to examine neurogenesis in both the subventricular and peri-infarct zones of vascular dementia patients compared to age-matched controls. The results were striking, showing a significant increase of progenitor cells in both the subventricular zone and in peri-infarct area in patients with vascular dementia compared to controls, which was sustained even in patients with infarcts occurring more than three months prior to autopsy. Moreover, the peri-infarct response appeared to be unified with that of the subventricular zone via a stream of cells, with some of them differentiating into immature neurons. We conclude that neurogenesis is stimulated in vascular dementia patients and, specifically, in patients with visible infarcts. Progenitors may migrate from the neurogenic niche to areas of infarction and differentiate into neurons, even three months after cerebrovascular damage, thus implicating the feasibility of enhancing neurogenesis as a novel treatment approach.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.01.007DOI Listing
December 2011

Outcome after severe head injury: focal surgical lesions do not imply a better Glasgow Outcome Score than diffuse injuries at 3 months.

J Trauma Manag Outcomes 2009 Apr 3;3. Epub 2009 Apr 3.

Division of Neurosurgery, GMNC, Manchester Academic Health Sciences Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.

Background: Historically neurosurgeons have accepted head injured patients only in the presence of a mass lesion requiring surgical decompression. Underpinning this is an assumption that these patients have a better outcome than patients without a surgical lesion. This has meant that many patients without a surgical lesion have been managed locally in the referring hospital. However, there is now evidence that treatment of all head injured patients in a specialist centre leads to improved outcomes. Therefore, we have asked the question: does the presence of a surgical lesion imply better outcome from severe head injury?

Results: We prospectively recorded the Glasgow Outcome score (GOS), at 3 months, of all the severely head injured patients treated at our institution over a two and a half year period. Of 116 patients admitted with an initial Glasgow Coma Score (GCS) of 8 or less, 58 had surgical lesions and 58 non-surgical head injuries. The two groups were well matched for presenting GCS and age. Overall our favourable outcome rate (GOS 4 and 5) at 3-months for the patients with a surgical lesion and for the non-surgical group were 47.3% and 46.6% respectively, with no significant difference between the two (P = 0.54).

Conclusion: The assumption in the past has always been that patients presenting in coma from traumatic diffuse brain injury will do worse than those that have a mass lesion amenable to surgical decompression. Our series would suggest that this is not the case and all severely head injured patients should expect similar outcome when cared for in a neuroscience centre.
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http://dx.doi.org/10.1186/1752-2897-3-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670292PMC
April 2009