Publications by authors named "Anita Huttner"

74 Publications

Spreading of Alzheimer Tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.

J Biol Chem 2021 Sep 1:101159. Epub 2021 Sep 1.

Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT, USA. Electronic address:

In Alzheimer's Disease (AD), deposition of pathological Tau and Amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded Tau aggregates extracted from human AD brains drives templated spreading of Tau pathology within wild type mouse brain. Here, we assessed the impact of Aß co-pathology, of deleting loci known to modify AD risk (Ptk2b, Grn, Tmem106b) and of pharmacological intervention with a Fyn kinase inhibitor on Tau spreading after injection of AD Tau extracts. The density and spreading of Tau inclusions triggered by human Tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and App knock-in mice. In mice with human Tau sequence replacing mouse Tau, template matching enhanced neuritic Tau burden. Human AD brain Tau-enriched preparations contained aggregated Aß, and the Aß co-injection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from Tau accumulation and could be ameliorated by depleting Aβ from Tau extracts. These data suggest that Aβ and Tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer (Aβo) induced signaling, or deleting expression of the PGRN and TMEM106B lysosomal proteins, did not alter the somatic Tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic Tau after injection of human AD Tau seeds into wild type mice. These studies refine our knowledge of factors capable of modulating Tau spreading.
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http://dx.doi.org/10.1016/j.jbc.2021.101159DOI Listing
September 2021

The Clinical Implications of Spontaneous Hemorrhage in Vestibular Schwannomas.

J Neurol Surg B Skull Base 2021 Jul 16;82(Suppl 3):e22-e32. Epub 2020 Mar 16.

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, United States.

 Spontaneous hemorrhage into vestibular schwannomas (VSs) is rare and can render more rapid symptom onset and a seemingly poorer prognosis for an otherwise benign pathology. We describe our series of hemorrhagic VS (HVSs) and systematically reviewed the literature to better understand relevant clinical factors and outcomes.  Retrospective case review series and systematic review of the literature using PRISMA guidelines.  Fifty-three patients with HVS met inclusion criteria. Compared with historical data for all VS, patients with HVS had relatively higher rates of perioperative mortality, significant preoperative facial weakness, and harbored relatively larger tumors. Regardless of the extent of resection (EOR), surgery for HVS resulted in significant improvement of facial weakness (  = 0.041), facial numbness (  < 0.001), vertigo (  < 0.001), and headache (  < 0.001). Patients with facial weakness tended to have larger tumors (  = 0.058) on average and demonstrated significant improvement after surgery, irrespective of EOR (  < 0.01). The use of blood-thinning medications did not affect patient health outcome. Histopathology of HVS samples showed an increased number of dilated/ectatic thin-walled vascular channels, reflective of potentially increased vascular permeability and hypervascularity.  HVS may be an aggressive subgroup of VS, associated with a surprisingly high mortality rate. When features of HVS are identified on imaging, these patients should be treated expeditiously, especially given that facial nerve dysfunction, which is identified in more than half of patients with HVS, appears to be reversible. Overall, this study has significant implications in the management of VS, raising awareness of a small, but highly morbid subgroup.
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http://dx.doi.org/10.1055/s-0040-1701676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289498PMC
July 2021

Brain Abscess in an Immunocompromised Patient.

Case Rep Infect Dis 2021 9;2021:6620049. Epub 2021 Jun 9.

Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA.

Objectives: Successful treatment for is not well elucidated in the literature. To the best of our knowledge, has not yet been described in the medical literature to cause central nervous system (CNS) infection from brain abscess. We report the case of an immunocompromised patient who underwent successful treatment to treat his brain abscess caused by .

Methods: After failing medical therapy, the patient underwent a craniotomy, and tissue was sent for culture. Upon identification by 16S rDNA sequencing, the organism causing infection was identified to be .

Results: Based on susceptibilities, the patient was treated with IV ceftriaxone 2 grams daily for five months. The patient demonstrated clinical and radiological improvement which persisted to 7 months after initiation of therapy.

Conclusions: To the best of our knowledge, this is the first documented case of a brain abscess due to which was successfully treated. Due to the location of the infection, ceftriaxone was chosen because of optimal CNS penetration. Ceftriaxone monotherapy demonstrated clinical and radiographic treatment success resulting in the successful treatment of this infection.
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http://dx.doi.org/10.1155/2021/6620049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216818PMC
June 2021

Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.

Neurologist 2021 Jul 6;26(4):122-124. Epub 2021 Jul 6.

Departments of Neurology.

Background: We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare.

Case Presentation: We evaluated a 21-year-old college student with migraine. Biopsy of numerous popular skin lesions on his nose revealed adenoma sebaceum. Magnetic resonance imaging brain showed a subependymal nodule near the foramen of Monro suspected to be SEGA. Genetic analysis identified a tuberous sclerosis complex-1 germ line mutation. Surveillance imaging was recommended for the subependymal tumor. Fourteen months later, he presented with spontaneous hemorrhage into the tumor. Hematoma evacuation and tumor resection revealed SEGA. The college graduate was able to return to full-time work.

Conclusions: We present an unusual cause of intracranial hemorrhage in a young adult. Thorough work-up and recognition of an underlying genetic predisposition can curtails diagnostic delay when life-threatening complications occur.
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http://dx.doi.org/10.1097/NRL.0000000000000338DOI Listing
July 2021

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

JCI Insight 2021 Jul 22;6(14). Epub 2021 Jul 22.

Department of Therapeutic Radiology and.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.
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http://dx.doi.org/10.1172/jci.insight.145875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410084PMC
July 2021

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

Circulation 2021 Aug 11;144(6):455-470. Epub 2021 Jun 11.

Departments of Medicine (Cardiovascular Medicine) (A.C.O., Y.X., R.C., A.J.S., M.D., J.H., K.A.M.), Yale University School of Medicine, New Haven, CT.

Background: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown.

Methods: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression.

Results: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner.

Conclusions: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050553DOI Listing
August 2021

Concurrent Myotonic Dystrophy and Inflammatory Myopathy in a Patient with HIV/AIDS.

Case Rep Infect Dis 2021 20;2021:9998415. Epub 2021 May 20.

Section of Infectious Diseases, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.

Neuromuscular complications are common in patients with HIV/AIDS at any stage of the disease process. Myopathies can be secondary to antiretroviral therapy, HIV myositis itself, or other etiologies. Here, we present the case of a middle-aged male with HIV who presented with myalgias and was diagnosed with myotonic dystrophy and HIV-associated polymyositis after extensive workup including clinical history and physical exam, laboratory markers, electromyogram, and muscle biopsy. This case illustrates the importance of a comprehensive workup for myopathy in HIV/AIDS and the possibility of multiple concurrent conditions.
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http://dx.doi.org/10.1155/2021/9998415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159637PMC
May 2021

Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.

Nat Biomed Eng 2021 May 27. Epub 2021 May 27.

Department of Biomedical Engineering, Yale University, New Haven, CT, USA.

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.
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http://dx.doi.org/10.1038/s41551-021-00728-7DOI Listing
May 2021

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

Clin Genet 2021 08 2;100(2):176-186. Epub 2021 Jun 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.
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http://dx.doi.org/10.1111/cge.13973DOI Listing
August 2021

Genomic Characterization of Radiation-Induced Intracranial Undifferentiated Pleomorphic Sarcoma.

Case Rep Genet 2021 8;2021:5586072. Epub 2021 Mar 8.

Department of Neurosurgery, Yale School of Medicine, New Haven 06511, CT, USA.

Intracranial undifferentiated pleomorphic sarcoma remains a rare pathology within the sarcoma literature that may arise primarily or secondary after radiation therapy. Despite first-line treatment with maximal surgical resection, followed by nonstandardized adjuvant chemotherapy/radiation regimens, clinical prognosis remains exceedingly poor. Furthermore, there is a lack of genetic or molecular characterization to guide potential for targeted therapies. We present genomic analysis of a radiation-induced intracranial undifferentiated pleomorphic sarcoma in an 83-year-old woman with notable KIT and PDGFRA alterations. Further similar genomic studies of intracranial pleomorphic sarcoma are needed to develop better therapies for this rare but challenging disease entity.
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http://dx.doi.org/10.1155/2021/5586072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960067PMC
March 2021

Exome sequencing identifies SLIT2 variants in primary CNS lymphoma.

Br J Haematol 2021 04 22;193(2):375-379. Epub 2021 Jan 22.

Department of Neurology, Yale School of Medicine, New Haven, USA.

SLIT2 constitutes a known tumour suppressor gene, which has not yet been implicated in the pathogenesis of primary central nervous system lymphoma (PCNSL). Performing exome sequencing on paired blood and tumour DNA samples from six treatment-naïve PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.T590M, p.T732S) that were associated with shorter progression-free survival in our cohort and shorter overall survival in a large validation cohort of lymphoid malignancies from the cBio Cancer Genomics Portal. WNT- and NF-κB-reporter luciferase assays suggest detected alterations are loss-of-function variants. Given the possible prognostic implications, the role of SLIT2 in PCNSL pathogenesis and progression warrants further investigation.
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http://dx.doi.org/10.1111/bjh.17319DOI Listing
April 2021

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.

Mol Genet Genomic Med 2021 02 14;9(2):e1597. Epub 2021 Jan 14.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.

Background: Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment-related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment.

Methods: We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma.

Results: We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor.

Conclusion: Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma.
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http://dx.doi.org/10.1002/mgg3.1597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077124PMC
February 2021

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

J Exp Med 2021 03;218(3)

Sorbonne Université, INSERM U1127, French National Centre for Scientific Research, Joint Research Unit 7225, Paris Brain Institute, Institut du Cerveau et de la Moelle Épinière, Paris, France.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1084/jem.20202135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808299PMC
March 2021

Clinical and genomic factors associated with seizures in meningiomas.

J Neurosurg 2020 Dec 4:1-10. Epub 2020 Dec 4.

Departments of1Neurosurgery.

Objective: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients.

Methods: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures.

Results: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis.

Conclusions: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.
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http://dx.doi.org/10.3171/2020.7.JNS201042DOI Listing
December 2020

[C]Methionine and [C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis.

Mol Imaging 2020 Jan-Dec;19:1536012120968669

Department of Radiology and Biomedical Imaging, Yale School of Medicine, 12228Yale University, New Haven, CT, USA.

Purpose: As stereotactic radiosurgery (SRS) and immunotherapy are increasingly used to treat brain metastases, incidence of radiation necrosis (RN) is consequently rising. Differentiating tumor regrowth (TR) from RN is vital in management but difficult to assess using MRI. We hypothesized that tumor methionine levels would be elevated given increased metabolism and high amino acid uptake, whereas RN would increase inflammation marked by upregulated translocator protein (PBR-TSPO), which can be quantified with specific PET tracers.

Procedures: We performed a feasibility study to prospectively evaluate [C]methionine and [C]PBR28 using PET in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate TR from RN.

Results: Sequential imaging with dual tracers was well-tolerated. [C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [C]PBR28 was only accurate in 3/7 lesions. Tumor PBR-TSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [C]PBR28-PET.

Conclusion: Sequential use of PET tracers is safe and effective. [C]Methionine was a reliable TR marker, but [C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging.
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http://dx.doi.org/10.1177/1536012120968669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649862PMC
November 2020

Associations of meningioma molecular subgroup and tumor recurrence.

Neuro Oncol 2021 05;23(5):783-794

Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.

Background: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients.

Methods: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling.

Results: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence.

Conclusion: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.
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http://dx.doi.org/10.1093/neuonc/noaa226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099468PMC
May 2021

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

bioRxiv 2020 Sep 8. Epub 2020 Sep 8.

Sorbonne Université, INSERM U1127, CNRS UMR 7225, Paris Brain Institute - ICM, Paris, France.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1101/2020.06.25.169946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491522PMC
September 2020

Genomic alterations in Turcot syndrome: Insights from whole exome sequencing.

J Neurol Sci 2020 10 25;417:117056. Epub 2020 Jul 25.

Department of Neurology, Yale School of Medicine, New Haven, CT, United States of America; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.117056DOI Listing
October 2020

A Critically Ill Patient With Central Nervous System Tuberculosis and Negative Initial Workup.

Front Neurol 2020 12;11:430. Epub 2020 Jun 12.

Department of Neurology, Yale School of Medicine, New Haven, CT, United States.

Empiric anti-tuberculous therapy should not be delayed in patients with a strong clinical suspicion for TB. Because confirmatory TB testing may be difficult to obtain, early and empiric treatment, when there is concern for central nervous system TB, may result in improved outcomes for patients. GeneXpert is currently an area of active research, and the test returns diagnostic results within hours, which would make it the preferred test for investigating TB meningitis.
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http://dx.doi.org/10.3389/fneur.2020.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304250PMC
June 2020

Persistent mutation despite multimodal therapy in recurrent pediatric glioblastoma.

NPJ Genom Med 2020 1;5:23. Epub 2020 Jun 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06511 USA.

Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently mutated clone, with rare mutations in and , the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying deficiency. As such, this case represents a novel report following the clinical and genetic progression of a mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for mutations in gliomagenesis and resistance to standard therapies.
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http://dx.doi.org/10.1038/s41525-020-0130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264170PMC
June 2020

Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS.

Neurol Neuroimmunol Neuroinflamm 2020 05 8;7(3). Epub 2020 Apr 8.

From the Departments of Neurology (L.E.L., B.A.L., C.P., D.D., B.H., V.P.K., G.P., K.R., D.A.H., D.P.); Immunobiology (L.E.L., B.A.L., B.H., K.R., D.A.H.); and Pathology (A.H.), Yale School of Medicine, New Haven, CT.

Objective: To identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy.

Methods: We collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry.

Results: We found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction.

Conclusions: The opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.
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http://dx.doi.org/10.1212/NXI.0000000000000712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188477PMC
May 2020

Leptomeningeal dissemination of low-grade neuroepithelial CNS tumors in adults: a 15-year experience.

Neurooncol Pract 2020 Jan 6;7(1):118-126. Epub 2019 Jul 6.

Department of Neurology, Yale School of Medicine, New Haven, CT, USA.

Background: Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome.

Methods: We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed.

Results: Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort.

Conclusions: LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.
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http://dx.doi.org/10.1093/nop/npz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104875PMC
January 2020

Primary dural lymphomas: Clinical presentation, management, and outcome.

Cancer 2020 06 16;126(12):2811-2820. Epub 2020 Mar 16.

Department of Neurology, Yale School of Medicine, New Haven, Connecticut.

Background: Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL.

Methods: The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded.

Results: A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044).

Conclusions: PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases.
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http://dx.doi.org/10.1002/cncr.32834DOI Listing
June 2020

A Rare Case of a Pediatric Medullary Intracranial Germinoma.

World Neurosurg 2020 06 5;138:137-140. Epub 2020 Mar 5.

Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA. Electronic address:

Background: Germinomas are rare intracranial lesions, with medulla germinomas being reported in only approximately 20 cases to date. These tumors are extremely sensitive to radiotherapy, and knowledge of them can allow for accurate diagnosis as well as significantly impact treatment and prognosis.

Case Description: We present a case of medullary germinoma and review the cases previously reported in the literature.

Conclusions: A few imaging characteristics are noted in multiple cases, such as cystic components, enhancement, and absence of hydrocephalus. These features can provide clues to diagnosis of this rare entity.
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http://dx.doi.org/10.1016/j.wneu.2020.02.147DOI Listing
June 2020

MRI-Guided Laser Interstitial Thermal Therapy for Radiation Necrosis in Previously Irradiated Brain Arteriovenous Malformations.

Pract Radiat Oncol 2020 Jul - Aug;10(4):e298-e303. Epub 2020 Feb 14.

Departments of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Departments of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.prro.2020.02.003DOI Listing
March 2021

Somatic PRKAR1A mutation in sporadic atrial myxoma with cerebral parenchymal metastases: a case report.

J Med Case Rep 2019 Dec 25;13(1):389. Epub 2019 Dec 25.

Departments of Pathology, Yale University School of Medicine, 310 Cedar Street, P.O. Box 208023, New Haven, CT, 06520-8023, USA.

Background: Atrial myxomas are generally considered benign neoplasms. The majority of tumors are sporadic and less than 10% are associated with an autosomal dominant condition known as the Carney complex, which is most often caused by germline mutation in the gene PRKAR1A. Whether this gene plays a role in the development of sporadic myxomas has been an area of debate, although recent studies have suggested that some fraction of sporadic tumors also carry mutations in PRKARIA. Extra-cardiac complications of atrial myxoma include dissemination of tumor to the brain; however, the dissemination of viable invasive tumor cells is exceedingly rare.

Case Presentation: We present here a 48-year-old white woman who developed multiple intracranial hemorrhagic lesions secondary to tumor embolism that progressed to 'false' aneurysm formation and invasion through the vascular wall into brain parenchyma 7 months after resection of an atrial myxoma. Whole exome sequencing of her tumor revealed multiple mutations in PRKAR1A not found in her germline deoxyribonucleic acid (DNA), suggesting that the myxoma in this patient was sporadic.

Conclusions: Our patient illustrates that mutations in PRKAR1A may be found in sporadic lesions. Whether the presence of this mutation affects the clinical behavior of sporadic tumors and increases risk for metastasis is not clear. Regardless, the protein kinase A pathway which is regulated by PRKAR1A represents a possible target for treatment in patients with metastatic cardiac myxomas harboring mutations in the PRKARIA gene.
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http://dx.doi.org/10.1186/s13256-019-2317-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930684PMC
December 2019

Clinical Reasoning: Progressive proximal weakness in a 56-year-old man with bone pain.

Neurology 2019 11;93(21):939-944

From the Departments of Pathology (A.H.) and Neurology (R.J.N., B.R.), Yale School of Medicine (T.T.), New Haven, CT.

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http://dx.doi.org/10.1212/WNL.0000000000008535DOI Listing
November 2019

Genomic alterations underlying spinal metastases in pediatric H3K27M-mutant pineal parenchymal tumor of intermediate differentiation: case report.

J Neurosurg Pediatr 2019 Oct 25:1-10. Epub 2019 Oct 25.

7Pathology, Yale School of Medicine.

Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient's PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.
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http://dx.doi.org/10.3171/2019.8.PEDS18664DOI Listing
October 2019

Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

J Neurosurg 2019 Oct 25:1-10. Epub 2019 Oct 25.

19Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Objective: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.

Methods: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.

Results: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation.

Conclusions: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.
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http://dx.doi.org/10.3171/2019.8.JNS191266DOI Listing
October 2019

Complications associated with immunotherapy for brain metastases.

Curr Opin Neurol 2019 12;32(6):907-916

Yale Cancer Center.

Purpose Of Review: Median survival after the diagnosis of brain metastases has historically been on the order of months. With the recent development of immune checkpoint inhibitors, intracranial activity and durable responses have been observed in brain metastases on multiple phase 2 clinical trials, which have primarily been conducted in patients with melanoma. Immune-related adverse events related to checkpoint inhibitor therapy of brain metastasis can present unique challenges for the clinician and underscore the need for a multidisciplinary team in the care of these patients. The goal of this review is to address the current knowledge, limitations of understanding, and future directions in research regarding immune therapy trials and neurologic toxicities based on retrospective, prospective, and case studies.

Recent Findings: Immune therapy has the potential to exacerbate symptomatic edema and increase the risk of radiation necrosis in previously irradiated lesions. Neurologic toxicities will likely increase in prevalence as more patients with brain metastatic disease are eligible for immune therapy.

Summary: An improved understanding and heightened awareness of the unique neurologic toxicities that impact this patient group is vital for mitigating treatment-related morbidity and mortality.
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http://dx.doi.org/10.1097/WCO.0000000000000756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398556PMC
December 2019
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