Publications by authors named "Mary Fowkes"

52 Publications

Circulating Levels of Calcitonin Gene-Related Peptide Are Lower in COVID-19 Patients.

J Endocr Soc 2021 Mar 4;5(3):bvaa199. Epub 2021 Jan 4.

Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain.

Background: To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in severe acute respiratory syndrome coronavirus 2 positive patients.

Methods: Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n = 24) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of receptor activity modifying protein 1 (RAMP1), one of the components of the CGRP receptor, in autopsy lung specimens.

Results: CGRP levels were greatly decreased in COVID-19 patients ( < 0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment ( = 0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree and in the airways´ epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients.

Conclusions: The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.
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http://dx.doi.org/10.1210/jendso/bvaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798995PMC
March 2021

Postmortem Findings Associated With SARS-CoV-2: Systematic Review and Meta-analysis.

Am J Surg Pathol 2021 01 20. Epub 2021 Jan 20.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY Department of Pathology, University of Michigan, Ann Arbor, MI Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona Department of Pathology, Cannizzaro Hospital, Catania, Italy Department of Pathology, University of Washington Medical Center, Seattle, WA.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P <0.001), splenic necrosis (P<0.006) and white pulp depletion (P <0.001) that were more common with SARS-CoV-1. Remarkable postmortem findings in association with COVID-19 apart from DAD include pulmonary hemorrhage, viral cytopathic effect within pneumocytes, thromboembolism, brain infarction, endotheliitis, acute renal tubular damage, white pulp depletion of the spleen, cardiac myocyte necrosis, megakaryocyte recruitment, and hemophagocytosis.
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http://dx.doi.org/10.1097/PAS.0000000000001650DOI Listing
January 2021

Malignant transformation of a polymorphous low grade neuroepithelial tumor of the young (PLNTY).

Acta Neuropathol 2021 01 23;141(1):123-125. Epub 2020 Nov 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.

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http://dx.doi.org/10.1007/s00401-020-02245-4DOI Listing
January 2021

COVID-19: Staging of a New Disease.

Cancer Cell 2020 11 10;38(5):594-597. Epub 2020 Oct 10.

Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Coronavirus disease 2019 (COVID-19), like cancer, is a complex disease with clinical phases of progression. Initially conceptualized as a respiratory disease, COVID-19 is increasingly recognized as a multi-organ and heterogeneous illness. Disease staging is a method for measuring the progression and severity of an illness using objective clinical and molecular criteria. Integral to cancer staging is "metastasis," defined as the spread of a disease-producing agent, including neoplastic cells and pathogens such as certain viruses, from the primary site to distinct anatomic locations. Staging provides valuable frameworks and benchmarks for clinical decision-making in patient management, improved prognostication, and evidence-based treatment selection.
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http://dx.doi.org/10.1016/j.ccell.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547574PMC
November 2020

Innervation of human soft palate muscles.

Anat Rec (Hoboken) 2020 Oct 9. Epub 2020 Oct 9.

Linguaflex, Inc, Pittsburgh, Pennsylvania, USA.

Our objective was to determine the branching and distribution of the motor nerves supplying the human soft palate muscles. Six adult specimens of the soft palate in continuity with the pharynx, larynx, and tongue were processed with Sihler's stain, a technique that can render large specimens transparent while counterstaining their nerves. The cranial nerves were identified and dissection followed their branches as they divided into smaller divisions toward their terminations in individual muscles. The results showed that both the glossopharyngeal (IX) and vagus (X) nerves have three distinct branches, superior, middle, and inferior. Only the middle branches of each nerve contributed to the pharyngeal plexus to which the facial nerve also contributed. The pharyngeal plexus was divided into two parts, a superior innervating the palatal and neighboring muscles and an inferior innervating pharyngeal constrictors. The superior branches of the IX and X nerves contributed innervation to the palatoglossus, whereas their middle branches innervated the palatopharyngeus. The palatoglossus and palatopharyngeus muscles appeared to be composed of at least two neuromuscular compartments. The lesser palatine nerve not only supplied the palatal mucosa and palatine glandular tissue but also innervated the musculus uvulae, palatopharyngeus, and levator veli palatine. The latter muscle also received its innervation from the superior branch of X nerve. The findings would be useful for better understanding the neural control of the soft palate and for developing novel neuromodulation therapies to treat certain upper airway disorders such as obstructive sleep apnea.
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http://dx.doi.org/10.1002/ar.24531DOI Listing
October 2020

COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City.

Mod Pathol 2020 11 2;33(11):2156-2168. Epub 2020 Sep 2.

Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

SARS-CoV-2, the etiologic agent of COVID-19, is a global pandemic with substantial mortality dominated by acute respiratory distress syndrome. We systematically evaluated lungs of 68 autopsies from 3 institutions in heavily hit areas (2 USA, 1 Italy). Detailed evaluation of several compartments (airways, alveolar walls, airspaces, and vasculature) was performed to determine the range of histologic features. The cohort consisted of 47 males and 21 females with a median age of 73 years (range 30-96). Co-morbidities were present in most patients with 60% reporting at least three conditions. Tracheobronchitis was frequently present, independent from intubation or superimposed pneumonia. Diffuse alveolar damage (DAD) was seen in 87% of cases. Later phases of DAD were less frequent and correlated with longer duration of disease. Large vessel thrombi were seen in 42% of cases but platelet (CD61 positive) and/or fibrin microthrombi were present at least focally in 84%. Ultrastructurally, small vessels showed basal membrane reduplication and significant endothelial swelling with cytoplasmic vacuolization. In a subset of cases, virus was detected using different tools (immunohistochemistry for SARS-CoV-2 viral spike protein, RNA in situ hybridization, lung viral culture, and electron microscopy). Virus was seen in airway epithelium and type 2 pneumocytes. IHC or in situ detection, as well as viable form (lung culture positive) was associated with the presence of hyaline membranes, usually within 2 weeks but up to 4 weeks after initial diagnosis. COVID-19 pneumonia is a heterogeneous disease (tracheobronchitis, DAD, and vascular injury), but with consistent features in three centers. The pulmonary vasculature, with capillary microthrombi and inflammation, as well as macrothrombi, is commonly involved. Viral infection in areas of ongoing active injury contributes to persistent and temporally heterogeneous lung damage.
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http://dx.doi.org/10.1038/s41379-020-00661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463226PMC
November 2020

Peritumoral edema correlates with mutational burden in meningiomas.

Neuroradiology 2021 Jan 12;63(1):73-80. Epub 2020 Aug 12.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Purpose: Meningiomas are the most common primary central nervous system tumor. Emerging data supports that higher mutational burden portends worse clinical outcomes in meningiomas. However, there is a lack of imaging biomarkers that are associated with tumor genomics in meningiomas.

Methods: We performed next-generation targeted sequencing in a cohort of 75 primary meningiomas and assessed preoperative imaging for tumor volume and peritumoral brain edema (PTBE). An Edema Index was calculated.

Results: Meningiomas that were high grade (WHO grade II or grade III) had significantly larger tumor volume and were more likely to present with PTBE. Moreover, PTBE was associated with brain invasion on histopathology and reduced overall survival. There was a direct association between Edema Index and mutational burden. For every one increase in Edema Index, the number of single nucleotide variants increased by 1.09-fold (95% CI: 1.02, 1.2) (P = 0.01).

Conclusion: These data support that Edema Index may serve as a novel imaging biomarker that can inform underlying mutational burden in patients with meningiomas.
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http://dx.doi.org/10.1007/s00234-020-02515-8DOI Listing
January 2021

Fatal Pulmonary Thromboembolism in SARS-CoV-2-Infection.

Cardiovasc Pathol 2020 Sep - Oct;48:107227. Epub 2020 May 12.

Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1016/j.carpath.2020.107227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214296PMC
August 2020

A COMMON PITUITARY AUTOANTIBODY IN TWO PATIENTS WITH IMMUNE CHECKPOINT INHIBITOR-MEDIATED HYPOPHYSITIS: ZCCHC8.

AACE Clin Case Rep 2020 Jul-Aug;6(4):e151-e160. Epub 2020 Apr 3.

Objective: Hypophysitis is an increasingly recognized adverse effect of immune checkpoint inhibitor (ICI) therapy for malignancy. However, the mechanisms through which ICIs induce hypophysitis are largely unknown. We aim to describe 2 cases of ICI-mediated hypophysitis and perform autoantibody profiling on serial samples from these patients to determine if common autoantibodies could be identified.

Methods: We describe 2 cases of patients with metastatic urothelial cancer who received ICI therapy and subsequently developed severe fatigue, prompting a hormonal workup consistent with hypopituitarism. Patient 1 received the ICI ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) and patient 2 received the ICI pembrolizumab (anti-programmed cell death protein 1). Both patients had serial seromic immune biomarker profiling using high-density protein arrays before and after developing hypophysitis. Once a common autoantibody was found, zinc finger CCHC-type containing 8 (ZCCHC8), we used immunohistochemistry to assess its presence in pituitary tissue.

Results: Of a limited number of increased autoantibodies detected, those to ZCCHC8 were the only common antibodies to increase at least 3-fold post-hypophysitis in both patients. Using immunohistochemistry staining, we show for the first time that ZCCHC8 is expressed in pituitary gland tissue.

Conclusion: Seromic profiling identified a common autoantibody, ZCCHC8, in 2 patients who developed hypophysitis on ICI therapy, and other serial autoantibody increases in each patient. These findings warrant validation in other cohorts to determine if the response is to self or tumor antigen, and may reveal novel insights into pituitary gland physiology and the pathogenesis of ICI-mediated hypophysitis.
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http://dx.doi.org/10.4158/ACCR-2019-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357610PMC
April 2020

NF2 mutation status and tumor mutational burden correlate with immune cell infiltration in meningiomas.

Cancer Immunol Immunother 2021 Jan 13;70(1):169-176. Epub 2020 Jul 13.

Department of Pathology, Icahn School of Medicine At Mount Sinai, New York, NY, USA.

Background: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown.

Methods: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study.

Results: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046.

Conclusions: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.
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http://dx.doi.org/10.1007/s00262-020-02671-zDOI Listing
January 2021

Cerebral Fungal Abscess in an Immunocompetent Patient.

Neurohospitalist 2020 Apr 26;10(2):145-147. Epub 2019 Aug 26.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1177/1941874419870985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191670PMC
April 2020

Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

J Med Virol 2020 Jul;92(7):699-702

Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York City, New York.

Neurologic sequelae can be devastating complications of respiratory viral infections. We report the presence of virus in neural and capillary endothelial cells in frontal lobe tissue obtained at postmortem examination from a patient infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Our observations of virus in neural tissue, in conjunction with clinical correlates of worsening neurologic symptoms, pave the way to a closer understanding of the pathogenic mechanisms underlying central nervous system involvement by SARS-CoV-2.
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http://dx.doi.org/10.1002/jmv.25915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264598PMC
July 2020

STK11 mutation status is associated with decreased survival in meningiomas.

Neurol Sci 2020 Sep 7;41(9):2585-2589. Epub 2020 Apr 7.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Background: Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer.

Materials And Methods: Next-generation targeted sequencing of STK11 mutation status in a large cohort of 188 meningiomas.

Results: STK11 loss-of-function mutations were identified in 3.7% of meningiomas. STK11 mutations were found in both low- and high-grade lesions and samples from primary and recurrent disease. There was a 2.8-fold increased risk of death for patients whose meningioma harbored an STK11 mutation, after controlling for lesion grade and occurrence status. The median overall survival for patients with STK11-mutated meningiomas was 4.4 years compared with 16.8 years.

Conclusion: These data identify recurrent STK11 mutations in a subset of meningiomas. Genotyping of STK11 is encouraged for meningioma patients undergoing immunotherapy-based therapy.
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http://dx.doi.org/10.1007/s10072-020-04372-yDOI Listing
September 2020

In Reply: Emerging Therapeutic Targets in Chordomas: A Review of the Literature in the Genomic Era.

Neurosurgery 2020 05;86(5):E483

Department of Neurosurgery Icahn School of Medicine Mount Sinai Medical Center New York, New York.

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http://dx.doi.org/10.1093/neuros/nyaa008DOI Listing
May 2020

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report.

BMC Cancer 2020 Jan 20;20(1):47. Epub 2020 Jan 20.

Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Glioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations.

Case Presentation: A 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMT-unmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre- and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor.

Conclusion: This case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.
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http://dx.doi.org/10.1186/s12885-020-6540-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971940PMC
January 2020

In Reply: Retention of ATRX and DAXX Expression in Meningiomas.

Neurosurgery 2020 02;86(2):E244-E246

Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York, New York.

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http://dx.doi.org/10.1093/neuros/nyz504DOI Listing
February 2020

Brain Metastases from Biliary Tract Cancers: A Case Series and Review of the Literature in the Genomic Era.

Oncologist 2020 05 6;25(5):447-453. Epub 2019 Nov 6.

Department of Neurosurgery, Mount Sinai Medical Center, New York, New York, USA.

Background: Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC.

Materials And Methods: We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed.

Results: We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1-16.9).

Conclusion: Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes.

Implications For Practice: In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.
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http://dx.doi.org/10.1634/theoncologist.2019-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216433PMC
May 2020

ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures.

Cancer Cell 2019 11 17;36(5):512-527.e9. Epub 2019 Oct 17.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

ATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase region. We demonstrate that ATRX IFF proteins are redistributed from H3K9me3-enriched chromatin to promoters of active genes and identify REST as an ATRX IFF target whose activation promotes silencing of neuronal differentiation genes. We further show that ATRX IFF cells display sensitivity to EZH2 inhibitors, due to derepression of neurogenesis genes, including a subset of REST targets. Taken together, we demonstrate that ATRX structural alterations are not loss-of-function and put forward EZH2 inhibitors as a potential therapy for ATRX IFF neuroblastoma.
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http://dx.doi.org/10.1016/j.ccell.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851493PMC
November 2019

Targeting Cannabinoid 1 and Delta Opioid Receptor Heteromers Alleviates Chemotherapy-Induced Neuropathic Pain.

ACS Pharmacol Transl Sci 2019 Aug 5;2(4):219-229. Epub 2019 Jun 5.

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Cannabinoid 1 (CBR) and delta opioid receptors (DOR) associate to form heteromers that exhibit distinct pharmacological properties. Not much is known about CBR-DOR heteromer location or signaling along the pain circuit in either animal models or patients with chemotherapy-induced peripheral neuropathy (CIPN). Here, we use paclitaxel to induce CIPN in mice and confirm the development of mechanical allodynia. Under these conditions, we find significant increases in CBR-DOR heteromers in the dorsal spinal cord of mice with CIPN as well as in postmortem spinal cords from human subjects with CIPN compared to controls. Next, we investigated receptor signaling in spinal cords of mice with CIPN and found that treatment with a combination of low signaling doses of CBR and DOR ligands leads to significant enhancement in G-protein activity that could be selectively blocked by the CBR-DOR antibody. Consistent with this, administration of subthreshold doses of a combination of ligands (CBR agonist, Hu-210, and DOR agonist, SNC80) leads to significant attenuation of allodynia in mice with CIPN that is not seen with the administration of individual ligands, and this could be blocked by the CBR-DOR antibody. Together, these results imply that CBR-DOR heteromers upregulated during CIPN-associated mechanical allodynia could serve as a potential target for treatment of neuropathic pain including CIPN.
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http://dx.doi.org/10.1021/acsptsci.9b00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764458PMC
August 2019

Emerging Therapeutic Targets in Chordomas: A Review of the Literature in the Genomic Era.

Neurosurgery 2020 02;86(2):E118-E123

Department of Neurosurgery, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York.

Chordomas are rare primary malignant tumors of the bones that occur along the skull base, spine, and sacrum. Long-term survival and neurological outcome continue to be challenging with continued low percentages of long-term survival. Recent studies have used genome, exome, transcriptome, and proteome sequencing to assess the mutational profile of chordomas. Most notably, Brachyury, or T-protein, has been shown to be an early mutational event in chordoma evolution. Clinically actionable mutations, including in the PI3K pathway, were identified. Preliminary evidence suggests that there may be mutational differences associated with primary tumor location. In this study, we review the therapeutic landscape of chordomas and discuss emerging targets in the genomic era.
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http://dx.doi.org/10.1093/neuros/nyz342DOI Listing
February 2020

Tau Phosphorylation and Aggregation in the Developing Human Brain.

J Neuropathol Exp Neurol 2019 10;78(10):930-938

Iowa Neuroscience Institute.

Tau hyperphosphorylation, mostly at serine (Ser) or threonine (Thr) residues, plays a key role in the pathogenesis of Alzheimer disease (AD) and other tauopathies. Rodent studies show similar hyperphosphorylation in the developing brain, which may be involved in regulating axonal growth and plasticity, but detailed human studies are lacking. Here, we examine tau phosphorylation by immunohistochemistry and immunoblotting in human fetal and adult autopsy brain tissue. Of the 20 cases with sufficient tissue preservation, 18 (90%) showed positive staining for S214 (pSer214), with the majority also positive for CP13 (pSer202), and PHF-1 (pSer396/pSer404). AT8 (pSer202/pThr205) and RZ3 (pThr231) were largely negative while PG5 (pSer409) was negative in all cases. Immunoblotting showed tau monomers with a similar staining pattern. We also observed phospho-tau aggregates in the fetal molecular layer, staining positively for S214, CP13, and PHF1 and negative for thioflavin S. These corresponded to high-molecular weight (∼150 kD) bands seen on Western blots probed with S214, PHF1, and PG5. We therefore conclude that fetal phosphorylation overlaps with AD in some residues, while others (e.g. T231, S409) appear to be unique to AD, and that tau is capable of forming nontoxic aggregates in the developing brain. These findings suggest that the fetal brain is resilient to formation of toxic aggregates, the mechanism for which may yield insights into the pathogenesis of tau aggregation and toxicity in the aging brain.
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http://dx.doi.org/10.1093/jnen/nlz073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751069PMC
October 2019

Perfusion fixation in brain banking: a systematic review.

Acta Neuropathol Commun 2019 09 5;7(1):146. Epub 2019 Sep 5.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Background: Perfusing fixatives through the cerebrovascular system is the gold standard approach in animals to prepare brain tissue for spatial biomolecular profiling, circuit tracing, and ultrastructural studies such as connectomics. Translating these discoveries to humans requires examination of postmortem autopsy brain tissue. Yet banked brain tissue is routinely prepared using immersion fixation, which is a significant barrier to optimal preservation of tissue architecture. The challenges involved in adopting perfusion fixation in brain banks and the extent to which it improves histology quality are not well defined.

Methodology: We searched four databases to identify studies that have performed perfusion fixation in human brain tissue and screened the references of the eligible studies to identify further studies. From the included studies, we extracted data about the methods that they used, as well as any data comparing perfusion fixation to immersion fixation. The protocol was preregistered at the Open Science Framework: https://osf.io/cv3ys/ .

Results: We screened 4489 abstracts, 214 full-text publications, and identified 35 studies that met our inclusion criteria, which collectively reported on the perfusion fixation of 558 human brains. We identified a wide variety of approaches to perfusion fixation, including perfusion fixation of the brain in situ and ex situ, perfusion fixation through different sets of blood vessels, and perfusion fixation with different washout solutions, fixatives, perfusion pressures, and postfixation tissue processing methods. Through a qualitative synthesis of data comparing the outcomes of perfusion and immersion fixation, we found moderate confidence evidence showing that perfusion fixation results in equal or greater subjective histology quality compared to immersion fixation of relatively large volumes of brain tissue, in an equal or shorter amount of time.

Conclusions: This manuscript serves as a resource for investigators interested in building upon the methods and results of previous research in designing their own perfusion fixation studies in human brains or other large animal brains. We also suggest several future research directions, such as comparing the in situ and ex situ approaches to perfusion fixation, studying the efficacy of different washout solutions, and elucidating the types of brain donors in which perfusion fixation is likely to result in higher fixation quality than immersion fixation.
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http://dx.doi.org/10.1186/s40478-019-0799-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728946PMC
September 2019

The Distal Spine: Normal Embryogenesis and Derangements Leading to Malformation.

Neuroimaging Clin N Am 2019 Aug;29(3):385-409

Department of Pathology, Icahn School of Medicine at Mt. Sinai, One Gustave Levy Place, New York, NY 10029, USA.

The spine and spinal cord are composed of multiple segments initiated by different embryologic mechanisms and advanced under different systems of control. In humans, the upper central nervous system is formed by primary neurulation, the lower by secondary neurulation, and the intervening segment by junctional neurulation. This article focuses on the distal spine and spinal cord to address their embryogenesis and the molecular derangements that lead to some distal spinal malformations.
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http://dx.doi.org/10.1016/j.nic.2019.04.001DOI Listing
August 2019

Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

Oncotarget 2019 May 28;10(37):3506-3517. Epub 2019 May 28.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, NY, New York, USA.

A significant proportion of low-grade WHO grade I and higher-grade WHO grade II or III meningiomas are at risk to develop post-resection recurrence. Though recent studies investigated genomic alterations within histological subtypes of meningiomas, few have compared genomic profiles of primary meningiomas matched to their recurrences. The present study aimed to identify oncogenic driver mutations that may indicate risk of meningioma recurrence and aggressive clinical course. Seventeen patients treated for low-grade ( = 8) or high-grade ( = 9) meningioma and underwent both primary and recurrent resection between 2007-2017 were reviewed. Tumor specimens ( = 38) underwent genomic sequencing of known oncogenic driver mutations. Primary and recurrent tumors were compared using matched-pair analyses for mutational associations with clinical outcomes including functional status, progression-free survival (PFS) and overall survival (OS). Most common driver mutations included and . There was no enrichment for any driver mutation from primary to recurrent tumor specimen. mutant meningiomas were associated with larger tumor size (8-fold increase), presence of vasogenic edema, and higher mitotic proliferation on univariate and independently on multivariate regression (p's < 0.05) after controlling for preoperative and tumor features. Tumors with driver mutations were associated with decreased functional status at last postoperative follow-up ( = 0.022) relative to presentation. Mutation status was not associated with PFS or OS on multivariate Cox regression, but rather with grade of resection ( = 0.046) for PFS. While primary and recurrent tumors exhibited similar driver mutations within patients, the identification of driver mutations associated with clinical outcomes is crucial for guiding potential targeted treatments in recurrent meningiomas.
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http://dx.doi.org/10.18632/oncotarget.26941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544407PMC
May 2019

Formalin tissue fixation biases myelin-sensitive MRI.

Magn Reson Med 2019 10 24;82(4):1504-1517. Epub 2019 May 24.

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Purpose: Chemical fixatives such as formalin form cross-links between proteins and affect the relaxation times and diffusion properties of tissue. These fixation-induced changes likely also affect myelin density measurements produced by quantitative magnetization transfer and myelin water imaging. In this work, we evaluate these myelin-sensitive MRI methods for fixation-induced biases.

Methods: We perform quantitative magnetization transfer, myelin water imaging, and deuterium oxide-exchanged zero TE imaging on unfixed human spinal cord tissue at 9.4 Tesla and repeat these measurements after 1 day and 31 days of formalin fixation.

Results: The quantitative magnetization-transfer bound pool fraction increased by 30.7% ± 21.1% after 1 day of fixation and by 42.6% ± 33.9% after 31 days of fixation. Myelin water fraction increased by 39.7% ± 15.5% and 37.0% ± 15.9% at these same time points, and mean T of the myelin water pool nearly doubled. Reference-normalized deuterium oxide-exchanged zero TE signal intensity increased by 8.17% ± 6.03% after 31 days of fixation but did not change significantly after 1 day of fixation. After fixation, specimen cross-sectional area decreased by approximately 5%; after correction for shrinkage, changes in deuterium oxide-exchanged zero TE intensity were nearly eliminated.

Conclusion: Bound pool fraction and myelin water fraction are significantly increased by formalin fixation, whereas deuterium oxide-exchanged zero TE intensity is minimally affected. Changes in quantitative magnetization transfer and myelin water imaging may be due in part to delamination and formation of vacuoles in the myelin sheath. Deuterium oxide-exchanged signal intensity may be altered by fixation-induced changes in myelin lipid solid-state H T . We urge caution in the comparison of these measurements across subjects or specimens in different states, especially unfixed versus fixed tissue.
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http://dx.doi.org/10.1002/mrm.27821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626568PMC
October 2019

Preoperative and Histological Predictors of Recurrence and Survival in Atypical Meningioma After Initial Gross Total Resection.

World Neurosurg 2019 Aug 14;128:e148-e156. Epub 2019 Apr 14.

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Objective: Atypical (World Health Organization grade II) meningiomas (AMs) have been associated with a substantial risk of recurrence even after complete, gross total resection (GTR). The present study evaluated the clinical and AM tumor histopathological features that might predict for the risk of recurrence and survival within this patient population.

Methods: The data from 72 consecutive patients who had undergone primary GTR for AM from 2007 to 2016 and corresponding tumor specimens at a single institution were reviewed. The preoperative patient and tumor characteristics were correlated with the postresection outcomes, including recurrence and 1-year survival. Cox regression models on recurrence-free survival (RFS) and Kaplan-Meier survival estimates were performed.

Results: The overall 1-, 3-, and 5-year RFS estimates for the AM cohort were 100.0%, 82.4%, and 78.1% after resection, respectively. A high mitotic index was an independent predictor of RFS on Cox regression analysis (hazard ratio, 1.26; P = 0.008), and the tumor volume showed a trend toward a significant association (hazard ratio, 0.93; P = 0.079). Patient age and the mitotic index were significantly associated with 1-year mortality (odds ratio, 1.11 and 1.36, respectively; P = 0.028 and P = 0.045, respectively).

Conclusions: AM tumors with a high proliferative index showed an increased likelihood of recurrence and short-term survival even after complete GTR. A smaller tumor volume might also have contributed to an increased risk of recurrence for patients with AM. Although other histopathological features were not linked to recurrence or mortality for patients with AM, the biopsy findings can indicate key predictive information, and further molecular analysis might reveal additional prognostic markers.
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http://dx.doi.org/10.1016/j.wneu.2019.04.069DOI Listing
August 2019

Biopsy During Minimally Invasive Intracerebral Hemorrhage Clot Evacuation.

World Neurosurg 2018 Dec 24. Epub 2018 Dec 24.

Department of Neurosurgery, Mount Sinai Hospital, New York, New York, USA. Electronic address:

Background: The safety and efficacy of brain parenchyma biopsy during minimally invasive (MIS) intracerebral hemorrhage (ICH) clot evacuation has not been previously reported. The objective of this study was to establish the safety and diagnostic efficacy of brain biopsy during MIS ICH clot evacuation and to validate the modified Boston criteria as a predictor of cerebral amyloid angiopathy (CAA) in this cohort.

Methods: From October 2016 to March 2018, superficial and perihematomal biopsies were collected for 40 patients undergoing MIS ICH clot evacuation and analyzed by the pathology department to assess for various ICH etiologies. Additionally, the admission magnetic resonance imaging or computed tomography scan of each patient was analyzed and evaluated for the likelihood of a CAA etiology based on the modified Boston criteria. Student t test was used to analyze intergroup differences in continuous variables, and a 2-tailed Fisher exact test was used to determine intergroup differences of categorical variables, with significance set at P < 0.05.

Results: Two of the 40 patients (5%) experienced postoperative rebleed. Four of the 40 patients (10%) had evidence of CAA on biopsy. Patients with CAA on biopsy were older (P = 0.005) and had a higher prevalence of parietal lobe (P = 0.02) and occipital lobe (P = 0.001) hemorrhage. The modified Boston criteria had a sensitivity of 100% (95% confidence interval [CI], 39.6%-100%) and a specificity of 72.2% (95% CI, 54.6%-84.2%) for predicting CAA on biopsy.

Conclusions: Brain biopsy in MIS ICH clot evacuation is safe and allows for the diagnosis of various ICH etiologies.
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http://dx.doi.org/10.1016/j.wneu.2018.12.058DOI Listing
December 2018

Aicardi syndrome in a 20-year-old female.

Am J Ophthalmol Case Rep 2018 Dec 6;12:61-64. Epub 2018 Sep 6.

Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.

Purpose: To describe an unusual case of Aicardi Syndrome that both affirms hallmark characteristics of the condition and introduces new observations.

Observations: We report the case of a 20-year-old woman with Aicardi Syndrome who presented in respiratory distress with bradycardia and died soon thereafter. She had a history of severe mental retardation, seizure disorder, advanced scoliosis and numerous contractures in addition to congenital ocular malformations resulting in bilateral blindness. The case is notable for her age and longevity, as most patients with Aicardi Syndrome expire much younger, as well as the presence of intact nuclei under the posterior lens capsule.

Conclusions And Importance: Aicardi Syndrome is a rare X-linked cerebro-retinal disorder typified by seizures, agenesis of the corpus callosum, and chorioretinal lacunae. Documenting alterations from and additions to this triad of symptoms is critical to better understanding both the syndrome itself, as well as the full breadth of its clinical impact on the patient.
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http://dx.doi.org/10.1016/j.ajoc.2018.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143771PMC
December 2018

Sensory Innervation of the Human Soft Palate.

Anat Rec (Hoboken) 2018 11 6;301(11):1861-1870. Epub 2018 Aug 6.

Linguaflex, Inc, 322 North Shore Drive, Suite 200, Pittsburgh, Pennsylvania 15212.

The human soft palate plays an important role in respiration, swallowing, and speech. These motor activities depend on reflexes mediated by sensory nerve endings. To date, the details of human sensory innervation to the soft palate have not been demonstrated. In this study, eight adult human whole-mount (soft palate-tongue-pharynx-larynx-upper esophagus) specimens were obtained from autopsy. Each specimen was bisected in the midline, forming two equal and symmetrical halves. Eight hemi-specimens were processed with Sihler's stain, a whole-mount nerve staining technique. The remaining eight hemi-soft palates were used for immunohistochemical study. The soft palatal mucosa was dissected from the oral and nasal sides and prepared for neurofilament staining. Our results showed that the sensory nerve fibers formed a dense nerve plexus in the lamina propria of the soft palatal mucosa. There was a significant difference in the innervation density between both sides. Specifically, the oral side had higher density of sensory nerve fibers than the nasal side of the soft palate. The mean number and percent area of the sensory nerve fibers in the mucosa of the nasal side was 78% and 72% of those in the mucosa of the oral side, respectively (P < 0.0001). The data presented here could be helpful for further investigating the morphological and quantitative alterations in the sensory nerves in certain upper airway disorders involving the soft palate such as obstructive sleep apnea (OSA) and for designing effective therapeutic strategies to treat OSA. Anat Rec, 301:1861-1870, 2018. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ar.23864DOI Listing
November 2018