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Individuals with dementia may come to forensic autopsy, partly because of non-natural deaths (e.g. fall-related), and/or concerns of abuse/neglect. At the New York City Office of Chief Medical Examiner (NYC OCME), brains from such cases are submitted for neurodegenerative disease (ND) work-up. Seventy-eight sequential cases were evaluated using a recently published condensed protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer disease (AD), a cost-cutting innovation in diagnostic neuropathology. ND was identified in 74 (94.9%) brains; the most common were AD (n = 41 [52.5%]), primary age-related tauopathy (n = 26 [33.3%]), and Lewy body disease ([LBD], n = 25 [32.1%]). Others included age-related tau astrogliopathy, hippocampal sclerosis of aging, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, argyrophilic grain disease, and Creutzfeldt-Jakob disease. 26.8% of AD cases involved a non-natural, dementia-related death, versus 40.0% for LBD. Finally, 70 (89.7%) cases had chronic cerebrovascular disease, 53 (67.9%) being moderate-to-severe. We present a diverse distribution of NDs notable for a high rate of diagnoses associated with falls (e.g. LBD), a potential difference from the hospital neuropathology experience. We also report a high burden of cerebrovascular disease in demented individuals seen at the NYC OCME. Finally, we demonstrate that the aforementioned condensed protocol is applicable for a variety of ND diagnoses.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

Microvascular Changes in the Brain in Covid-19 High-resolution MRI and histopathological study of the brains of patients who had died from Covid-19 showed punctate hyperintensities and punctate or ...

Key Points Question Is prenatal exposure to maternal drinking and smoking associated with the risk of stillbirth? Findings In this cohort study of 8506 pregnant women (with 11 892 pregnancies) in Cape Town, South Africa, and the Northern Plains in the US, dual exposure to drinking and smoking after the first trimester of pregnancy had 2.78 times the risk of late stillbirth compared with those with no exposure or who had quit before the end of the first trimester of pregnancy. Meaning These findings suggest that dual exposure to drinking and smoking after the first trimester of pregnancy is associated with nearly 3 times the risk of late stillbirth., Importance Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures The main outcomes were stillbirth, defined as fetal death at 20 or more weeks’ gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks’ gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth., This cohort study assesses whether prenatal exposure to alcohol, tobacco cigarettes, or both is associated with the risk of stillbirth in pregnant women from Cape Town, South Africa, and the Northern Plains region of the US.

Background and Importance: Choristomas of the internal auditory canal and cerebellopontine angle are rare, non-neoplastic lesions that mimic vestibular schwannomas and may subsequently be subject to treatment by surgical resection or radiosurgery.

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002–0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla—a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9,912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

In infants and toddlers (less than four years of age), determination of cause and manner of death often requires a complete autopsy. Few evidence-based guidelines exist regarding optimum nervous system sectioning in this population. Over a six-month interval and using a comprehensive section protocol, we categorized cases having neuropathological findings that were critical (Class A), contributory (Class B), or noncontributory (Class C) to the final cause and manner of death. We further evaluated which sections helped make this determination. Among 53 cases (44 infants, 9 toddlers; 26 girls, 27 boys), Class A neuropathology was noted in nine (16.9%). Seven infants had meningoencephalitis (2/7, 28.6%), craniospinal trauma (3/7, 42.8%), brainstem necrosis suggesting Leigh Disease (1/7, 14.3%), and hydrocephalus in Dandy-Walker malformation (1/7, 14.3%); two toddlers had inflicted craniospinal trauma (2/2, 100%). Class B factors were identified in 11/53 (20.8%), including recent hypoxic-ischemic lesions (2/11, 18.2%), meningitis or dural venous sinus thrombosis in systemic sepsis (2/11, 18.2%), multicystic encephalopathy following peripartum asphyxia (2/11, 18.2%), and microcephaly and delayed myelination (Cri-du-Chat Syndrome) (1/11, 9.09%). Class B also included three toddlers (3/11, 27.2%) with features of hippocampal dysgenesis, two in the setting of febrile seizures. Class C comprised normal brains (3/53, 5.7%), and those with findings of uncertain significance, such as white matter and brainstem gliosis (30/53, 56.6%). The sections most valuable for detection of relevant pathology, and thus recommended for routine sampling, were: 1) bilateral hippocampus; 2) cerebral cortex and leptomeninges; and 3) pons or medulla.

Upon detection of foreign-body embolization to the central nervous system (CNS) following a specific invasive cardiovascular procedure in 1 autopsied child, we undertook a quality assurance analysis to determine whether other patients had had similar events. Autopsies of all infants and children with history of cardiac catheterization, heart surgery on cardiopulmonary bypass, and/or extracorporeal membrane oxygenation over a 5-year period at a single tertiary care institution were reviewed for light-microscopic evidence of foreign material. Of the 24 patients meeting clinical criteria (13 females, 11 males; ages 6 days to 20 years, median age 7.5 months), 8 (33%) had foreign embolic material to the CNS. The material was associated with a cellular inflammatory reaction in all cases, with a subset associated with infarcts. No embolic foreign material was detected in 14 age-matched patients without history of cardiovascular procedures. Particles acquired from ex vivo manipulation of a catheter type utilized in at least 1 of the affected patients demonstrated similar histologic characteristics. We conclude that, in addition to recognized risks of hypoxic-ischemic brain damage in congenital cardiopulmonary disease, potential brain insult exists in the form of instrumentation-related foreign emboli to the cerebral vasculature. Cardiac catheters are a potential source of foreign embolic material.

We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease., Measurement(s)nuclear magnetic resonance assayTechnology Type(s)MRI ScannerFactor Type(s)flip angleSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9958688

No abstract available.

The rate for the sudden infant death syndrome (SIDS) in Cape Town, South Africa, is estimated to be among the highest in the world (3.41/1000 live births). In several of these areas, including those of extreme poverty, only sporadic, nonstandardized infant autopsy, and death scene investigation (DSI) occurred. In this report, we detail a feasibility project comprising 18 autopsied infants with sudden and unexpected death whose causes of death were adjudicated according to the 1991 NICHD definitions (SIDS, n = 7; known cause of death, n = 7; and unclassified, n = 4). We instituted a standardized autopsy and infant DSI through a collaborative effort of local forensic pathology officers and clinical providers. The high standard of forensic investigation met international standards, identified preventable disease, and allowed for incorporation of research. We conclude that an effective infant autopsy and DSI protocol can be established in areas with both high sudden unexpected infant death, and elsewhere. (SUID)/SIDS risk and infrastructure challenges.

The Safe Passage Study is an international, prospective study of approximately 12 000 pregnancies to determine the effects of prenatal alcohol exposure (PAE) upon stillbirth and the sudden infant death syndrome (SIDS). A key objective of the study is to elucidate adverse effects of PAE upon binding to serotonin (5-HT) 1A receptors in brainstem homeostatic networks postulated to be abnormal in unexplained stillbirth and/or SIDS. We undertook a feasibility assessment of 5-HT1A receptor binding using autoradiography in the medulla oblongata (6 nuclei in 27 cases). 5-HT1A binding was compared to a reference dataset from the San Diego medical examiner’s system. There was no adverse effect of postmortem interval ≤100 h. The distribution and quantitated values of 5-HT1A binding in Safe Passage Study cases were essentially identical to those in the reference dataset, and virtually identical between stillbirths and live born fetal cases in grossly non-macerated tissues. The pattern of binding was present at mid-gestation with dramatic changes in binding levels in the medullary 5-HT nuclei over the second half of gestation; there was a plateau at lower levels in the neonatal period and into infancy. This study demonstrates feasibility of 5-HT1A binding analysis in the medulla in the Safe Passage Study.

Background: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. Methods: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. Findings: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59–53·7, p

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole–mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

Bacillus cereus typically causes a self-limited foodborne gastrointestinal (GI) illness. Severe invasive infection occurs rarely, mainly among immunocompromised hosts. We describe a cluster of B. cereus infections among 5 patients with acute myeloid leukemia and chemotherapy-induced neutropenia. The initial case presented with occipital lobe abscess and was found on biopsy to have organisms consistent with Bacillus species. Within 1 week, a second patient died of fulminant brain swelling and hemorrhage. Neuropathologic autopsy and culture revealed B. cereus; hospital infection control and public health officials were notified. Three more patients died within the subsequent 9 months (2 patients had rapid massive hemorrhage and many bacilli reminiscent of Bacillus anthracis infection, and 1 patient had sparse bacilli, petechial hemorrhages, and border zone infarcts). Blood cultures yielded positive results in 3 of 5 cases. A possible route of infection was hematogenous dissemination via GI mucosal breaches (GI symptoms occurred in 3 of 5 cases, and postmortem GI ulceration was found in 3 of 4 cases). Bacilli were seen in 2 of 3 GI ulcerations. Epidemiologic work-up, including a site visit conducted by the Centers for Disease Control and Prevention, did not identify a clear common source but suggested the possibility of bananas as a food source. Bacillus cereus causes a rapidly progressive, hemorrhagic meningoencephalitis with high mortality among patients with neutropenia. Neuropathologists can play a key role in the detection of outbreaks.

The association of sensorineural hearing loss and vertigo with inflammatory eye disease, usually interstitial keratitis, has been called Cogan’s syndrome. The pathogenesis of Cogan’s syndrome is unknown, but it has been assumed to be an immune mediated disorder with vasculitis. The histopathology of the inner ear in Cogan’s syndrome has been described in 6 case reports. Although common pathologic findings in these reports include degeneration of the auditory and vestibular neuroepithelium, endolymphatic hydrops, fibrosis, and new bone formation, direct pathologic evidence of a vasculitis has not been published. A possible reason for this failure to identify vasculitis was a substantial delay (range, 4-40 years) between the onset of symptoms and examination of the otopathology. In the current case report, the patient had both auditory and vestibular symptoms and interstitial keratitis with a time delay of only 2 to 4 weeks between symptoms and death. Evidence of a vasculitis as a possible underlying etiology included H&E histopathology and anti-CD45 immunostaining of vessels both in the auditory and vestibular systems, supporting the hypothesis of a vasculitis as a mechanism in this disorder.

To the Editor: In this issue of the JNEN , Olasode and Onyia take us through their early steps of modernization of neuropathologic service in a tertiary medical center and university-based teaching hospital in Nigeria, one of our sister countries in Africa currently looking to the developed world for guidance (1). By “early steps”, we mean the identification and compilation of information of clinical cases referred to neurosurgeons, (and hence generating tissue to be examined), in their practice locale. Such a stage is essential to understanding the region-specific spectrum of neuropathologic disease, and thus what ancillary techniques need to be developed. Their data are likely broadly generalizable to other sites on the continent, judging from their comprehensive discussion and cited literature. Few of us practicing outside of Africa have much sense of the huge challenges that exist in resource-poor settings, which are often also areas of conflict, in the majority of countries there. Having spent time in Rwanda and Malawi (R.D.F.), in South Africa (R.D.F. and D.Z., currently in practice there), and in Nigeria (A.M.A.), we offer our personal observations as a means of illustrating some of these challenges. As a singular example, one is astounded to learn that in many places surgical specimens (eg, colectomies, soft tissue masses, and so on), are examined macroscopically by the surgeon, (to the best of his or her ability), and then discarded because there is no readily available pathology laboratory. In Rwanda until just a few years ago, provincial points of care were able only to refer the patient to obtain fixative for and then transport their own specimen, at their own expense, to one of a handful of regional centers in the entire country; needless to say, very few were ever processed. In turn, without tissue diagnoses, adjuvant treatments could not be …

Background Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

// Malak S. Abedalthagafi 1 , Parker H. Merrill 1 , Wenya Linda Bi 2 , Robert T. Jones 1 , Marc L. Listewnik 3 , Shakti H. Ramkissoon 1 , Aaron R. Thorner 4,5 , Ian F. Dunn 2 , Rameen Beroukhim 4,6,9 , Brian M. Alexander 7 , Priscilla K. Brastianos 4,6,8 , Joshua M. Francis 4,6 , Rebecca D. Folkerth 1 , Keith L. Ligon 1,4 , Paul Van Hummelen 4,5 , Azra H. Ligon 3 and Sandro Santagata 1,9 1 Department of Pathology, Division of Neuropathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 3 Clinical Cytogenetics Laboratory, Center for Advanced Molecular Diagnostics, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 5 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA 6 Broad Institute of MIT and Harvard, Cambridge, MA, USA 7 Department of Radiation Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 8 Department of Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 9 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Correspondence: Sandro Santagata, email: // Keywords : meningioma, angiomatous, polysomy, aCGH, molecular diagnostics, Next Generation Sequencing Received : September 14, 2014 Accepted : September 24, 2014 Published : September 25, 2014 Abstract Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.

Background: The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. Methods: The results provided are based on an interim assessment of 6004 women enrolled, out of the 12 000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. Results: Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. Conclusions: The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/ infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.

Schistosomiasis is the second most socioeconomically devastating parasitic disease worldwide, affecting over 240million people in 77 countries on 5 continents and killing 300,000 people annually in sub-Saharan Africa alone. Neuroschistosomiasis is caused by granuloma formation around eggs that lodge in the CNS, with Schistosoma mansoni and Schistosoma haematobium usually affecting the spinal cord and Schistosoma japonicum causing most reported cerebral disease. We report a case of a previously healthy 25-year-old woman native to the United States who presented with a single generalized tonic–clonic seizure without other neurologic symptoms four years after spending a semester in Ghana where she went swimming once in a river. Brain MRI showed areas of signal abnormality and mottled nodular linear enhancement in the left temporal and right posterior temporal/parietal lobes and right cerebellum without mass effect. A biopsy of the left temporal lesion showed prominent granulomas with dense mixed inflammatory infiltrates composed of eosinophils, plasma cells, and lymphocytes surrounding refractile egg shells containing characteristic embryonal cells and von Lichtenberg's envelope and displaying the pathognomonic spine shape of S. mansoni. Serum ELISA and antibody immunoblots confirmed exposure to S. mansoni. In summary, we describe the atypical combination of cerebral schistosomiasis due to S. mansoni, after a prolonged interval of four years, from a single known exposure.

Zika virus (ZIKV) is a member of the Flaviviridae family that had been associated only with mild disease prior to the 2015 outbreak in Brazil. A dramatic increase in reported cases of microcephaly and Guillain-Barre syndrome during this time prompted significant research into possible associations with ZIKV and its neurotropic properties. Infection of neural progenitor cells and organoids have been shown to induce apoptosis and dysregulation of growth, and mouse studies have demonstrated viral replication in brain tissue in adults, as well as vertical transmission resulting in embryonic brain abnormalities. Large case series of clinical and radiological findings of congenital ZIKV infection have begun to be published; however, pathology reports have been limited to two case reports and two small case series. Thus far, the findings have largely been restricted to the brain and include diffuse grey and white matter involvement consisting of dystrophic calcifications, gliosis, microglial nodules, neuronophagia, and scattered lymphocytes. Mild chronic villitis was observed in the placental tissue in some cases, and the remaining organs were essentially uninvolved. Larger, systematic studies, including correlation of histological findings with gestational age at the time of maternal infection, will be required to determine the full range of Zika virus-induced abnormalities and to help guide future clinical decision making.

Objective Describe the classification system for assigning the cause of stillbirth in the Safe Passage Study, an international, multi-institutional, prospective analysis conducted by the NIAAA/NICHD-funded Prenatal Alcohol in SIDS and Stillbirth (PASS) Research Network. The study mission is to determine the role of prenatal alcohol and/or cigarette smoke exposure in adverse pregnancy outcomes, including stillbirth, in a high-risk cohort of 12,000 maternal/fetal dyads. Methods The PASS Network classification system is based upon 5 “sites of origin” for cause of stillbirth, further subdivided into mechanism subcategories; both are employed to assign an ultimate cause of death. Each PASS stillbirth was assigned a cause of death and status of sporadic versus recurrent. Adjudication involved review of maternal and obstetrical records; fetal autopsy and placental findings; and required complete consensus in each case. Two published classification systems, ie, INCODE and ReCoDe, were used for comparison. Results Causes of stillbirth classified were fetal (26%), placental (53%), external (5%), and undetermined (16%). Nine cases (47%) had placental causes of death due to maternal disorders that carry recurrence risks. There was full agreement for cause of death across the 3 classification systems in 26% of cases and partial agreement among them in 42% of cases. Conclusions The proposed PASS schema employs a user-friendly classification that provides comparable information to previously published systems. Advantages include its simplicity, mechanistic formulations, tight clinicopathologic integration, provision for an undetermined category, and its wide applicability to perinatal mortality review boards with access to information routinely collected during clinicopathologic evaluations.

Meningioangiomatosis consists of benign hamartomatous lesions of the brain and the leptomeninges, which typically present with seizure. Management is predicated on resection and control of seizures with medication. Lesions are typically solitary. Multifocal meningioangiomatosis is extremely rare, with only 2 cases reported in adults and none in children. The authors report the first case, to their knowledge, of multifocal meningioangiomatosis in a child. This unique case highlights therapeutic challenges associated with these lesions and demonstrates that multifocality is possible in the pediatric population. This finding has implications for diagnosis and follow-up for children afflicted with these tumors.

Intravascular large B-cell lymphoma, also known as angiotrophic large cell lymphoma, is a rare disorder where neoplastic lymphoid cells proliferate within the walls of small- to medium-sized blood vessels. Peripheral neuropathy and other neurological manifestations, including stroke and dementia, are common, but cases of isolated multiple mononeuropathies in the absence of systemic symptoms are distinctly rare. We present an unusual case of biopsy-proved angiotrophic large cell lymphoma presenting exclusively with multiple mononeuropathies.

BACKGROUND: We report two cases of infantile tectal gliomas initially concerning on biopsy for high-grade features, but which are proving over time to have indolent clinical courses. Case I. A three-months-old female presented with hydrocephalus and a small tectal mass; she underwent an endoscopic third ventriculostomy (ETV). The first follow-up MRI performed 5 months later showed relief of hydrocephalus but marked increase (three- to four-fold) in mass size, likely due to decompression post-alleviation of hydrocephalus. A biopsy yielded a tiny fragment of diffuse low-grade glioma, low Ki-67; IHC for H3.3 K27M was initially reported as mutant, but on more recent review as indeterminate, in view of the tiny tumor fragment and high background staining. Therapeutic recommendations included proton-beam irradiation, marrow-ablative chemotherapy, conventional-dose chemotherapy - and observation only. The parents elected careful follow-up. Now 16 months following biopsy, the child is developing well and the MRI is stable, with advanced imaging characteristics of a low-grade glial lesion. Case 2. A male was diagnosed in utero with hydrocephalus, a post-natal MRI confirming this and revealing a small tectal mass. An ETV and biopsy were performed, yielding a tiny tumor fragment; pathology was consistent with a diffuse glial tumor, with rare mitoses; IDH1 and ATRX intact, P53 negative, GFAP positive and Ki67 20–30%. The tumor was deemed a high-grade glioma. Insufficient tissue for sequencing was available. The infant has been followed with close follow-up MRI scans with advanced imaging, which remain consistent with a low-grade glioma, and continues stable at 3 months since birth; a repeat biopsy is planned concomitant with shunt revision. CONCLUSION: Infants with tectal gliomas are rare, and anecdotally never undergo progression to high-grade. In the absence of definitive sequencing data, extreme caution should be exercised in offering treatment recommendations.

The pathogenesis of injury to the developing brain encompasses low oxygen tension and decreased perfusion, often termed "hypoxia-ischemia." Factors playing key roles in this setting include (1) inherent vulnerability of immature cells to conditions such as oxidative stress, cytokines, and excitotoxicity; (2) imperfect autoregulation of cerebral blood flow in the face of fluctuations in systemic perfusion pressure, especially in prematurity; (3) presence of blood products in direct contact with developing brain regions, such as the germinal matrix and cerebellum; (4) frequent co-occurrence of other serious illnesses, such as lung disease in the premature infant, or congenital heart disease in the term infant; and (5) significant antenatal conditions, for example, maternal pre-eclampsia with chronic placental hypoperfusion, or acute chorioamnionitis precipitating preterm delivery. The totality of neuropathology experienced by an infant is a summation over time of all of the above circumstances, which may be singular, intermittent, or continuous, or, most likely, a combination thereof. This article will attempt to shed light on the spectrum of injury seen in the perinatal brain and will comprise lesions encountered in the stillborn, the premature, and the term infant through the presentation of 4 illustrative case studies. These include a term stillbirth with diffuse white matter gliosis and selective neuronal vulnerability (pontosubicular necrosis); a 3-week-old premature infant with periventricular leukomalacia and thalamic/basal ganglionic injury; a premature infant with germinal matrix hemorrhage, complicated by periventricular hemorrhagic infarction; and a term infant with congenital heart disease requiring extracorporeal membrane oxygenation therapy, and global hypoxic-ischemic encephalopathy.

Phaeohyphomycosis is an increasingly recognized cause of brain abscess in both immunocompetent and immunocompromised hosts. We report a case of cerebral phaeohyphomycosis in a 55-year-old male heart transplant recipient caused by Bipolaris spicifera. We review the literature regarding the pathogenesis, epidemiology, diagnosis, and management of infections with dematiaceous fungi.

Contains fulltext : 95644.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973. 01 december 2011 10 p.

Extraadrenal paragangliomas are most commonly found in the carotid body and are also found with lower frequency in the CNS. These lesions are derived from the sympathoadrenal lineage of neural crest cells. Here, the authors report a rare case of a composite paraganglioma with ganglioneuromatous components found at the filum terminale in a patient who presented with a brief history of low-back pain and paresthesias in the inguinal region. Immunohistochemical analysis of the resected lesion revealed admixed elements of neuroendocrine and neuroblastoma lineages, indicating the presence of divergent differentiation of sympathoadrenal progenitor cells. This case represents a unique opportunity to understand the cell fate of sympathoadrenal progenitor cells. Here, the authors propose that paragangliomas at the filum terminale can revert to a neural crest cell precursor fate, giving rise to divergent neoplastic populations.

30-year-old primigravida woman underwent a screening antenatal ultrasound study at 19 weeks of gestation that revealed a posterior fossa cystic lesion and ventriculomegaly in the fetus. She was referred with the diagnosis of a Dandy-Walker malformation (DWM) to our Fetal Neurology Program in the Advanced Fetal Care Center at Children’s Hospital Boston. The pregnancy had been conceived naturally, and other than a longstanding history of hypothyroidism and hypertension, which was controlled with levothyroxine and labetalol, respectively, the pregnancy had been uncomplicated. There was no family history of syndromic or childhood-onset neurologic conditions, bleeding, or thrombophilic disorders. There had been no known infectious, toxic, or traumatic exposure during this pregnancy and no history of aspirin intake. Fetal movements had recently been experienced and were consistent. At our center, a repeat obstetric ultrasound (Fig 1) showed a single active fetus with a normal heart rate and amniotic fluid volume. Again, a large posterior fossa cyst was noted, with moderate to severe distention of the lateral and third ventricles. Little if any cerebellar tissue was evident. Several cysts were noted within the brain parenchyma at the left caudothalamic groove associated with a focal area of increased echogenicity likely representing intraparenchymal hemorrhage. No calcifications were present. A structural survey of the fetal anatomy was otherwise unremarkable. A fetal magnetic resonance imaging (MRI) study performed at the same visit (Figs 2-4) confirmed moderate to severe distention of the lateral and third ventricles, an enlarged fourth ventricle, and enlargement of the posterior fossa by a large cerebrospinal fluid-filled lesion, with elevation of the tentorium and Torcula. A small remnant of superior vermis was present (Fig 3). Susceptibility-weighted sequences showed hemorrhage in the caudothalamic notch bilaterally within the lateral ventricles (Fig 4) and in the subarachnoid spaces around the cerebral convexity and enlarged posterior fossa. The corpus callosum and brainstem were grossly normal, and the cerebral surface was appropriately lissencephalic for gestational age. An amniocentesis showed a normal 46XX karyotype. An extensive panel of coagulation studies on both parents was negative. Based on the severity of these brain anomalies, the parents decided to terminate the pregnancy. Termination was performed by a medically induced labor. Because the underlying etiology remained unclear and given the differing implications of acquired and primary dysgenetic lesions for future pregnancies, the parents consented to a formal autopsy. Examination of the placenta showed a 3-vessel umbilical cord. Except for scattered avascular villi and increased intervillous fibrin, no significant histopathologic changes were identified, including no fetal thrombosis or inflammatory changes.

Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30–50% of very preterm (

BACKGROUND Meningioangiomatosis is a meningovascular disorder that only rarely occurs in association with a meningioma. Occasionally, as in this case, imaging studies do not readily identify this disorder as a benign process. In addition, this disorder may infiltrate the underlying cerebral cortex, simulating, intraoperatively, a malignant infiltrative process. To allow better recognition of this disorder, we report a case with emphasis on the unique cytologic features of the 2 components (meningioangiomatosis and meningioma) and potential pitfalls in diagnosis. CASE A 3-year-old girl was examined in the neurosurgery service for history of refractory seizure. Neuroimaging showed an ill-defined signal abnormality in the left frontal lobe suggestive of a high-grade tumor. Tumor resection was performed, and intraoperative smear preparation showed meningioangiomatosis associated with meningioma. CONCLUSION Familiarity with cytologic preparations of this rare variant is very important in providing accurate intraoperative consultation. To our knowledge, this is the first description of the cytologic features on smear preparation of meningioangiomatosis occurring in association with meningioma.

We previously identified immunocytochemical evidence of nitrative and oxidative injury in premyelinating oligodendrocytes in periventricular leukomalacia (PVL). Here, we tested the hypothesis that free radical injury occurs in the overlying cerebral cortex and subplate neurons in PVL. We immunostained for nitrotyrosine, malondialdehyde, and hydroxynonenal adducts and scored neuron staining density in PVL (n = 11) and non-PVL (n = 15) cases (postconceptional ages from 34 to 109 weeks). Analysis of covariance controlled for age. Mean malondialdehyde scores in PVL cases were increased over controls (p = 0.005). Hydroxynonenal scores increased with age only in PVL cases (diagnosis vs age interaction; p = 0.024). Nitrotyrosine scores were not significantly increased. In 11 PVL and 23 control cases between 20 and 183 postconceptional weeks, cells morphologically consistent with subplate and Cajal-Retzius neurons showed qualitatively increased free radical modification in PVL over control cases with statistically significant odds ratios for hydroxynonenal and nitrotyrosine in both subplate neurons and Cajal-Retzius cells. Glial fibrillary acidic protein and CD68 scores for reactive astrocytes and microglia, respectively, were not significantly increased, suggesting a minimal inflammatory response. Thus, oxidative/nitrative damage to cortical and "pioneer" neurons, although mild overall, may contribute to cortical volume loss and cognitive/behavioral impairment in survivors of prematurity.

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histol- ogy: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diVuse white matter gliosis (DWMG) (n = 17) without necrosis; and " Negative" group (n = 7) with no abnormalities. Neuronal loss was found almost exclusively in PVL, with signiW- cantly increased incidence and severity in the thalamus (38%), globus pallidus (33%), and cerebellar dentate nucleus (29%) compared to DWMG cases. The incidence of gliosis was signiWcantly increased in PVL compared to DWMG cases in the deep gray nuclei (thalamus/basal ganglia; 50-60% of PVL cases), and basis pontis (100% of PVL cases). Thalamic and basal ganglionic lesions occur almost exclusively in infants with PVL. Gray matter lesions occur in a third or more of PVL cases suggesting that white matter injury generally does not occur in isolation, and that the term "perinatal panencephalopathy" may better describe the scope of the neuropathology.

Acquired pre- and perinatal brain injuries comprise a significant proportion of perinatal neuropathology. They are associated with placental abnormalities, maternal factors, multiple gestations, and preterm labor, as well as with the later development of cerebral palsy and developmental delay. The patterns of perinatal brain injury depend on the etiology (often hypoxic-ischemic) and the timing relative to the development of the fetal nervous system, since the vulnerabilities of gray and white matter differ across postconceptional age and by neuroanatomic site. Nevertheless, characteristic features allow determination of the approximate age and cause of each pattern of injury in the perinatal brain.

Background Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. Methods We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Results Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. Conclusion This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Background. Five neuroinvasive Bacillus cereus infections (4 fatal) occurred in hospitalized patients with acute myelogenous leukemia (AML) during a 9-month period, prompting an investigation by infection control and public health officials. Methods. Medical records of case-patients were reviewed and a matched case-control study was performed. Infection control practices were observed. Multiple environmental, food, and medication samples common to AML patients were cultured. Multilocus sequence typing was performed for case and environmental B cereus isolates. Results. All 5 case-patients received chemotherapy and had early-onset neutropenic fevers that resolved with empiric antibiotics. Fever recurred at a median of 17 days (range, 9–20) with headaches and abrupt neurological deterioration. Case-patients had B cereus identified in central nervous system (CNS) samples by (1) polymerase chain reaction or culture or (2) bacilli seen on CNS pathology stains with high-grade B cereus bacteremia. Two case-patients also had colonic ulcers with abundant bacilli on autopsy. No infection control breaches were observed. On case-control analysis, bananas were the only significant exposure shared by all 5 case-patients (odds ratio, 9.3; P = .04). Five environmental or food isolates tested positive for B cereus, including a homogenized banana peel isolate and the shelf of a kitchen cart where bananas were stored. Multilocus sequence typing confirmed that all case and environmental strains were genetically distinct. Multilocus sequence typing-based phylogenetic analysis revealed that the organisms clustered in 2 separate clades. Conclusions. The investigation of this neuroinvasive B cereus cluster did not identify a single point source but was suggestive of a possible dietary exposure. Our experience underscores the potential virulence of B cereus in immunocompromised hosts.