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Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.

Meningiomas are a central nervous system tumor primarily afflicting adults, with

Molecular testing has become essential for the optimal workup of central nervous system (CNS) tumors. There is a vast array of testing from which to choose, and it can sometimes be challenging to appropriately incorporate findings into an integrated report. This article reviews various molecular tests and provides a concise overview of the most important molecular findings in the most commonly encountered CNS tumors. Many molecular alterations in CNS tumors have been identified over recent years, some of which are incorporated into the 2016 World Health Organization (WHO) classification and the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) updates. Array-based methylation profiling has emerged over the past couple of years and will likely replace much of currently used ancillary testing for diagnostic purposes. A combination of next-generation sequencing (NGS) panel and copy number array is ideal for diffuse gliomas and embryonal tumors, with a low threshold to employ in other tumor types. With the recent advances in molecular diagnostics, it will be ever more important for the pathologist to recognize the molecular testing available, which tests to perform, and to appropriately integrate results in light of clinical, radiologic, and histologic findings.

In 2016, the World Health Organization (WHO) released the most recent update to the classification of central nervous system tumors. This update has led to the reshaping of tumor identification and subsequently changed current understanding of treatment options for patients. Moreover, the restructuring of the classification of central nervous system tumors to include molecular markers has led to the need to re-evaluate how to interpret pivotal trials. These trials originally enrolled patients purely based upon histologic diagnoses without the use of adjunctive, and frequently diagnostic molecular testing. With this new paradigm also comes the need to assess how one should incorporate molecular markers into current trials as well as shape future trials. First, we will discuss updates on the molecular classification of glioblastoma (GBM) (and its histologic mimics). This will be followed by a review of key pivotal trials which have defined our standard of care for glioblastoma within the context of molecular classification of their study populations. This will be followed by preliminary results of ongoing phase 3 cooperative group trials for high-grade gliomas that were initiated prior to routine molecular classification of tumors and how one could interpret these results in light of advances in molecular classification. Finally, we will end with suggestions for future clinical trial design with a focus on enrollment based upon molecular diagnostics.

Background Chronic myeloid leukemia (CML) is a common hematologic malignancy; however, its occurrence during pregnancy is unusual due to its low prevalence in females of childbearing age. There are conflicting reports of how to best manage CML in pregnancy, particularly in the setting of leukocytosis. Hemapheresis A 30-year-old female was diagnosed with CML at 18 weeks' estimated gestational age. On initial presentation she reported fatigue, night sweats, and early satiety, and was found to have a white blood cell (WBC) count of 69.3 × 109 /L and platelet count of 366 × 109 /L. Her disease was managed during pregnancy using interferon-α alone despite persistent leukocytosis. Conclusion CML may be effectively managed during pregnancy, even in the setting of leukocytosis, without the application of leukocytapheresis. Management relies not only upon the coordination of drug therapy and fetal monitoring, but requires close communication between multiple medical disciplines. Leukocytapheresis has been safely performed during pregnancy and may be a suitable adjunct management strategy in pregnant patients diagnosed with CML with specific clinical presentations, such as hyperleukocytosis (WBC count > 150 × 109 /L) and/or symptomatic leukostasis.

A 15-year-old female presented for evaluation of progressive hearing loss over a year. Computed tomographic imaging revealed a 11 x 6 × 6 mm osseous lesion with 'groundglass' appearance within the left posterior petrous bone lateral to vestibular aqueduct suspicious for an endolymphatic sac tumor. Surgical excision revealed fibrous dysplasia on histological analysis. Fibrous dysplasia of the temporal bone is not uncommon, but few cases of extension causing sensorineural hearing loss exist in the literature. We describe the first reported case of fibrous dysplasia mimicking an endolymphatic sac tumor; interestingly, the patient also showed hearing improvement immediately following removal.

High-quality evidence supporting clinical practice is lacking in apheresis. A potential source of evidence is provided by abstracts submitted to the Annual Meetings of the American Association of Blood Banks (AABB) and the American Society for Apheresis (ASFA). However, there is potential for study conclusions to be altered significantly following abstract presentations prior to publications in peer-reviewed journals. Therefore, we evaluated the discordance rate between apheresis-related meeting abstracts and their corresponding published articles. Abstracts accepted to either AABB or ASFA Annual Meetings from 2005 to 2012 and corresponding PubMed-indexed peer-reviewed articles' abstracts published prior to 9/2014 were reviewed for altered methods, results, and conclusions. When present, changes were evaluated for clinical significance. During the 8-year period, 198 out of 1152 abstracts were published as peer-reviewed articles. Of these, 36 (18.2%) presented discordant results, six of which (16.7%) were potentially clinically significant. An alteration in results (58.3%) was the leading reason for discordance. The discordance rate for ASFA abstracts was significantly higher (HR = 4.69, P = 0.0028) than the AABB ones. However, clinically significant alterations occurred more frequently among AABB abstracts (P = 0.025). Approximately 18% of meeting abstracts demonstrated alterations prior to publication in peer-reviewed journals. Given that approximately one in six changes represented clinically significant alterations, potentially affecting clinical practice, we recommend caution when modifying one's clinical practice based on abstract presentations at Annual Meetings. Future studies involving abstracts from both the International Society for Apheresis and the World Apheresis Association should also be performed.

Heparin-induced thrombocytopenia (HIT) is a not-uncommon adverse effect of heparin exposure, with potentially serious and/or fatal thrombotic consequences. Recent studies looking at the off-label use of fondaparinux for HIT show similar efficacy and adverse-effect profiles, as well as improved costs, compared with some commonly used direct thrombin inhibitors. Although routine laboratory monitoring of fondaparinux-specific anti-Xa levels typically is not recommended, we present a case report that suggests fondaparinux monitoring may be needed in patients with hepatic impairment causing acquired antithrombin deficiency. We performed daily assessment of antithrombin- and fondaparinux-specific anti-Xa levels in a 50-year-old female of unknown ethnicity to ensure that fondaparinux dosing was maintained within an acceptable range. With this management strategy, the patient experienced no thrombotic or hemorrhagic complications during the hospital admission or the following 2 months in outpatient treatment.

Chronic myeloid leukemia (CML) is a common hematologic malignancy; however, its occurrence during pregnancy is unusual due to its low prevalence in females of childbearing age. There are conflicting reports of how to best manage CML in pregnancy, particularly in the setting of leukocytosis.A 30-year-old female was diagnosed with CML at 18 weeks' estimated gestational age. On initial presentation she reported fatigue, night sweats, and early satiety, and was found to have a white blood cell (WBC) count of 69.3 × 10CML may be effectively managed during pregnancy, even in the setting of leukocytosis, without the application of leukocytapheresis. Management relies not only upon the coordination of drug therapy and fetal monitoring, but requires close communication between multiple medical disciplines. Leukocytapheresis has been safely performed during pregnancy and may be a suitable adjunct management strategy in pregnant patients diagnosed with CML with specific clinical presentations, such as hyperleukocytosis (WBC count 150 × 10

Many studies have suggested that inappropriate plasma usage is common. An important factor contributing to futile plasma administration in most patients is the nonlinear relationship between coagulation-factor levels and the volume of plasma transfused. In this review, a validated mathematical model and data from the literature will be used to illuminate 3 key properties of plasma transfusion. Those properties are as follows: the effect of plasma transfusion on international normalized ratio (INR) is transient; for the same volume of transfused plasma, a greater reduction in INR is observed at higher initial INRs; and the effect of plasma transfusion on INR correction (ie, the difference between initial and final INRs) diminishes as more plasma is transfused. Frequent misunderstanding of these properties may contribute to inappropriate plasma usage. Therefore, this review will assist physicians in navigating these common pitfalls. Stronger understanding of these principles may result in a reduction of inappropriate plasma transfusions, thus potentially enhancing patient safety and reducing healthcare costs.

CD5 antigen expression in B-cell acute lymphoblastic leukemia (B-ALL) is exceptionally rare. There are six detailed case reports in the literature, with only 16 cases described. Case series analyzing the frequency of aberrant B-ALL immunophenotypes suggest that this variant may occur in as little as 2-4.5% of all B-ALL cases, with one series having no CD5+ positive cases. Herein we report a case of CD5+ B-ALL in a 15-year-old female, and review the previously reported cases. As limited information is available, more data from prospective clinical trials are required to determine whether CD5 positivity portends a poorer prognosis.

Background: Acquired TTP is a potentially fatal syndrome, resulting from autoantibodies against ADAMTS13; however, ADAMTS13 deficiency or the presence of autoantibodies is not sufficient to cause disease or predict outcome. Infection or systemic inflammation often precedes the onset of acute TTP. We hypothesize that human neutrophil peptides (HNPs) 1-3, released from activated neutrophils or activation of complement, may be a trigger and a potential biomarker for acquired TTP; thus, we sought to determine the association between these biomarkers with in-hospital mortality during the acute setting. Methods: All patients admitted to our institution with the diagnosis of autoimmune TTP and ADAMTS13 level Results: Fifty one patients (28 females, 23 males; mean age: 43.8 years; 35 patients with initial TTP episode) were eligible and had frozen plasma for laboratory analysis. On admission, prior to the initiation of therapeutic plasma exchange, the mean hematocrit (Hct), platelet count (Plt), and lactate dehydrogenase (LDH) were 24.3%, 19,130/mL, and 1,132.5 IU/L, respectively. The mean plasma levels of HNPs1-3, Bb, iC3b, C4d, and sC5b-9 were 47.1 ng/mL, 15.8 mg/mL, 3.3 mg/mL, 3.1 mg/mL, and 1.7 mg/mL, respectively. Nine patients died during hospitalization. Univariate analysis demonstrated that the patients who died tended to be older (p=0.01) and had relapsed disease (p=0.02). Other clinical variables (gender, ethnicity, neurologic symptoms) and laboratory variables (Hct, Plt, absolute neutrophil count [ANC], creatinine [Cr], LDH, HNPs1-3, and complement markers) were not statistically different between survivors and non-survivors; however, age, Cr, and LDH had high effect sizes (Cohen'd=0.81, 1.13, and 0.82) while ANC and HNPs had moderate effect sizes (Cohen'd=0.48 and 0.56). These results indicate that the differences have practical significance and would have reached statistical significance if the sample sizes were increased. Decision tree analysis (see Figure 1) further showed that all 3 TTP patients that had Cr ≥3 mg/dL died. Moreover, none of the 30 TTP patients younger than 48.5 years old died. Interestingly, in the group older than or equal to 48.5 years, the mortality rate was higher if the patients had HNPs Conclusions: Mortality is increased in patients with acquired TTP if they are older (≥48.5 years), have worsened baseline renal function (Cr ≥3 mg/dL), or have baseline HNPs levels lower than 26.5 ng/dL or greater than or equal to 82.9 ng/dL. Complement activation markers and other baseline clinical and routine laboratory parameters were not different between survivors and non-survivors. Larger multicenter studies should be performed to confirm these findings, with attention to parameters with moderate to high effect sizes (i.e. age, Cr, LDH, ANC, and HNPs levels). Furthermore, basic science research is warranted to elucidate the role of HNPs in the pathogenesis of autoimmune TTP. Disclosures Zheng: Ablynx: Consultancy; Alexion: Research Funding.

LG-44. OCCURRENCE OF BRAF V600E MUTATION IN A PEDIATRIC BRAINSTEM GANGLIOGLIOMA WITH NEAR EXCLUSIVE GLIAL COMPONENT IN THE ORIGINAL BIOPSY Alex Feldman, David Kelly, Alyssa Reddy, Jeffrey Blount, and Rong Li; University of Alabama at Birmingham, Birmingham, AL, USA A five-year-old male who initially presented with apneic episodes and morbid obesity underwent imaging studies, which revealed a dorsally exophytic medullary tumor in 2014. A biopsy showed a classic pilocytic astrocytoma (PA) with no apparent neoplastic neuronal component. Following completion of chemotherapy, the patient presented again in January of 2016 with worsening symptoms; the tumor was found to have grown in size with brainstem compression. Debulking was performed. Unexpectedly, the histology of this tumor showed a ganglioglioma (GG) with many clusters of enlarged, misshapen, dysmorphic-appearing and occasionally binucleated neurons. Furthermore, BRAF V600E mutations were identified in both prior and recurrent tumors. Recent publications have found that the BRAF V600E mutation is seen in 20-58% of all GGs. In particular, pediatric brainstem GGs appear to harbor this mutation at a rate greater than 50%. Few studies have investigated the distribution of BRAF aberrations among neuronal and glial components in GGs. Pilocytic astrocytomas often possess BRAF abnormalities, though fusion genes (i.e BRAF-KIAA1549) are considerably more common (60-80%) than the BRAF V600E missense mutations (only seen in 10-12% of pediatric brainstem PAs). This case highlights the presence of the BRAF point mutation in both glial and neuronal component of a pediatric brainstem GG, supporting the hypothesis that a glioneuronal lineage precursor is initially affected by the mutation. Additionally, the presence of the BRAF point mutation in a brainstem pilocytic astrocytoma should raise the possibility of a GG in which sampling artifact highlights a near exclusive glial component. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.44 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.