Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease.

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.

The impact of the molecular classification of glioblastoma on the interpretation of therapeutic clinical trial results.

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.

Prognostic Value of J (Osborn) Waves on Surface Electrocardiogram Tracing during Therapeutic Hypothermia in Out-of-Hospital Cardiac Arrest Survivors (JOW trial).

BACKGROUND: Patients admitted to the hospital after successful resuscitation from sudden cardiac death (SCD) are treated with therapeutic hypothermia (TH) to facilitate brain preservation. The prognostic significance of J (Osborn) waves (JOW) in the 12 leads electrocardiogram in this setting has not been elucidated as yet. OBJECTIVES: To ascertain retrospectively the prognostic significance of JOW recorded during TH in SCD survivors. METHODS: The study comprised 55 consecutive patients who underwent TH. All patients achieved a core temperature of 33°C at the time of electrocardiogram analysis. We compared 33 patients with JOW to 22 patients without JOW. The endpoints were in-hospital, long-term all-cause mortality, and irreversible anoxic brain injury (IABI). RESULTS: Patients with JOW compared to patients without JOW were younger (55.1 ± 11.6 vs. 64.5 ± 11.7 years, respectively, P < 0.006), with a lower incidence of hypertension (52% vs. 86%, P < 0.007), diabetes mellitus (15% vs. 50%, P < 0.005), and congestive heart failure (15% vs. 45%, P < 0.013). In-hospital and long-term mortality were significantly higher in patients without JOW (86% vs. 21%, 91% vs. 24%, respectively, P < 0.000001). Among patients without JOW who survived hospitalization, 66.7% presented with IABI versus 7.7% of the patients with JOW (P < 0.0001). In multivariate analysis, the absence of JOW was a significant predictor for poor prognosis. CONCLUSIONS: The absence of J (Osborn) waves on electrocardiograms obtained during TH is associated with poor prognosis among SCD survivors.

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

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.

YAP1-FAM118B Fusion Defines a Rare Subset of Childhood and Young Adulthood Meningiomas.

Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in ∼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children's Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention.

Predicting Long-Term Respiratory Outcomes in Premature Infants: Is It Time to Move beyond Bronchopulmonary Dysplasia?

Premature birth has been shown to be associated with adverse respiratory health in children and adults; children diagnosed with bronchopulmonary dysplasia (BPD) in infancy are at particularly high risk. Since its first description by Northway et al. about half a century ago, the definition of BPD has gone through several iterations reflecting the changes in the patient population, advancements in knowledge of lung development and injury, and improvements in perinatal care practices. One of the key benchmarks for optimally defining BPD has been the ability to predict long-term respiratory and health outcomes. This definition is needed by multiple stakeholders for hosts of reasons including: providing parents with some expectations for the future, to guide clinicians for developing longer term follow-up practices, to assist policy makers to allocate resources, and to support researchers involved in developing preventive or therapeutic strategies and designing studies with meaningful outcome measures. Long-term respiratory outcomes in preterm infants with BPD have shown variable results reflecting not only limitations of the current definition of BPD, but also potentially the impact of other prenatal, postnatal and childhood factors on the respiratory health. In this manuscript, we present an overview of the long-term respiratory outcomes in infants with BPD and discuss the role of other modifiable or non-modifiable factors affecting respiratory health in preterm infants. We will also discuss the limitations of using BPD as a predictor of respiratory morbidities and some of the recent advances in delineating the causes and severity of respiratory insufficiency in infants diagnosed with BPD.

The Essentials of Molecular Testing in CNS Tumors: What to Order and How to Integrate Results.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

[STRATEGIES FOR IMPLEMENTATIONS OF REMOTE MONITORING FOR PATIENTS WITH CARDIOVASCULAR IMPLANTABLE ELECTRONIC DEVICES (CIED) IN ISRAEL].

INTRODUCTION: Remote monitoring (RM) of patients with cardiovascular implantable electronic devices (CIED) offers clinical benefits by providing early alert for system failure and actionable changes in patient health. Professional societies recommend utilization of RM for CIED patients (Level of recommendation I Level of evidence A). It must be emphasized that RM technology does not provide continuous monitoring but rather "remote snapshot clinics". On the other hand, pacemakers (PCM) and implantable cardiac defibrillators (ICD) are designed to work automatically and continuously without any need for immediate external intervention. Therefore, the guidelines recommend that the clinical response to RM notification will take place during the normal office hours. With appropriate organization, the utilization of RM will save a significant number of unnecessary pacemaker clinic visits and will allow better utilization of healthcare resources on patients in whom early intervention may prevent hospitalization, complication and mortality. The guidelines recommend offering RM to all patients with CIED. In Israel however, RM is offered sporadically only to a few patients. If a patient will suffer from delayed or inadequate treatment due to lack of RM, grave ethical and legal consequences may occur. Follow-up of CIED patients utilizing RM should be performed by a team including a primary physician, primary cardiologist, electrophysiologist, nurses and CIED technologist working in concert utilizing modern information technologies. Data should be shared electronically (with strict data security protocols) utilizing the electronic patient file with secure connection to RM systems. In summary, we believe that RM should be offered to all CIED patients in Israel.

Frequency of Alterations in Apheresis-Related Abstracts Prior to Publications as Peer-Reviewed Articles.

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.

Fibrous dysplasia mimicking a pediatric endolymphatic sac tumor.

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.

CD5 positive B-ALL, a uniquely aggressive subcategory of B-ALL? A case report and brief review of the literature.

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.

Monitoring Fondaparinux in the Setting of Antithrombin Deficiency.

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.

Management of chronic myeloid leukemia in the setting of pregnancy: when is leukocytapheresis appropriate? A case report and review of the literature.

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.

Secondary Malignancies of the Bladder: Avoiding the Diagnostic Pitfall.

Although rare, secondary tumors of the bladder can present a diagnostic dilemma to pathologists considering a differential diagnosis of primary bladder cancer. We investigated the clinicopathologic and imaging characteristics of metastatic tumors to the bladder. We retrospectively reviewed the surgical pathology databases from 2 sites from 2013 to 2016, identifying 66 cases of secondary bladder tumors. Clinical, pathologic, and imaging findings were reviewed. Mean age at diagnosis was 63 years (range = 25-87). Females had a significantly higher proportion (44/66, 66.7%) of secondary bladder tumors compared with males (22/66, 33.3%; P = .007). In total, 56/66 (84.8%) patients had a clinical history of an in situ or invasive malignancy in another organ, and 54/66 (81.8%) patients had imaging supporting a metastatic tumor. Only 2/66 (3.0%) patients had a prior history of urothelial carcinoma. In total, 4/66 (6.1%) cases (all females) were originally misdiagnosed as primary bladder malignancies and were corrected after clinicoradiologic correlation. Overall, colorectal origin was most common (15/66, 22.7%), followed by cervical and ovarian primaries (10/66, 15.2% each). Cervical and ovarian origins predominated in the female cohort (10/44, 22.7% each), followed by endometrial (8/44, 18.2%). Colorectal and prostate primaries were the most common among males (10/22, 45.5%, and 7/22, 31.8%, respectively). Secondary bladder tumors can mimic urothelial carcinomas. In our cohort, gynecological, colorectal, and prostatic origins were most common. Clinical history, imaging, and immunohistochemical studies can be useful in avoiding this diagnostic pitfall.

Plasma Transfusion Demystified: A Review of the Key Factors Influencing the Response to Plasma Transfusion.

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.