Abstract
Background
To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There ...are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.
Methods
We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.
Results
ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT− pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT.
Conclusions
We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.
Mucoepidermoid carcinoma (MEC) of the upper aerodigestive tract (UADT) is an uncommon malignancy, with limited literature available on its clinical and pathologic characteristics. Here, we describe ...the behavior of MEC of the UADT including pathologic characteristics and predictors of nodal metastasis.
Retrospective cohort study of patients with MEC of the UADT treated at an academic medical center from January 2008 to May 2018. Data was collected about demographics and tumor characteristics including clinical and histological data. The two-tailed Student t test and χ2 analysis were performed to assess for predictors of nodal metastasis.
We identified 44 patients with minor salivary gland MEC of the oral cavity (OC) and oropharynx (OP). All patients were treated with primary site surgery. The primary site was the OC in 25 patients (57%) and OP in 19 (43%). Low-grade histology was seen in 27 specimens (61.4%), intermediate histology in 9 specimens (20.5%), and high-grade histology in 8 specimens (18.2%). Perineural invasion was noted in 10 specimens (22.7%). Neck dissection was performed in 17 patients (39%), with pathologically positive nodes found in 9 (20.5%). Notably, 5 of the 9 positive nodal specimens were found in clinically node-negative necks. Pathologically positive cervical lymph nodes were significantly associated with the OP as the primary site (p = 0.0005), perineural invasion (p = 0.012), lymphovascular invasion (p < 0.001), and high-grade histology (p = 0.004) in the primary specimen.
MEC of the UADT is an uncommon malignancy. Our findings suggest elective neck dissection should be considered with perineural and lymphovascular invasion, high-grade tumor, and the OP as the primary site.
Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have ...suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.
Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.
We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.
Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.
To review the existing literature on pigmented villonodular synovitis (PVNS) of the temporomandibular joint (TMJ) and report a rare case of PVNS of the TMJ presenting with unilateral hearing loss.
...Review of the existing literature and a description of personal experience with PVNS of the TMJ presenting with unilateral hearing loss.
Review of the existing literature revealed 76 reported cases of PVNS of the TMJ. The most common presenting symptom was of a slowly enlarging mass or swelling of the preauricular area, with dysfunctional TMJ also frequently reported. All patients underwent surgical excision with some pursuing radiation as adjuvant therapy. Presented Patient: A 46-year-old man presented with several months of unilateral subjective hearing loss and aural fullness. Imaging revealed a mass centered along the superior TMJ with expansion through the squamous temporal bone and extra-axial intracranial extension into the middle cranial fossa. Imaging characteristics and fine-needle aspiration biopsy were consistent with PVNS.
The patient underwent near-total excision of the mass via frontotemporal craniectomy and lateral temporal bone resection.
At the 16-month follow-up there was no evidence of disease recurrence.
PVNS of the TMJ represents a rare entity that can present with a variety of symptoms including unilateral hearing loss.
Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer’s disease ...(AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrPC with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly 4-styrenesulfonic acid-co-maleic acid, PSCMA) origin. Association of PSCMA with PrPC prevents Aβo/PrPC-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1ΔE9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.
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•Screen for antagonist of PrPC binding to Aβo identifies polymeric antibiotic degradant•Class of polymeric nM-potent PrPC antagonists rescue Aβo-induced phenotypes in vitro•PrPC antagonists also clear neuroblastoma cells of PrPSc replication•Oral PrPC antagonist rescues transgenic AD mouse synapse loss and memory deficits
Gunther et al. search for antagonists for Aβ oligomer binding to PrPC and identify a class of potent polymeric compounds. These molecules bind PrPC and competitively antagonize Aβo action at synapses, while also clearing PrPSc replication from neuroblastoma cells. An orally available PrPC antagonist rescues transgenic mouse Alzheimer phenotypes.
To review current literature and experience with glomangiomas, or true glomus tumors of the middle ear and mastoid as well asto report on the exceptionally rare case of a glomangiomastemming from the ...middle ear space with multiple recurrences.
Review of existing world literature and description of personal experience with rare cases of a glomangioma of the middle ear and mastoid.
Review of existing literature revealed two cases of patients presenting with tinnitus and hearing loss refractory to medical management. Both patients were ultimately diagnosed with glomangioma on histopathology. Complete surgical excision is thought to be curative.
A 36-year-old woman presented with a rare case of a glomangioma of the middle ear presenting with unilateral hearing loss. She was noted to have a mass behind the tympanic membrane. Imaging revealed a diffuse mass filling the mastoid air cells. Imaging characteristics and histology were consistent with a glomangioma.
Initial resection via mastoidectomy using a postauricular approach. The tympanic membrane was reconstructed with temporalis tissue. Follow-up revision tympanomastoidectomy was performed upon recurrence of disease. The chorda tympani were sacrificed due to tumor involvement. The incus and head of the malleus were removed to gain better access to the tumor. The ossicular chain was reconstructed with a Goldenberg Total Ossicular Prosthesis.
Recurrence of disease.
In the 67 months since her most recent surgery, there has been no evidence of recurrence by CT or physical exam.
Glomangioma of the middle ear represents an exceptionally rare entity that can present in a similar fashion to a paraganglioma.
Abstract
Objectives
A persistent craniopharyngeal canal (CPC) is a rare embryologic remnant that presents as a well-corticated defect of the midline sphenoid body extending from the sellar floor to ...the nasopharynx. Our case series aims to describe three unique presentations of this congenital anomaly and their subsequent management.
Design
Retrospective review.
Setting
Tertiary academic medical center.
Participants
Patients who underwent endoscopic transnasal surgical repair of a CPC lesion.
Main Outcome Measures
Resolution of symptoms and surgical outcomes.
Results
A total of three patients were identified. The clinical presentation varied, however, all cases prompted further imaging which demonstrated a persistent CPC and associated pathologic lesion. The presentation of a persistent CPC with nasal obstruction and subsequent iatrogenic cerebrospinal fluid leak as in Case 1 demonstrates the importance of imaging in this work-up. Cases 2 and 3 in the series were representative of the larger subset of patients in the literature who present with the defect incidentally but still warrant surgical management. Nonetheless, a standard approach to diagnosis with preoperative imaging and subsequent transnasal endoscopic repair of the skull base defect was undertaken.
Conclusion
The persistent CPC is a rare congenital anomaly associated with diverse pathology and careful review of preoperative radiology is critical to the management. When warranted, subsequent surgical repair and reconstruction is associated with excellent postoperative outcomes.
Interchromosomal duplications are especially important for the study of X-linked genes. Males inheriting a mutation in a vital X-linked gene cannot survive unless there is a wild-type copy of the ...gene duplicated elsewhere in the genome. Rescuing the lethality of an X-linked mutation with a duplication allows the mutation to be used experimentally in complementation tests and other genetic crosses and it maps the mutated gene to a defined chromosomal region. Duplications can also be used to screen for dosage-dependent enhancers and suppressors of mutant phenotypes as a way to identify genes involved in the same biological process. We describe an ongoing project in Drosophila melanogaster to generate comprehensive coverage and extensive breakpoint subdivision of the X chromosome with megabase-scale X segments borne on Y chromosomes. The in vivo method involves the creation of X inversions on attached-XY chromosomes by FLP-FRT site-specific recombination technology followed by irradiation to induce large internal X deletions. The resulting chromosomes consist of the X tip, a medial X segment placed near the tip by an inversion, and a full Y. A nested set of medial duplicated segments is derived from each inversion precursor. We have constructed a set of inversions on attached-XY chromosomes that enable us to isolate nested duplicated segments from all X regions. To date, our screens have provided a minimum of 78% X coverage with duplication breakpoints spaced a median of nine genes apart. These duplication chromosomes will be valuable resources for rescuing and mapping X-linked mutations and identifying dosage-dependent modifiers of mutant phenotypes.
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