A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

Bronchoscopic retrieval of an aspirated tooth following high-speed motor vehicle accident.

A 28-year-old man aspirated a tooth into his right lower lobe bronchus following a high-speed motor vehicle accident. Initial retrieval attempts failed with a flexible bronchoscope, but a cryoprobe successfully dislodged and retrieved the tooth. Cryoprobe should be considered for bronchoscopic foreign body removal when conventional methods are unsuccessful.

Catatonia associated with pediatric postoperative cerebellar mutism syndrome.

OBJECTIVE: To ascertain the presence of catatonia in cases of pediatric postoperative cerebellar mutism syndrome (PPCMS). METHOD: A systematic review of PPCMS case reports of patients aged 0-17 years with sufficient clinical information to extract catatonic phenomena was undertaken following PRISMA guidelines. Standardized catatonia rating scales were applied to selected cases retrospectively to ascertain whether diagnostic criteria for catatonia were met. A case known to the authors is also presented. RESULTS: Two hundred twenty-one suitable full-text articles were identified. Following screening and application of inclusion criteria, 51 articles were selected plus seven more from their references, reporting on 119 subjects. All cases met Bush and Francis (BF) diagnostic criteria for catatonia, 92.5% Pediatric Catatonia Rating Scale (PCRS), 52.9% ICD-11, and 44.5% DSM-5. All patients presented with mutism. The next most frequent signs were immobility/stupor (77.3%), withdrawal (35.3%), mannerisms (23.5%), and excitement/agitation (18.5%). Most cases presented with stuporous catatonia (75.6%). Catatonia most frequently occurred following resection of medulloblastoma (64.7%). Preoperative hydrocephalus occurred in 89 patients (74.8%). CONCLUSION: Catatonia was frequent in this PPCMS sample, with a predominant stuporous variant; it should be considered in patients with PPCMS and assessed with reliable and validated instruments for prompt diagnosis and management.

Point-of-Care Ultrasound Aids in the Management of Patient Taking Semaglutide Before Surgery: A Case Report.

Semaglutide, a glucagon-like peptide-1 (GLP-1) analog, has various effects on the gastrointestinal tract. In patients undergoing anesthesia delayed gastric emptying time can have sequelae if not identified preoperatively. Modalities include thorough history regarding the last dose administration of a GLP-1 analog and ultrasound of gastric contents before induction of anesthesia. We present a case in which gastric ultrasound identified a patient at increased risk for aspiration on induction and allowed for appropriate alterations in the anesthetic plan.

Development and validation of an electronic version of Sydney Swallow Questionnaire.

BACKGROUND AND AIMS: Accurate assessment of patient-reported oropharyngeal dysphagia (OPD) is essential to guide appropriate management and evaluate response. The Sydney Swallow Questionnaire (SSQ) is a paper-based 17-item inventory developed and validated to objectively detect risk of OPD. An easy-to-use electronic version with digital output has significant potential in streamlining patient assessment. This study aims to develop and validate an electronic version of the SSQ (eSSQ) against the original paper version. METHOD: The English-based paper SSQ was adapted on the online REDcap (Research Electronic Data Capture) platform to be accessible on computer and mobile devices. Patients with OPD and asymptomatic controls completed both electronic and paper versions in randomized order. Patients with stable symptoms then repeated the eSSQ after ≥14 days for test-retest reliability. Paper-based and eSSQs were also collected from an independent cohort for external validation. Agreement of total scores between both versions and eSSQ test-retest reliability were calculated using two-way mixed-effects intra-class correlation coefficient (ICC). RESULTS: 47 dysphagic patients, 32 controls, and 31 patients from an external validation cohort were recruited. The most common underlying etiology was head and neck cancer. Mean eSSQ total score was 789 in dysphagic patients, and 68 in controls. eSSQ had excellent agreement with paper SSQ in total scores among all participants, with ICC 0.97 (95% CI [0.93, 0.98]) in controls, 0.97 (95% CI [0.94, 0.98]) in dysphagic patients and 0.96 (95% CI [0.92, 0.98]) in validation cohort. Test-retest reliability was also excellent (ICC 0.96, 95% CI [0.90, 0.98]). CONCLUSION: The newly developed eSSQ shows excellent agreement with the paper version and test-retest reliability. Future applications of its use may allow for more efficient and accessible patient assessment.

A high-performance neuroprosthesis for speech decoding and avatar control.

Speech neuroprostheses have the potential to restore communication to people living with paralysis, but naturalistic speed and expressivity are elusive1. Here we use high-density surface recordings of the speech cortex in a clinical-trial participant with severe limb and vocal paralysis to achieve high-performance real-time decoding across three complementary speech-related output modalities: text, speech audio and facial-avatar animation. We trained and evaluated deep-learning models using neural data collected as the participant attempted to silently speak sentences. For text, we demonstrate accurate and rapid large-vocabulary decoding with a median rate of 78 words per minute and median word error rate of 25%. For speech audio, we demonstrate intelligible and rapid speech synthesis and personalization to the participant's pre-injury voice. For facial-avatar animation, we demonstrate the control of virtual orofacial movements for speech and non-speech communicative gestures. The decoders reached high performance with less than two weeks of training. Our findings introduce a multimodal speech-neuroprosthetic approach that has substantial promise to restore full, embodied communication to people living with severe paralysis.

Benign Glioma.

Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may also be described as "low-grade" glioma (LGG) and are classified as WHO grade I or II lesions according to the Classification of Tumors of the Central Nervous System (CNS) (Louis et al. in Acta Neuropathol 114:97-109, 2007). Advances in molecular genetics have improved understanding of glioma tumorigenesis, leading to the identification of common mutation profiles with significant treatment and prognostic implications. The most recent WHO 2016 classification system has introduced several notable changes in the way that gliomas are diagnosed, with a new emphasis on molecular features as key factors in differentiation (Wesseling and Capper in Neuropathol Appl Neurobiol 44:139-150, 2018). Benign gliomas have a predilection for younger patients and are among the most frequently diagnosed tumors in children and young adults (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). These tumors can be separated into two clinically distinct subgroups. The first group is of focal, well-circumscribed lesions that notably are not associated with an increased risk of malignant transformation. Primarily diagnosed in pediatric patients, these WHO grade I tumors may be cured with surgical resection alone (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). Recurrence rates are low, and the prognosis for these patients is excellent (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). Diffuse gliomas are WHO grade II lesions with a more infiltrative pattern of growth and high propensity for recurrence. These tumors are primarily diagnosed in young adult patients, and classically present with seizures (Pallud et al. Brain 137:449-462, 2014). The term "benign" is a misnomer in many cases, as the natural history of these tumors is with malignant transformation and recurrence as grade III or grade IV tumors (Jooma et al. in J Neurosurg 14:356-363, 2019). For all LGG, surgery with maximal safe resection is the treatment of choice for both primary and recurrent tumors. The goal of surgery should be for gross total resection (GTR), as complete tumor removal is associated with higher rates of tumor control and seizure freedom. Chemotherapy and radiation therapy (RT), while not typically a component of first-line treatment in most cases, may be employed as adjunctive therapy in high-risk or recurrent tumors and in some select cases. The prognosis of benign gliomas varies widely; non-infiltrative tumor subtypes generally have an excellent prognosis, while diffusely infiltrative tumors, although slow-growing, are eventually fatal (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). This chapter reviews the shared and unique individual features of the benign glioma including diffuse glioma, pilocytic astrocytoma and pilomyxoid astrocytoma (PMA), subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), subependymoma (SE), angiocentric glioma (AG), and chordoid glioma (CG). Also discussed is ganglioglioma (GG), a mixed neuronal-glial tumor that represents a notable diagnosis in the differential for other LGG (Wesseling and Capper 2018). Ependymomas of the brain and spinal cord, including major histologic subtypes, are discussed in other chapters.

What Should I Know About Medication Deprescribing?

This JAMA Internal Medicine Patient Page describes the process of slowly and carefully cutting down on unnecessary medications with the guidance of a health care professional.

Supine headache and papilledema: A case and review of cerebral venous sinus thrombosis.

Key clinical message: Cerebral venous sinus thrombosis (CVST) should be on the differential for intracranial hypertension, and the preferred diagnostic tests are CT venogram or MR venography. Abstract: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke and is on the differential for intracranial hypertension. Non-contrast head CT is often normal. CT venogram or MR venography are the preferred diagnostic tests, as was required in our patient. We review the presentation, diagnosis, and management of CVST.

Intradiscal treatment of the cartilage endplate for improving solute transport and disc nutrition.

Poor nutrient transport through the cartilage endplate (CEP) is a key factor in the etiology of intervertebral disc degeneration and may hinder the efficacy of biologic strategies for disc regeneration. Yet, there are currently no treatments for improving nutrient transport through the CEP. In this study we tested whether intradiscal delivery of a matrix-modifying enzyme to the CEP improves solute transport into whole human and bovine discs. Ten human lumbar motion segments harvested from five fresh cadaveric spines (38-66 years old) and nine bovine coccygeal motion segments harvested from three adult steers were treated intradiscally either with collagenase enzyme or control buffer that was loaded in alginate carrier. Motion segments were then incubated for 18 h at 37 °C, the bony endplates removed, and the isolated discs were compressed under static (0.2 MPa) and cyclic (0.4-0.8 MPa, 0.2 Hz) loads while submerged in fluorescein tracer solution (376 Da; 0.1 mg/ml). Fluorescein concentrations from site-matched nucleus pulposus (NP) samples were compared between discs. CEP samples from each disc were digested and assayed for sulfated glycosaminoglycan (sGAG) and collagen contents. Results showed that enzymatic treatment of the CEP dramatically enhanced small solute transport into the disc. Discs with enzyme-treated CEPs had up to 10.8-fold (human) and 14.0-fold (bovine) higher fluorescein concentration in the NP compared to site-matched locations in discs with buffer-treated CEPs (p < 0.0001). Increases in solute transport were consistent with the effects of enzymatic treatment on CEP composition, which included reductions in sGAG content of 33.5% (human) and 40% (bovine). Whole disc biomechanical behavior-namely, creep strain and disc modulus-was similar between discs with enzyme- and buffer-treated CEPs. Taken together, these findings demonstrate the potential for matrix modification of the CEP to improve the transport of small solutes into whole intact discs.

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Malignant Mixed Mullerian Tumor Arising from Endometriosis in the Groin: A Case Report and Literature Review.

This was a 57-year-old woman who presented with mild discomfort in the right groin. Physical examination revealed a mass in the right groin, and by ultrasound, the mass was hypoechoic and solid with some internal vascularity. The clinical differential diagnosis included lymphoma and others. The mass was excised for pathologic evaluation. Gross examination of the specimen revealed a 3 × 2.4 × 2 cm, solid and cystic mass. Microscopically, it was a biphasic tumor consisting of carcinomatous and sarcomatous components. The tumor was seen contiguous with endometriosis and atypical endometrioid hyperplasia. The histologic findings were consistent with malignant mixed Mullerian tumor (MMMT) arising from endometriosis in the right groin. The tumor involved the resection margin. Subsequent chest/abdominal/pelvic computed tomography did not reveal evidence of tumors, and diagnostic peritoneal/pelvic laparoscopy did not show diseases. Postoperatively, the patient received 6 cycles of chemotherapy consisting of carboplatin and paclitaxel, followed by radiation in the right groin. Malignant transformation from endometriosis occurs in less than 1% of endometriosis cases, and about 80% of the transformed tumors occur in the ovaries. The most commonly transformed malignant tumors are endometrioid and clear cell carcinomas, with rare adenosarcoma and endometrial stromal sarcoma reported. To our knowledge, we are reporting the first case of MMMT arising from endometriosis in the groin.

Using high resolution manometry impedance to diagnose upper esophageal sphincter and pharyngeal motor disorders.

BACKGROUND: Oro-pharyngeal pathophysiology, including upper esophageal sphincter (UES) and pharyngeal disorders, can be assessed by pharyngeal high-resolution manometry impedance (P-HRM-I). We aimed to establish methodology to diagnose disorders utilizing P-HRM-I, hypothesizing that the objective measures could be used to diagnose disordered deglutition evidenced by greater aspiration scores. METHODS: Patients (n = 509, 18-91 years) were compared to controls (n = 120, 20-94 years). Variables measuring UES relaxation, UES opening extent, intrabolus pressure, and pharyngeal contractile strength were derived for 10 ml liquid swallows. Three associated pharyngeal pressurization patterns, which may be indicative of obstructed flow, were characterized: pan-pressurization (Type 1), distal compartmentalized pressurization (Type 2), and transient pressurization (Type 3). Deglutitive aspiration was determined from video fluoroscopy. RESULTS: UES relaxation pressure was best able to differentiate patients from controls (T 6.528, p < 0.0001). Patients with abnormal relaxation pressure (>8 mmHg) more frequently exhibited pharyngeal pressurization patterns and had adjunct evidence of reduced luminal distensibility (high intrabolus pressure and/or reduced UES opening). Utilizing this information, a diagnostic scheme was devised identifying 138 patients with UES disorder. A further 96 patients without evidence of UES disorder had abnormally weak pharyngeal pressures, confirming propulsive disorder. Amongst a sub-sample of 320 patients undergoing video fluoroscopy, those with pharyngeal pressurizations and adjunct evidence of reduced UES relaxation and/or distensibility had higher aspiration scores (Chi-square 60.169, p < 0.0001). CONCLUSION: P-HRM-I can provide evidence for UES disorder based on pharyngeal pressurization patterns and abnormal findings for UES relaxation pressure, UES opening, and intrabolus pressure. Measuring pharyngeal contractility requires further optimization.

Dysbiosis in Head and Neck Cancer: Determining Optimal Sampling Site for Oral Microbiome Collection.

Recent research suggests that dysbiosis of the oral microbial community is associated with head and neck cancer (HNC). It remains unclear whether this dysbiosis causes chemo-radiotherapy (CRT)-related complications. However, to address this question, it is essential to determine the most representative oral site for microbiome sampling. In this study, our purpose was to determine the optimal site for oral sample collection and whether the presence of HNC is associated with altered oral microbiome from this site. In 21 newly diagnosed HNC patients and 27 healthy controls, microbiome samples were collected from saliva, swabs from buccal mucosa, tongue, hard palate, faucial pillars and all mucosal sites combined. Microbial DNA was extracted and underwent 16S rRNA amplicon gene sequencing. In healthy controls, analysis of observed taxonomic units detected differences in alpha- and beta-diversity between sampling sites. Saliva was found to have the highest intra-community microbial diversity and lowest within-subject (temporal) and between-subject variance. Feature intersection showed that most species were shared between all sites, with saliva demonstrating the most unique species as well as highest overlap with other sites. In HNC patients, saliva was found to have the highest diversity but differences between sites were not statistically significant. Across all sites, HNC patients had lower alpha diversity than healthy controls. Beta-diversity analysis showed HNC patients' microbiome to be compositionally distinct from healthy controls. This pattern was confirmed when the salivary microbiome was considered alone. HNC patients exhibited reduced diversity of the oral microbiome. Salivary samples demonstrate temporal stability, have the richest diversity and are sufficient to detect perturbation due to presence of HNC. Hence, they can be used as representative oral samples for microbiome studies in HNC patients.