Methodological and analytical considerations for intra-operative microdialysis.

BACKGROUND: Microdialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations. METHODS: Intra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: Use of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed. CONCLUSIONS: Intra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.

Plasma exchange as a tool for removal of bevacizumab: Highlighting application for urgent surgery.

Background: Bevacizumab is commonly used to manage cerebral edema associated with brain tumors. However, its long half-life poses challenges for patients requiring urgent surgery due to wound complications. We present a case of utilizing therapeutic plasma exchange (TPE) to remove bevacizumab in a patient with recurrent glioblastoma requiring urgent surgery. Methods: A 58-year-old male with recurrent glioblastoma, IDH-wildtype, presented with clinical and radiographic concern for ventriculitis requiring urgent wound washout only 4 days after his last bevacizumab infusion. TPE was performed for 3 sessions after surgery using a centrifugation-based cell separator. Replacement fluids included normal serum albumin, normal saline, and fresh frozen plasma. Bevacizumab levels were quantified using an enzyme-linked immunoabsorbent assay before and after each TPE session. Results: TPE effectively removed bevacizumab, enabling safe surgery without new complications. Plasma bevacizumab levels decreased from 1087.63 to 145.35 ng/mL (13.4% of original) by the end of the last TPE session. This decline is consistent with nearly 3 half-lives, which compares favorably to the expected timeline of natural decline given the 21-day half-life. Conclusions: We report a complex clinical scenario of a patient requiring urgent wound washout 4 days after last bevacizumab infusion for CNS infection. Surgery was successfully performed without new complications with use of TPE to remove bevacizumab immediately following surgery. This case highlights the feasibility of this approach, which may be utilized effectively in patients requiring surgery after having recently received bevacizumab.

An untapped window of opportunity for glioma: targeting therapy-induced senescence prior to recurrence.

High-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing tumor aggressiveness at recurrence. Finally, senolytics could improve the long-term sequelae of prior therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying senolytics against latent glioma. In conclusion, senescence in glioma and the microenvironment are critical and potential targets for delaying or preventing tumor recurrence and improving patient functional outcomes through senotherapeutics.

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma.

High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12-15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

Clinical manifestation, management and prognosis of clear cell meningioma: an evidence-based review.

Clear cell meningioma (CCM) is an uncommon histologic subtype of meningioma classified as a WHO grade II tumor and accounting for less than 1% of all meningiomas. Demographically, younger patients are commonly affected without any remarkable gender preference. Moreover, CCM shows a unique anatomical site of involvement. It tends to occur in the cranium than the spine, whereas the basilar skull, posterior fossa and lumbar spine have been the most frequently affected area. Although most cases present as typical the mass effect by the tumor, CCM exhibits characteristic imaging and histologic patterns. Even though surgical resection is the treatment of choice, recurrence-free survival is the biggest challenge and has been attempting to improve by adjuvant therapy. There is still debate about its management, outcome and factors defining it. Herein, we aimed to summarize natural history, radiographic characteristics, histological features, treatment strategies to guide the best possible individualized care for the most favorable outcome.

Use of the 5-Factor Modified Frailty Index to Predict Hospital-Acquired Infections and Length of Stay Among Neurotrauma Patients Undergoing Emergent Craniotomy/Craniectomy.

OBJECTIVE: Traumatic brain injury is a significant public health concern often complicated by hospital-acquired infections (HAIs); however, previous evaluations of factors predictive of risk for HAI have generally been single-center analyses or limited to surgical site infections. Frailty assessment has been shown to provide effective risk stratification in neurosurgery. We evaluated whether frailty status or age is more predictive of HAIs and length of stay among neurotrauma patients requiring craniectomy/craniotomy. METHODS: In this cross-sectional analysis, the American College of Surgeons National Surgical Quality Improvement Program 2015-2019 dataset was queried to identify neurotrauma patients who underwent craniectomies/craniotomies. The effects of frailty status (using the 5-factor modified frailty index [mFI-5]) and age on occurrence of HAIs and other 30-day adverse events were compared using univariate analysis. The discriminative ability of each measure was defined by multivariate modeling. RESULTS: Of 3284 patients identified, 1172 (35.7%) contracted an HAI postoperatively. Increasing frailty score predicted increased HAI risk (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.05-1.77, P = 0.022 for mFI-5 = 1 and OR = 2.01, 95% CI = 1.30-3.11, P = 0.002 for mFI-5≥3), whereas increasing age did not (OR = 0.996, 95% CI = 0.989-1.002, P = 0.009). Median length of stay was significantly longer in patients with HAI (16 days [IQR = 9-23]) versus no HAI (7 days [IQR = 4-13]) (P < 0.001). Median daily costs on the ward and neuro-intensive care unit were higher with HAI than with no HAI (neuro-ICU: $111,818.08 [IQR = 46,418.05-189,947.34] vs. $48,920.41 [IQR = 20,185.20-107,712.54], P < 0.001). CONCLUSIONS: Increasing mFI-5 correlated with increased HAI risk. Neurotrauma patients who developed an HAI after craniectomy/craniotomy had longer hospitalizations and higher care costs. Frailty scoring improves risk stratification among these patients and may assist in reducing total hospital length of stay and total accrued costs to patients.

Mixed germ cell tumor of the pineal gland in a pediatric patient.

Tumors of the pineal region are a rare clinical entity, comprising approximately 3%-8% of pediatric tumors. Based on their histopathological features, they are typically classified as pineal parenchymal tumors and germ cell tumors, with the latter being more prevalent. Clinical presentation is heterogeneous, with symptoms arising either due to tumor invasion or compression of adjacent neurovascular structures and increased intracranial pressure. Imaging studies are paramount in evaluating pineal region lesions and establishing an accurate diagnosis, with MRI representing the gold standard. Herein, we present the case of a 16-year-old boy presented with recurrent headaches. A head MRI revealed a pineal gland lesion. Histopathological examination confirmed the diagnosis, and the patient underwent a successful gross total resection (GTR) of the tumor. This case report seeks to draw attention to the elusive clinical presentation and management of this infrequently encountered tumor, as well as emphasize the importance of considering pineal gland tumors in the differential diagnosis of recurrent, chronic headaches in pediatric patients.

Outcomes and Principles of Patient Selection for Laser Interstitial Thermal Therapy for Metastatic Brain Tumor Management: A Multisite Institutional Case Series.

BACKGROUND: Laser interstitial thermal therapy (LITT) is an emerging treatment modality for both primary brain tumors and metastases. We report initial outcomes after LITT for metastatic brain tumors across 3 sites at our institution and discuss potential strategies for optimal patient selection and outcomes. METHODS: International Classification of Diseases, Ninth Revision and Tenth Revision codes were used to identify patients with malignant brain tumors treated via LITT across all 3 Mayo Clinic sites with at least 6 months follow-up. Local control was based on radiologic and clinical evidence. Overall survival was measured from time of receiving LITT until death or end of the study period. RESULTS: Twenty-three patients were treated for progression of a single (n = 21) or multiple (n = 2) previously radiated metastatic lesions and/or radiation necrosis. Median age was 56 years (interquartile range, 47-66.5 years). LITT achieved local control of the lesion in most patients with metastatic tumors or radiation necrosis (n = 18; 81.8%) for the duration of follow-up. One patient did not have local control data available. Thirteen (56.5%) patients remained alive at the end of the study period. No other patients died of their treated disease during the study period; 5 of 10 deaths were attributable to central nervous system progression outside the treated lesion. Although median survival for this cohort has not yet been reached, the current median survival is 16 months (interquartile range, 12-48.5 months) after LITT for metastatic/radiation necrosis lesions. CONCLUSIONS: LITT was associated with sustained local control in 81.8% of patients treated for radiographic progression of metastatic central nervous system disease.

Assessing Nordihydroguaiaretic Acid Therapeutic Effect for Glioblastoma Multiforme.

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA's impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA's beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.

Corrigendum to 'Anterior interosseous nerve lesion and distal myoclonus revealing a Parsonage Turner Syndrome associated with Hashimoto's thyroiditis' [Radiology Case Reports 16 (2021) 3176-3181].

[This corrects the article DOI: 10.1016/j.radcr.2021.07.067.].

Giant cholesterol granuloma of petrous apex.

Cholesterol granulomas are chronic inflammatory lesions located primarily in the apex of the petrous part of the temporal bone. They are benign, tumor-like lesions, consisting of a cystic cavity filled with a chocolate-brown fluid and present as hyperintense masses on T1 and T2 sequences on MRI. The most common causes of cholesterol granulomas are chronic middle ear infections and traumas, explaining their prevalence in young to middle aged patients. Due to their progressively expanding nature, clinical presentation include vertigo, diplopia, tinnitus, hearing loss and seizures. Treatment of cholesterol granulomas consists of two different approaches: watch and wait or radical surgery to remove the granulomatous tissue. We present the case of a 38-year-old male patient who was admitted to the Neurology Clinic with complaints of loss of consciousness, headache, pain on the left side of the face and tinnitus in the left ear. These symptoms had been present for some time and gradually worsened in intensity and frequency. Initially after an EEG was performed, the patient showed signs of focal epilepsy and began treatment accordingly. Subsequently, a CT and an MRI of the head and neck were performed, which showed a large, well demarcated expansile mass within the left petrous apex, which was hyperintense on T1 and T2. Based on his clinical presentation and radiologic findings, a diagnosis of cholesterol granuloma was established. Through this case report we hope to emphasize the role imaging modalities play in the diagnosis and appropriate management of cholesterol granulomas.

Lumbar radiculopathy associated radicular schwannoma: A case report and literature review.

Lumbar radiculopathy is a clinical condition defined by symptoms of pain, weakness, numbness, or tingling due to lumbar nerve root compression in levels L1-L4. Typically, it is characterized by a narrowing near the nerve root possibly caused by stenosis, bone osteophytes, disc herniation, and similar conditions. Reports of lumbar radiculopathy brought about by the presence of a radicular schwannoma are exceedingly rare. In this paper, we discuss the case of a 67-year-old female patient, presenting with complaints of low back pain, numbness, and antalgic gait for the past eight months. Her physical examination revealed motor and sensor neurological deficits affecting the left lower limb. The electromyoneurography evaluation showed neurogenic atrophy of the left radicular area, while the MRI revealed the presence of a giant, radicular schwannoma at L4-L5 level. This case report aims to underscore the clinical course and management of lumbar radiculopathy caused by a rare L4-L5 radicular schwannoma. Our patient had no significant risk factors or previous spinal pathology.

Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition.

Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called "senolytic" drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. IMPLICATIONS: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.

Percutaneous image-guided cryoablation of spinal metastases: A systematic review.

Percutaneous cryoablation (PCA) is a minimally invasive technique that has been recently used to treat spinal metastases with a paucity of data currently available in the literature. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prospective or retrospective studies concerning metastatic spinal neoplasms treated with current generation PCA systems and with available data on safety and clinical outcomes were included. In the 8 included studies (7 retrospective, 1 prospective), a total of 148 patients (females = 63%) underwent spinal PCA. Tumors were located in the cervical (3/109 [2.8%], thoracic (74/109 [68.8%], lumbar (37/109 [33.9%], and sacrococcygeal (17/109 [15.6%] regions. Overall, 187 metastatic spinal lesions were treated. Thermo-protective measures (e.g., carbo-/hydro-dissection, thermocouples) were used in 115/187 [61.5%] procedures. For metastatic spinal tumors, the pooled mean difference (MD) in pain scores from baseline on the 0-10 numeric rating scale was 5.03 (95% confidence interval [CI]: 4.24 to 5.82) at a 1-month follow-up and 4.61 (95% CI: 3.27 to 5.95) at the last reported follow-up (range 24-40 weeks in 3/4 studies). Local tumor control rates ranged widely from 60% to 100% at varying follow-ups. Grade I-II complications were reported in 9/148 [6.1%] patients and grade III-V complications were reported in 3/148 [2.0%]) patients. PCA, as a stand-alone or adjunct modality, may be a viable therapy in appropriately selected patients with painful spinal metastases who were traditionally managed with open surgery and/or radiation therapy.

A rare case of anophthalmia without any family history and antenatal risk factors.

Anophthalmia is a rare genetic disorder. It is defined as the absence of one or both eyes in a patient. It can be unilateral or bilateral. Based on the absence of anatomical structures, it is divided into primary, secondary, and degenerative anophthalmia. It occurs in an infant with a diabetic mother or any exposure to teratogens. Most of the patients have a positive family history of anophthalmia or related genetic disorder. Its diagnosis is crucial as there is a similar condition called micro ophthalmia. Sometimes it is difficult to differentiate between severe microphthalmia and anophthalmia. We present a case of a 5-day-old infant diagnosed with bilateral anophthalmia. In the majority of the cases of bilateral anophthalmia the patients usually have a positive family history of antenatal exposure to teratogenic substances. But in our case, no family history or antenatal teratogenic exposure was noted.

MRI diagnosis of Takayasu arteritis in a young woman.

Takayasu arteritis is a rare type of chronic, granulomatous vasculitis, characterized by inflammation of blood vessels of large caliber, such as the aorta, and its branches. Clinical presentation varies, depending on the severity of symptoms. Onset may be gradual, however at times, presentation may be acute, and life threatening. Herein, we present the case of a 29-year-old female, 3 months post-op, following a right carotid artery stenting procedure. The patient presented with nonspecific symptoms of malaise, arthralgia, and blurry vision. Clinical presentation and imaging findings were consistent with Takayasu's Arteritis.

Anterior interosseous nerve lession and distal myoclonus revealing a parsonage turner syndrome associated with hashimoto thyroiditys.

Parsonage-Turner Syndrome (PTS), also known as brachial neuritis or neuralgic amyotrophy, is a rare disorder affecting 2 to 3 individuals per 100,000 each year. Abrupt onset shoulder pain, followed by motor weakness, paresthesia and hypoesthesia, is usually reported, lasting several months with variable recovery. The etiology of the disease may be idiopathic or triggered by an underlying autoimmune disease in genetically susceptible individuals. Our report addresses a unique case of Parsonage-Turner Syndrome in a patient suffering from concurrent Hashimoto Thyroiditis. A previously healthy A 22 year-old female was referred to the Department of Neurology after complaints of sudden-onset motor weakness in her left upper limb. On physical examination, the patient could not make an "Ok sign" with her thumb and distal phalanx or form a complete fist, revealing weakness within the anterior interosseous branch of the median nerve. Further testing with electromyography demonstrated muscular atrophy within the arm's anterior compartment, forearm, and triceps brachii of the posterior compartment. Additional imaging and physical examination were unremarkable, confirming our diagnosis of PTS. Furthermore, lab reports revealed elevated levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies and our patient was concurrently diagnosed with Hashimoto's thyroiditis. This case aims to highlight the rare co-occurrence of Hashimoto's thyroiditis with Parsonage-Turner Syndrome in an otherwise healthy patient. A 2014 study published by Nugent et al. had also shed light on brachial neuritis in a patient suffering from autoimmune connective tissue disease, and through this case study, we hope to add to the growing literature regarding the correlation between PTS and autoimmune diseases. Symptoms of PTS can easily be misdiagnosed given its similarity to other peripheral neuropathies, and careful assessment and thorough understanding of the disease is required to successfully distinguish it from other neurological pathologies.

Trigeminal neuralgia caused by Dandy-walker malformation: A case report and systematic review of the literature.

Trigeminal neuralgia is a pain condition that affects the face along the distribution of the trigeminal nerve and can be recurrent and chronic. Dandy-Walker syndrome is a complex congenital brain anomaly that occurs during embryonic development of the cerebellum and the fourth ventricle. It is characterized by inferior cerebellar vermis hypoplasia and incomplete formation of the fourth ventricle. Dandy-Walker Syndrome is associated with comorbid genetic conditions. It can include congenital heart defects, eye abnormalities, intellectual disability, congenital tumors, and other brain defects such as agenesis of the corpus callosum. However, associations of trigeminal neuralgia and Dandy Walker syndrome have been an infrequent entity. Herein, we report a case of a 23-year-old female patient that presented with complaints of severe left orofacial pain over two years. MRI evaluation was consistent with Dandy-Walker malformation findings that we suspect caused the compression in the trigeminal root entry zone that ultimately gave rise to the patient's symptoms.

Multifocal Langerhans cell histiocytosis in a child.

Langerhans Cell Histiocytosis (LCH) is a rare disorder sometimes called the disorder of the "monocyte-macrophage system". This condition is characterized by the proliferation of abnormal Langerhans cells within different tissues. Skin rash is the typical early feature, but bony involvement is the second most common presentation. The most common complications are musculoskeletal disabilities, hearing problems, skin scarring, neuropsychiatric defects and most importantly, progression to secondary malignancies like leukemia. Early recognition and treatment can reduce morbidity and mortality. Herein, we report a case of a 10-year-old male presenting with a tender, palpable mass in the lower limb. On initial imaging, a lesion involving the diaphysis of the fibula was observed, raising concerns of Ewing sarcoma. Biopsy was planned along with whole-body MRI, revealing multifocal single system Langerhans cell histiocytosis. Given the rarity of fibular involvement in LCH, distinguishing between LCH and common malignancies within this age-group can be challenging. Through this case report, we hope to emphasize the importance of considering LCH in the differential diagnosis to ensure a timely diagnosis, fitting treatment and improvement in prognosis of the condition.