Safety of the immediate use of nonsteroidal anti-inflammatory drugs after adult craniotomy for tumor.

OBJECTIVE: Poor pain control has a negative impact on postoperative recovery and patient satisfaction. However, overzealous pain management, particularly with opioids, can confound serial neurological assessments, increase morbidity, and predispose patients to long-term dependence. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating postoperative pain and can limit opioid intake, but their use has been limited in patients undergoing craniotomy for brain tumor resection due to concerns of an increased hemorrhage risk. Herein, the authors aim to 1) address the safety of NSAID use in the immediate postoperative setting and 2) determine whether NSAID administration decreases opioid use following craniotomy for tumor resection in adult patients. METHODS: The authors conducted a retrospective cohort study of patients 18 years and older with an estimated glomerular filtration rate ≥ 60 ml/min/body surface area who had undergone craniotomy for tumor resection at their institution between 2019 and 2021. NSAID use in the first 48 hours following surgery was recorded. Primary outcomes were postoperative hemorrhage requiring a return to the operating room before hospital discharge and within 30 days of surgery. Secondary outcomes were more-than-minimal hemorrhage that did not require reoperation, acute kidney injury, and total opioid use within 48 hours after craniotomy. RESULTS: Among 1765 reviewed patient records, 1182 were eligible for inclusion in this analysis. Amid these records were 114 patients (9.6%) who had received at least one dose of an NSAID within 48 hours of their craniotomy. Four (0.3%) patients experienced bleeding requiring a return to operating room, one of whom was from the NSAID-treated group (RR 3.12, 95% CI 0.33-29.77, p = 0.30). No significant difference in nonoperative intracranial hemorrhage (RR 1.34, 95% CI 0.54-3.35, p = 0.53), postoperative acute kidney injury, or clinically significant extracranial bleeding was found between the NSAID and no-NSAID groups. Patients in the NSAID group had significantly higher oral morphine equivalent use (median 68 vs 30, p < 0.001). CONCLUSIONS: Postoperative NSAID use following craniotomy for tumor resection was not associated with an increased risk of hemorrhage requiring a return to the operating room. The authors noted higher opioid use in the patients treated with NSAIDs, which may reflect underlying reasons for the decision to treat patients with NSAIDs in the immediate postoperative period. These data warrant further investigation of NSAIDs as a safe, opioid-sparing postoperative pain management strategy in patients with normal kidney function who are undergoing intracranial tumor resection.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Surgical resection of recurrent intramedullary subependymoma of the cervical spinal cord.

Spinal subependymomas (SE) are rare, often indolent benign tumors presenting most frequently as intramedullary tumors in the cervical spine or cervicothoracic junction. When symptomatic, patients often present with years of sensory changes, weakness, paresthesias, or bowel and bladder dysfunction. Preoperatively, SE are difficult to distinguish radiographically from ependymomas or astrocytomas; however, it is important to make the distinction intraoperatively as complete resection can be curative. Here the authors present a rare case of recurrent, symptomatic cervical subependymoma which underwent gross-total resection and discussion of management strategies and outcomes of all SE at their institution.

Operative Outcomes After Cervical Diffuse Idiopathic Skeletal Hyperostosis Fracture in the Elderly.

BACKGROUND: Cervical diffuse idiopathic skeletal hyperostosis (DISH) fractures are frequently unstable and carry significant risk of neurologic injury and death. Most patients with DISH fractures are elderly (>70 years) with significant comorbidities. We assessed factors that contribute to outcomes in elderly patients with cervical DISH fractures. METHODS: Elderly patients with cervical DISH fractures from 2008 to 2017 were included in this retrospective multi-institutional cohort study. Predictor variables included injury level, surgical approach, preinjury comorbidities, American Society of Anesthesiologists (ASA) score, American Spinal Injury Association (ASIA) impairment scale grade, preoperative anticoagulation status, and the subaxial cervical spine injury classification system (SLIC) score. Univariate and multivariate analyses were utilized to identify factors associated with 30-day mortality and ambulatory status at discharge. RESULTS: A total of 48 patients, mean age 74.7 years old (range 60-96), underwent cervical fixation for DISH fractures. Average SLIC score was 6.30 ± 1.2 (range 5-8), and most frequent fracture level was at C6 to -C7 (31.3%) followed by C7-T1 (25.0%). Forty (83.3%) patients underwent posterior fixation, 7 (14.6%) with anterior fixation, and 1 (2.1%) had combined approach. Ten (20.4%) patients died within 30 days of surgery. Multivariate analysis demonstrated that poorer preoperative ASIA grade (OR 2.35, P = 0.003, CI = 1.33-4.14) and ASA score >3 (P = 0.027) had increased risk of being nonambulatory at discharge. Higher SLIC score was associated with increased 30-day mortality (P = 0.021, CI = 1.20-9.60). CONCLUSIONS: Cervical DISH fractures can be highly unstable, for which instrumentation and fixation are indicated. Surgical decision-making should focus on preoperative ASIA grade, SLIC score, and ASA score. CLINICAL RELEVANCE: The study is relevant due to an aging poulation predisposed to cervical DISH fractures.

Safety and Efficacy of Balloon Kyphoplasty for Vertebral Fractures With Posterior Wall Disruption.

BACKGROUND: Percutaneous balloon kyphoplasty (BK) is widely accepted as both a safe and effective method for the treatment of symptomatic benign vertebral compression fractures (VCFs) of the thoracic and lumbar spines. A disruption in the posterior wall of the affected vertebra is often considered to be a relative or an absolute contraindication to BK. This study was performed to determine the safety as well as the efficacy of BK for vertebral body compression fractures associated with posterior wall disruption. METHODS: This was a retrospective, nonrandomized clinical cohort investigation of patients with VCF and posterior wall disruption treated with BK between 2010 and 2018. All cases were performed using a bipedicular technique. Each case was examined for cement leakage, anterior vertebral body height restoration, improvement in pain (determined by VAS) from baseline and 6-week postprocedure, and clinical sequelae from cement leakage. RESULTS: Ninety-eight consecutive patients with 157 VCF levels who underwent BK were evaluated. There was a significant improvement in anterior vertebral height, vertebral wedge angle, and local kyphotic angle in all cases. The mean preoperative VAS improved from 8.7 preprocedure to 2.5 postprocedure (P = .001). There were 14 (9%) cases with asymptomatic cement leakage outside of the vertebral body, and no patients experienced postprocedure neurological symptoms at the 6-week follow up. CONCLUSIONS: BK in the setting of posterior wall disruption was found to be a safe and highly effective treatment for patients with benign compression fractures. Posterior wall disruption should not be considered an absolute contraindication to BK.

From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM.

Here we review tumoricidal efficacy of Vitamin D analogues in glioblastoma multiforme (GBM) and potential synergisms with retinoic acid and temozolomide based on epidemiological and cellular studies. Epidemiological data suggest that winter birth is associated with higher risk of GBM, and GBM debulking in the winter enhanced mortality, which may relate with lower exposure to sunlight essential to convert cholecalciferol to Vitamin D. Comparative studies on blood bank specimens revealed that higher prediagnosis levels of calcidiol are associated with lower risk of GBM in elderly men. Supplemental Vitamin D reduced mortality in GBM patients in comparison to nonusers. Expression of Vitamin D Receptor is associated with a good prognosis in GBM. Conversely, Vitamin D increases glial tumor synthesis of neutrophins NGF and NT-3, the low affinity neurotrophin receptor p75NTR, IL-6 and VEGF, which may enhance glioma growth. Antitumor synergisms between temozolomide and Vitamin D and Vitamin D with Vitamin A derivatives were observed. Hence, we hypothesize that Calcitriol + ATRA (All-Trans Retinoic Acid) + Temozolomide - CAT combination might be a safer approach to benefit from Vitamin D in the management of high-grade glial tumors. Adding acetazolomide to this protocol may reduce the risk of pseudotumor cerebri, as both Vitamin D and Vitamin A excess may cause intracranial hypertension; this approach may provide further benefit as acetazolomide also exhibits anticancer activity.

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma.

Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic-resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non-proliferative, and treatment-resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

Salvage Stereotactic Radiosurgery in Breast Cancer Patients with Multiple Brain Metastases.

BACKGROUND: The overall survival rates for breast cancer are increasing due to controlled brain disease and improved systemic treatments. This study examined neurologic outcomes, tumor control, and survival data in breast cancer patients with multiple brain metastases and who required salvage stereotactic radiosurgery (SRS) for recurrent breast cancer brain metastases. METHODS: The study included 231 patients with a primary diagnosis of breast cancer who underwent SRS for more than 1 brain metastases from May 1993 and July 2007. Survival analyses via univariate and multivariate Cox regression demonstrated interactions between survival and predictor values including Karnofsky Performance Scale, Recursive Partitioning Analysis Class, number of brain metastases, whole-brain radiotherapy (WBRT), immunotherapy, and chemotherapy. RESULTS: Of the 231 patients, the survival rate was 53% at 1 year and 26% at 5 years from initial SRS. Controlled systemic disease, adjuvant chemotherapy, and Recursive Partitioning Analysis class II were significant predictors of increased survival, while WBRT was a significant predictor of decreased survival. The median survival in patients who received WBRT after SRS was 11 months versus 23 months in those who did not. The local tumor control rate at initial follow-up was 95%. Of these, 40% of patients underwent additional brain SRS. Following salvage SRS, 8% of patients developed symptomatic adverse radiation events; however, the development of symptomatic adverse radiation events had no effect on patient survival. CONCLUSIONS: This report indicated that both initial and salvage SRS procedures in breast cancer patients with multiple brain metastases are effective for local control of intracranial disease while minimizing adverse radiation effects.

Ruptured intracranial aneurysm in a patient with autosomal recessive polycystic kidney disease.

Aneurysmal rupture can result in devastating neurological consequences and can be complicated by comorbid disease processes. Patients with autosomal recessive polycystic kidney disease (ARPKD) have a low rate of reported aneurysms, but this may be due to the relative high rate of end-stage illnesses early in childhood. Authors here report the case of a 10-year-old boy with ARPKD who presented with a Hunt and Hess grade V subarachnoid hemorrhage requiring emergency ventriculostomy, embolization, and decompressive craniectomy. Despite initial improvements in his neurological status, the patient succumbed to hepatic failure. Given the catastrophic outcomes of subarachnoid hemorrhage in young patients, early radiographic screening in those with ARPKD may be warranted.

Use of Pipeline Endovascular Device in Patients with Nickel Allergies.

BACKGROUND: Metal allergies affect a significant portion of the population; intracranial flow diverters contain many of the most commonly allergenic metals. Prior literature has suggested patch testing for all patients with documented or suspected metal allergies before intracranial flow diverter placement; however, there remains a paucity of reports of patients with documented metal allergies undergoing intracranial flow diversion. CASE DESCRIPTION: We report 2 patients with documented nickel allergies, confirmed via patch testing by a board-certified allergist, and unruptured intracranial aneurysms that underwent treatment with the PED. Both patients developed contact dermatitis when a PED was affixed to their skin during their preoperative workup. Follow-up arteriography at 12 and 36 months post PED placement showed no evidence of in-stent stenosis or intimal hyperplasia, and both patients never developed systemic allergic reactions. CONCLUSIONS: In 2 patients with known nickel allergies and intracranial aneurysms treated with the PED, there were no clinically or radiographically apparent allergic reactions at greater than 2 years of follow-up.

Characterization of retinal regeneration in adult zebrafish following multiple rounds of phototoxic lesion.

Müller glia in the zebrafish retina respond to retinal damage by re-entering the cell cycle, which generates large numbers of retinal progenitors that ultimately replace the lost neurons. In this study we compared the regenerative outcomes of adult zebrafish exposed to one round of phototoxic treatment with adult zebrafish exposed to six consecutive rounds of phototoxic treatment. We observed that Müller glia continued to re-enter the cell cycle to produce clusters of retinal progenitors in zebrafish exposed to multiple rounds of phototoxic light. Some abnormalities were noted, however. First, we found that retinas exposed to multiple rounds of damage exhibited a greater loss of photoreceptors at 36 hours of light damage than retinas that were exposed to their first round of light damage. In addition, we found that Müller glia appeared to have an increase in the acute gliotic response in retinas exposed to multiple rounds of light treatment. This was evidenced by cellular hypertrophy, changes in GFAP cellular localization, and transient increases in stat3 and gfap expression. Finally, following the sixth round of phototoxic lesion, we observed a significant increase in mis-localized HuC/D-positive amacrine and ganglion cells in the inner plexiform layer and outer retina, and a decreased number of regenerated blue cone photoreceptors. These data add to recent findings that retinal regeneration in adult zebrafish occurs concomitant with Müller glia reactivity and can result in the generation of aberrant neurons. These data are also the first to demonstrate that Müller glia appear to modify their phenotype in response to multiple rounds of phototoxic lesion, exhibiting an increase in acute gliosis while maintaining a remarkable capacity for long-term regeneration of photoreceptors.

Epidural cerebrospinal fluid collection following lumbar puncture in an adult patient: A case report and literature review.

BACKGROUND: Cerebrospinal fluid (CSF) leakage into the epidural space following lumbar puncture (LP) has been documented in pediatric patients, but there have been no reported cases in adults. CASE DESCRIPTION: We report an epidural CSF leak in an adult who presented with back pain, positional headache, urinary retention, and constipation following an LP performed as a part of a research study. The patient's magnetic resonance (MR) scan showed an extensive epidural CSF collection. Following placement in a recumbent position for 72 h, the collection fully resolved along with his neurological complaints. CONCLUSION: Symptomatic epidural CSF collections rarely occur in adults following LPs. Nevertheless, the management remains the same as for pediatric patients; bed rest for 72 h results typically in full resolution of symptoms/signs and regression of the collection on MR studies.