Characterization of brain development with neuroimaging in a female mouse model of chemotherapy treatment of acute lymphoblastic leukemia.

Background: Survivors of pediatric acute lymphoblastic leukemia (ALL) exhibit abnormal neurocognitive outcomes that are possibly due to exposures to neurotoxic chemotherapy agents. This study aimed to determine the feasibility of characterizing long-term neuroanatomical changes with in vivo neuroimaging in a preclinical model of treatment for ALL. Methods: Female mice (C57BL/6) were randomly assigned to a saline control group (n=10) or a treatment group (n=10) that received intrathecal methotrexate and oral dexamethasone (IT-MTX + DEX). Mice were subsequently scanned three times on a 7T MRI at ages 3, 6, and 12 months (T1, T2, and T3, respectively), which corresponds with human age-equivalents spanning early to late adulthood. Regional brain volumes were automatically segmented, and volume change between timepoints (i.e., T1 to T2; and T2 to T3) were compared between groups (i.e., saline vs. IT-MTX + DEX). Results: Five mice in the IT-MTX + DEX group, and seven mice in the saline group completed all three scans. Between T1 and T2, volumetric change was significantly different between groups in total gray matter [estimate =2.06, 95% confidence interval (CI): 0.27-3.84], the cerebrum (estimate =1.62, 95% CI: 0.14-3.09), claustrum (estimate =0.06, 95% CI: 0.02-0.09), amygdala (estimate =0.16, 95% CI: 0.03-0.29), and striatum (estimate =0.18, 95% CI: 0.01-0.35), with the IT-MTX + DEX group exhibiting a more robust increase in volume than the saline-treated group. Between T2 and T3, group differences in structural brain development were evident for total white matter (estimate =-0.14, 95% CI: -0.27 to -0.01), and the corpus callosum (estimate =-0.09, 95% CI: -0.19 to 0.00) and amygdala (estimate =-0.05, 95% CI: -0.10 to 0.00). In contrast to the rapid brain growth observed earlier in development (i.e., T1 to T2), the IT-MTX + DEX group exhibited an attenuated increase in volume relative to the saline-treated group between T2 and T3. Conclusions: The results demonstrate feasibility of modeling pediatric ALL treatment in a preclinical model and highlight the potential of using preclinical neuroimaging models to gain insight into brain development throughout survivorship.

Hypogonadism and neurocognitive outcomes among childhood cancer survivors.

OBJECTIVE: Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors. DESIGN: Cross-sectional study using retrospective cohort. METHODS: In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes. RESULTS: The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2-2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P < .01) and indirect (from P < .01) impact on impairment in visual processing speed among females. Males demonstrated direct (P = .03) and indirect (P = .04) impact of hypogonadism on motor processing speed. CONCLUSION: Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function.

Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain.

While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that activates the intestinal membrane receptor guanylyl cyclase C (GUCY2C). Clinical trials revealed that linaclotide relieves both constipation and visceral pain. We recently demonstrated that the analgesic effect of linaclotide reflects the overexpression of GUCY2C on neuropod cells, a specialized subtype of EECs. While this brings some clarity to the relationship between linaclotide and visceral analgesia, questions remain about the intracellular signaling mechanisms and neurotransmitters mediating this communication. In this Fundamental Neurochemistry Review, we discuss what is currently known about visceral nociceptors, enteroendocrine cells, and the gut-brain axis, and ongoing areas of research regarding that axis and visceral pain.

Enteroendocrine cell regulation of the gut-brain axis.

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into separate classes based on the hormone each cell type secretes. Recent studies have revealed more diverse hormone profiles and communication modalities for EECs including direct synaptic communication with peripheral neurons. EECs known as neuropod cells rapidly relay signals from gut to brain via a direct communication with vagal and primary sensory neurons. Further, this review discusses the complex information processing machinery within EECs, including receptors that transduce intraluminal signals and the ion channel complement that govern initiation and propagation of these signals. Deeper understanding of EEC physiology is necessary to safely treat devastating and pervasive conditions like irritable bowel syndrome and obesity.

A machine learning approach to predict quality of life changes in patients with Parkinson's Disease.

OBJECTIVE: Parkinson disease (PD) is a progressive neurodegenerative disorder with an annual incidence of approximately 0.1%. While primarily considered a motor disorder, increasing emphasis is being placed on its non-motor features. Both manifestations of the disease affect quality of life (QoL), which is captured in part II of the Unified Parkinson's Disease Rating Scale (UPDRS-II). While useful in the management of patients, it remains challenging to predict how QoL will change over time in PD. The goal of this work is to explore the feasibility of a machine learning algorithm to predict QoL changes in PD patients. METHODS: In this retrospective cohort study, patients with at least 12 months of follow-up were identified from the Parkinson's Progression Markers Initiative database (N = 630) and divided into two groups: those with and without clinically significant worsening in UPDRS-II (n = 404 and n = 226, respectively). We developed an artificial neural network using only UPDRS-II scores, to predict whether a patient would clinically worsen or not at 12 months from follow-up. RESULTS: Using UPDRS-II at baseline, at 2 months, and at 4 months, the algorithm achieved 90% specificity and 56% sensitivity. INTERPRETATION: A learning model has the potential to rule in patients who may exhibit clinically significant worsening in QoL at 12 months. These patients may require further testing and increased focus.

Risk stratification of patients undergoing outpatient lumbar decompression surgery.

BACKGROUND CONTEXT: Reimbursement has slowly transitioned from a fee-for-service model to a bundled payment model after introduction of the United States Centers for Medicare and Medicaid Services bundled payment program. To minimize healthcare costs, some surgeons are trying to minimize healthcare expenditures by transitioning appropriately selected lumbar decompression patients to outpatient procedure centers. PURPOSE: To prepare a risk stratification calculator based on machine learning algorithms to improve surgeon's preoperative predictive capability of determining whether a patient undergoing lumbar decompression will meet inpatient vs. outpatient criteria. Inpatient criteria was defined as any overnight hospital stay. STUDY DESIGN/SETTING: Retrospective single-institution cohort. PATIENT SAMPLE: A total of 1656 patients undergoing primary lumbar decompression. OUTCOME MEASURES: Postoperative outcomes analyzed for inclusion into the risk calculator included length of stay. METHODS: Patients were split 80-20 into a training model and a predictive model. This resulted in 1,325 patients in the training model and 331 into the predictive model. A logistic regression analysis ensured proper variable inclusion into the model. C-statistics were used to understand model effectiveness. An odds ratio and nomogram were created once the optimal model was identified. RESULTS: A total of 1,656 patients were included in our cohort with 1,078 dischared on day of surgery and 578 patients spending ≥ 1 midnight in the hospital. Our model determined older patients (OR=1.06, p<.001) with a higher BMI (OR=1.04, p<0.001), higher back pain (OR=1.06, p=.019), increasing American Society of Anesthesiologists (ASA) score (OR=1.39, p=.012), and patients with more levels decompressed (OR=3.66, p<0.001) all had increased risks of staying overnight. Patients who were female (OR=0.59, p=.009) and those with private insurance (OR=0.64, p=.023) were less likely to be admitted overnight. Further, weighted scores based on training data were then created and patients with a cumulative score over 118 points had a 82.9% likelihood of overnight. Analysis of the 331 patients in the test data demonstrated using a cut-off of 118 points accurately predicted 64.8% of patients meeting inpatient criteria compared to 23.0% meeting outpatient criteria (p<0.001). Area under the curve analysis showed a score greater than 118 predicted admission 81.4% of the time. The algorithm was incorporated into an open access digital application available here: https://rothmanstatisticscalculators.shinyapps.io/Inpatient_Calculator/?_ga=2.171493472.1789252330.1671633274-469992803.1671633274 CONCLUSIONS: Utilizing machine-learning algorithms we created a highly reliable predictive calculator to determine if patients undergoing outpatient lumbar decompression would require admission. Patients who were younger, had lower BMI, lower preoperative back pain, lower ASA score, less levels decompressed, private insurance, lived with someone at home, and with minimal comorbidities were ideal candidates for outpatient surgery.

Expanding Educational Frontiers in Neurosurgery: Current and Future Uses of Augmented Reality.

BACKGROUND: Augmented reality (AR) technology is a new and promising option to advance and expand neurosurgical training because of recent advances in computer vision technology, improved AR software and hardware, and growing acceptance of this technology in clinical practice. OBJECTIVE: To analyze the current status of AR use cases with the goal of envisioning future uses of AR in neurosurgical education. METHODS: Articles applying to AR technology use in neurosurgical education were identified using PubMed, Google Scholar, and Web of Science databases following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines. Articles were included for review based on applicable content related to neurosurgical or neuroanatomy training. Assessment of literature quality was completed using standardized MERSQI scoring. RESULTS: The systematic search identified 2648 unique articles. Of these, 12 studies met inclusion criteria after extensive review. The average MERSQI score was 10.2 (SD: 1.7). The most common AR platform identified in this study was the Microsoft Hololens. The primary goals of the studies were to improve technical skills and approaches to surgical planning or improve understanding of neuroanatomy. CONCLUSION: Augmented reality has emerged as a promising training tool in neurosurgery. This is demonstrated in the wide range of cases in technical training and anatomic education. It remains unclear how AR-based training compares directly with traditional training methods; however, AR shows great promise in the ability to further enhance and innovate neurosurgical education and training.

In-Hospital Cost Comparison for Open Versus Endoscopic Endonasal Approach for Meningioma Resection.

OBJECTIVE: To determine the in-hospital cost implications of an endoscopic expanded endonasal approach (EEEA) for meningioma resection relative to the open transcranial approach. METHODS: All anterior skull base meningioma surgeries performed over a period from January 1st, 2015 to October 31th, 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate analysis was performed using R software. All cost data were converted into August 2021-equivalent dollar amounts using the United States Bureau of Labor Statistics consumer price index. RESULTS: Thirty-five patients met study criteria, including 27 patients undergoing an open transcranial approach and 8 undergoing an EEEA. Average length of stay for patients undergoing an open approach was 9.3 days compared to 5.6 within the EEEA group (P = .126). The average total in-hospital cost of patient undergoing an EEEA was $35417.1 compared to $46406.9 among patients undergoing an open transcranial approach (P = .168). On univariate analysis, the cost of an open transcranial approach relative to the EEEA was $10989.8 (P = .411). CONCLUSIONS: The open transcranial approach remained the dominant surgical approach to anterior skull base meningiomas over our study time period. However, despite limited patient numbers the EEEA was associated with decreased total in-hospital costs.

Intestinal neuropod cell GUCY2C regulates visceral pain.

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.

Endonasal transsphenoidal surgery for planum sphenoidale versus tuberculum sellae meningiomas.

OBJECTIVE: The aim of this study was to determine if the distinction between planum sphenoidale (PS) and tuberculum sellae (TS) meningiomas is clinically meaningful and impacts the results of the endoscopic endonasal approach (EEA). METHODS: A consecutive series of patients who were 18 years of age or older and underwent EEA for newly diagnosed grade I PS meningiomas (PSMs) and TS meningiomas (TSMs) between October 2007 and May 2021 were included. The PS and TS were distinguished by drawing a line passing through the center of the TS and perpendicular to the PS on postcontrast T1-weighted MRI. Probabilistic heatmaps were created to display the actual distribution of tumor volumes. Tumor volume, extent of resection (EOR), visual outcome, and complications were assessed. RESULTS: The 47 tumors were distributed in a smooth continuum. Using an arbitrary definition, 24 (51%) were PSMs and 23 (49%) were TSMs. The mean volume of PSMs was 5.6 cm3 compared with 4.5 cm3 for TSMs. Canal invasion was present in 87.5% of PSMs and 52% of TSMs. GTR was achieved in 38 (84%) of 45 cases in which it was the goal, slightly less frequently for PSMs (78%) compared with TSMs (91%), although the difference was not significant. Th mean EOR was 99% ± 2% for PSMs and 98% ± 11% for TSMs. Neither the suprasellar notch angle nor the percentage of tumor above the PS impacted the rate of GTR. After a median follow-up of 28.5 months (range 0.1-131 months), there were 2 (5%) recurrences after GTR (n = 38) both of which occurred in patients with PSMs. Forty-two (89%) patients presented with preoperative impaired vision. Postoperative vision was stable or improved in 96% of patients with PSMs and 91% of patients with TSMs. CSF leakage occurred in 4 (16.6%) patients with a PSM, which resolved with only lumbar drainage, and in 1 (4.3%) patient with a TSM, which required reoperation. CONCLUSIONS: PSM and TSMs arise in a smooth distribution, making the distinction arbitrary. Those classified as PSMs were larger and more likely to invade the optic canals. Surgical outcome for both locations was similar, slightly favoring TSMs. The arbitrary distinction between PSMs and TSMs is less useful at predicting outcome than the lateral extent of the tumor, regardless of the site of origin.

In-Hospital Costs for Open versus Endoscopic Endonasal Approach for Craniopharyngioma Resection.

OBJECTIVE: To determine the in-hospital cost implications of an expanded endoscopic endonasal approach (EEEA) for craniopharyngioma resection relative to the traditional open transcranial approach. METHODS: All craniopharyngioma surgeries performed at a single institution over a period from January 1st 2001 to October 31th 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate regression analysis was performed using R software. RESULTS: Thirty-six patients met study criteria, including 22 undergoing an open approach and 14 undergoing an EEEA. There was a significantly longer average length of stay among patients undergoing open resection (21.5 vs. 10.6 days, p = 0.024). The average total in-hospital cost of a patient undergoing an EEEA was $58979.3 compared to $89142.3 for an open approach (p = 0.127). On univariate regression analysis, the total in-hospital cost for a patient undergoing an open approach relative to an EEEA was $30163.0 (p = 0.127). The open approach was exclusively performed from study onset until April 2010 (16 patients). From April 2010 to August 2013, 6 open approaches and 5 EEEA were performed. The EEEA has been exclusively performed from August 2013 until the conclusion of our study period (9 patients). CONCLUSIONS: There has been a shift toward surgical resection of craniopharyngioma via an EEEA approach for amenable tumors. Our study demonstrates that the EEEA has become the preferred surgical approach at our institution, and shows that the EEEA is associated with shorter postoperative length of stay and lower total in-hospital cost. Laryngoscope, 133:83-87, 2023.

Tunable Action Potential Repolarization Governed by Kv3.4 Channels in Dorsal Root Ganglion Neurons.

The Kv3.4 channel regulates action potential (AP) repolarization in nociceptors and excitatory synaptic transmission in the spinal cord. We hypothesize that this is a tunable role governed by protein kinase-C-dependent phosphorylation of the Kv3.4 cytoplasmic N-terminal inactivation domain (NTID) at four nonequivalent sites. However, there is a paucity of causation evidence linking the phosphorylation status of Kv3.4 to the properties of the AP. To establish this link, we used adeno-associated viral vectors to specifically manipulate the expression and the effective phosphorylation status of Kv3.4 in cultured dorsal root ganglion (DRG) neurons from mixed-sex rat embryos at embryonic day 18. These vectors encoded GFP (background control), wild-type (WT) Kv3.4, phosphonull (PN) Kv3.4 mutant (PN = S[8,9,15,21]A), phosphomimic (PM) Kv3.4 mutant (PM = S[8,9,15,21]D), and a Kv3.4 nonconducting dominant-negative (DN) pore mutant (DN = W429F). Following viral infection of the DRG neurons, we evaluated transduction efficiency and Kv3.4 expression and function via fluorescence microscopy and patch clamping. All functional Kv3.4 constructs induced current overexpression with similar voltage dependence of activation. However, whereas Kv3.4-WT and Kv3.4-PN induced fast transient currents, the Kv3.4-PM induced currents exhibiting impaired inactivation. In contrast, the Kv3.4-DN abolished the endogenous Kv3.4 current. Consequently, Kv3.4-DN and Kv3.4-PM produced APs with the longest and shortest durations, respectively, whereas Kv3.4-WT and Kv3.4-PN produced intermediate results. Moreover, the AP widths and maximum rates of AP repolarization from these groups are negatively correlated. We conclude that the expression and effective phosphorylation status of the Kv3.4 NTID confer a tunable mechanism of AP repolarization, which may provide exquisite regulation of pain signaling in DRG neurons.SIGNIFICANCE STATEMENTThe AP is an all-or-none millisecond-long electrical impulse that encodes information in the frequency and patterns of repetitive firing. However, signaling may also depend on the plasticity and diversity of the AP waveform. For instance, the shape and duration of the AP may regulate nociceptive synaptic transmission between a primary sensory afferent to a secondary neuron in the spinal cord. Here, we used mutants of the Kv3.4 voltage-gated potassium channel to manipulate its expression and effective phosphorylation status in dorsal root ganglion neurons and directly show how the expression and malleable inactivation properties of Kv3.4 govern the AP duration and repolarization rate. These results elucidate a mechanism of neural AP plasticity that may regulate pain signaling.

Perioperative Outcomes of a Hydrocortisone Protocol after Endonasal Surgery for Pituitary Adenoma Resection.

Introduction In pituitary adenomas (PAs), the use of postoperative steroid supplementation remains controversial, as it reduces peritumoral edema and sinonasal complaints but disrupts the detection of adrenal insufficiency (AI). It is unclear whether postoperative cortisol supplementation has a measurable effect on improving outcomes in patients with pituitary adenoma undergoing endoscopic transsphenoidal surgery (ETS). The objective of the study was to evaluate a postoperative steroid treatment protocol on various surgical outcomes in patients with PA undergoing ETS. Methods A retrospective cohort study was performed for patients undergoing ETS from 2005 to 2020 for PA at a single tertiary academic center. Patients were divided into two groups: those managed by a routine postoperative glucocorticoid supplementation protocol (steroid protocol) and those who received supplementation based on postoperative cortisol laboratory assessment (steroid sparing protocol). Management was otherwise the same between groups. Evaluation of length of stay (LOS), sinonasal outcomes, 30-day readmission, and perioperative complications, including AI, were performed. Results Among 535 patients, 21% ( n = 111) received postoperative steroids, while the remainder ( n = 424) did not. There were no differences in mean LOS (3 vs. 3 days, p = 0.72), sinonasal complaints (27 vs. 19%, p = 0.12), 30-day readmission (5% vs. 5%, p = 0.44), and perioperative complications (5 vs. 5%, p = 0.79) between both the groups. A multivariate model supported that both groups were comparable in predicting LOS, 30-day readmission, and complications. No reduction in readmission for AI was seen. Conclusion Routine administration of postoperative glucocorticoids did not significantly improve patient outcomes in patients with PA who underwent ETS.

Surgical Outcomes of Endoscopic Transsphenoidal Pituitary Adenoma Resection in Elderly Versus Younger Patients.

Introduction Pituitary adenomas (PAs) are one of the most common types of intracranial neoplasm with increased incidence in elderly patients. The outcomes of endoscopic transsphenoidal surgery (ETS) specifically on elderly patients remain unclear. Methods We performed a retrospective cohort study to compare elderly patients (age ≥65 years) with nonelderly patients (age <65 years) who underwent ETS for PA from January 2005 to December 2020. Surgical outcomes, including extent of resection, complication profile, length of stay, and endocrinopathy rates, were compared between elderly and nonelderly patients. Results A total of 690 patients were included, with 197 (29%) being elderly patients. Elderly patients showed higher rates of hypertension ( p < 0.05), myocardial infarction ( p < 0.01), and atrial fibrillation ( p = 0.01) but not other comorbidities. Elderly patients also had more frequent optic nerve involvement (72 vs. 61% of cases, p = 0.01). Tumor characteristics and other patient variables were otherwise similar between younger and elderly patients. Postoperative cerebrospinal fluid (CSF) leaks (2 vs. 2%, p = 0.8), 30-day readmission, reoperation, postoperative complications, and postoperative endocrinopathies were similar between younger and older patients. Subdividing patients into age <65, 65 to 79, and >80 years also did not demonstrate a worsening of surgical outcomes with age. Conclusion For well-selected elderly patients in experienced endoscopic skull base centers, good surgical outcomes similarly to younger patients may be achieved.

Serious Illness Communication Practices in Glioblastoma: An Institutional Perspective.

Background: Early, high-quality advance care planning discussions are essential for supporting goal-concordant care among glioblastoma (GBM) patients. Objective: Using mixed methods, we sought to characterize current serious illness (SI) communication practices at our institution. Methods: The electronic medical records of 240 deceased GBM patients cared for at the Abramson Cancer Center in Philadelphia, PA between 2017 and 2019 were systematically reviewed for documented SI conversations about four domains: prognosis, goals, end-of-life planning, and code status. Patient outcomes and SI conversation characteristics were analyzed using descriptive statistics. Standardized interviews about GBM care were held with five clinicians. Interview transcripts were analyzed using grounded-theory coding to identify emergent themes. Results: Nearly all patients (96%) had at least one documented SI conversation (median: 4, interquartile range [IQR] 2-7), mostly outpatient with medical oncology physicians. Median timing of first SI conversation was 360 days before death. SI conversations were not significantly associated with patient outcomes, including inpatient death and hospice enrollment. Seven themes emerged from clinician interviews: balancing hope and reality, anticipatory guidance, neglect of the "big picture," need for earlier conversations, care coordination, the role of clinical expertise, and communication training. Conclusion: SI conversations were documented early and often in our sample, but their quality was difficult to assess. Contrary to our quantitative findings, interviewees reported that SI conversations were late, infrequent, inadequate, and fragmented across specialties, failing to explore critical issues such as prognosis and functional decline.

Encapsulation of bryostatin-1 by targeted exosomes enhances remyelination and neuroprotection effects in the cuprizone-induced demyelinating animal model of multiple sclerosis.

Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFRα ligand that could anchor the membrane. Exosome targeting tests were carried out in vitro and in vivo. The modified exosomes showed an apparent ability to target OPCs in the lesion area. Next, the exosomes were loaded with Bryostatin-1 (Bryo), and the cuprizone-fed mice were administered with the targeting exosomes. The data show that Bryo exhibits a powerful therapeutic effect compared with Bryo alone after exosome encapsulation. Specifically, this novel exosome-based targeting delivery of Bryo significantly improves the protection ability of the myelin sheath and promotes remyelination. Moreover, it blocks astrogliosis and axon damage, and also has an inhibitory effect on pro-inflammatory microglia. The results of this investigation provide a straightforward strategy to produce targeting exosomes and indicate a potential therapeutic approach for demyelinating disease.

Effects of chemotherapy for acute lymphoblastic leukemia on cognitive function in animal models of contemporary protocols: A systematic literature review.

Survival rates of childhood acute lymphoblastic leukemia (ALL) have improved greatly due to advanced therapies and supportive care. Intrathecal chemotherapy replaced cranial radiation due to radiation-induced neurotoxicity and late-effects. Survivors treated with chemotherapy-only experience neurologic and cognitive problems following cessation of treatment. Very long-term cognitive outcomes remain unclear. Animal models are being generated to assess late-effects of chemotherapy on cognitive function. Although, few address juvenile models of chemotherapy-induced cognitive impairment (CICI) and developing brain, results of this review outline neurocognitive effects of chemotherapy consistent with childhood ALL therapy. Studies demonstrate deficits across cognitive domains including spatial memory, executive function, short-term memory, anxiety and depression. Inflammation, oxidative stress, excitotoxity, and other metabolic disruptions may lead to neurodegeneration associated with cognitive impairment observed in ALL survivors. Interventions directly targeting these mechanisms may prevent and/or promote recovery of cognitive function and improve long-term outcomes. Evidence suggests success of anti-inflammatory and antioxidant treatments in reducing cognitive decline. Animal models provide basis for assessing effects of chemotherapy on neurologic processes to guide future clinical investigations.

Machine Learning Using Multiparametric Magnetic Resonance Imaging Radiomic Feature Analysis to Predict Ki-67 in World Health Organization Grade I Meningiomas.

BACKGROUND: Although World Health Organization (WHO) grade I meningiomas are considered "benign" tumors, an elevated Ki-67 is one crucial factor that has been shown to influence tumor behavior and clinical outcomes. The ability to preoperatively discern Ki-67 would confer the ability to guide surgical strategy. OBJECTIVE: In this study, we develop a machine learning (ML) algorithm using radiomic feature analysis to predict Ki-67 in WHO grade I meningiomas. METHODS: A retrospective analysis was performed for a cohort of 306 patients who underwent surgical resection of WHO grade I meningiomas. Preoperative magnetic resonance imaging was used to perform radiomic feature extraction followed by ML modeling using least absolute shrinkage and selection operator wrapped with support vector machine through nested cross-validation on a discovery cohort (n = 230), to stratify tumors based on Ki-67 <5% and ≥5%. The final model was independently tested on a replication cohort (n = 76). RESULTS: An area under the receiver operating curve (AUC) of 0.84 (95% CI: 0.78-0.90) with a sensitivity of 84.1% and specificity of 73.3% was achieved in the discovery cohort. When this model was applied to the replication cohort, a similar high performance was achieved, with an AUC of 0.83 (95% CI: 0.73-0.94), sensitivity and specificity of 82.6% and 85.5%, respectively. The model demonstrated similar efficacy when applied to skull base and nonskull base tumors. CONCLUSION: Our proposed radiomic feature analysis can be used to stratify WHO grade I meningiomas based on Ki-67 with excellent accuracy and can be applied to skull base and nonskull base tumors with similar performance achieved.

Cranial irradiation impairs juvenile social memory and modulates hippocampal physiology.

Cranial and craniospinal irradiation are the oldest central nervous system prophylaxis treatments considered for pediatric patients with acute lymphoblastic leukemia (ALL). However, survivors of childhood ALL that received cranial radiotherapy are at increased risk for deficits in neurocognitive skills. The continuous and dynamic response of normal tissue after irradiation has been identified as one of the causative factors for cognitive changes after cranial radiation therapy. The aim of our study was to investigate the radiation effects on social behavior and neuronal morphology in the hippocampus of adult mice. Twenty-oneday-old male C57BL/6 mice were irradiated with the small-animal radiation research platform (SARRP). Animals were given a single 10-Gy dose of radiation of X-ray cranial radiation. One month following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability paradigm. Radiation affected social discrimination during the third stage eliciting an inability to discriminate between the familiar and stranger mouse, while sham successfully spent more time exploring the novel stranger. Proteomic analysis revealed dysregulation of metabolic and signaling pathways associated with neurocognitive dysfunction such as mitochondrial dysfunction, Rac 1 signaling, and synaptogenesis signaling. We observed significant decreases in mushroom spine density in the Cornu Ammonis 2 of the hippocampus, which is associated with sociability processing.