Incidence Of Central Nervous System Research Articles

Nanoparticles in CNS Therapeutics: Pioneering Drug Delivery Advancements.

The incidence of Central Nervous System (CNS) disorders, including Parkinson's disease, Alzheimer's disease, stroke, and malignancies, has risen significantly in recent decades, contributing to millions of deaths annually. Efficacious treatment of these disorders requires medicines targeting the brain. The Blood-Brain Barrier (BBB) poses a formidable challenge to effective drug delivery to the brain, hindering progress in CNS therapeutics. This review explores the latest developments in nanoparticulate carriers, highlighting their potential to overcome BBB limitations. This study aimed to evaluate and summarise the critical factors and pathways in the nanoparticle- based central nervous system's targeted drug delivery. An extensive literature search was conducted, comprising the initial development of nanoparticle- based central nervous system-targeted drug delivery approaches to the latest advancements using various online search tools. The properties of nanoparticles, such as type of nanoparticles, size, shape, surface charge, hydrophobicity, and surface functionalisation, along with properties of the blood-brain barrier during normal and pathological conditions and their impact on the delivery of nanoparticles across the BBB, are identified and discussed here. Important properties and pathways that determine the penetration of nanoparticles across the central nervous system are reviewed in this article, along with recent advances in the field.

Central Nervous System Infections in Patients With Ventriculoperitoneal Shunts Admitted for Primary Abdominal Infections: A US Nationwide Cohort Analysis.

Although ventriculoperitoneal (VP) shunts are a common treatment for hydrocephalus, there are complication risks including infections. Late complications such as ventriculitis from ascending abdominal infections can have severe consequences. However, the incidence of central nervous system (CNS) infections in VP shunt patients with abdominal infections is not well understood. We aimed to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. Using the National Inpatient Sample, we studied patients from 2016 to 2019 to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. Results were compared with VP shunt patients admitted for primary pneumonia. Among 725 VP shunt patients presenting with abdominal infections, 20 (2.8%) had CNS infections. Chronic obstructive pulmonary disease, hypertension, older age, and a smoking history were more common in patients with CNS infections and primary abdominal infection (P < .05). Patients who developed CNS infection had a significantly higher likelihood of both blood transfusion and coma but a lower likelihood of seizures. VP shunt patients with CNS infections were more likely to undergo shunt removal (odds ratio [OR] = 23.167, P < .001). 4.1% of VP shunt patients with primary abdominal infections died during admission. In a population of primary abdominal infection and pneumonia patients with VP shunts, a multivariate logistic regression analysis controlling for age, sex, and comorbidities identified abdominal infection as an independent risk factor for both CNS infection (OR = 51.208, P < .001) and inpatient death (OR = 3.417, P < .001). Among 6620 VP shunt patients admitted with primary pneumonia, only 5 (0.1%) had CNS infection compared with 20 (2.8%) in those with a primary abdominal infection (OR = 37.532, P < .001), and mortality was 1.6% vs 4.1% for those with a primary abdominal infection (P < .05). CNS infections in VP-shunted patients with abdominal infections are relatively rare but may lead to increased risks of death and other serious adverse outcomes.

Recent advances in CD5+ diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin's lymphoma (NHL), is substantially heterogeneous. Approximately 5-10% of DLBCLs express CD5, which makes CD5+ DLBCL a rare subgroup. Different studies have shown that CD5+ DLBCL patients are often older and female and have higher lactate dehydrogenase levels, an Eastern Cooperative Oncology Group (ECOG) performance status > 1, and higher International Prognostic Index (IPI) scores. Moreover, patients often have advanced stage disease with a high incidence of central nervous system (CNS) relapse and bone marrow involvement. CD5+ DLBCL cells are more likely to express MYC, BCL-2, and MUM-1, less likely to express CD10, and most belong to the activated B-cell-like (ABC) subtype. The potential mechanisms underlying the poor prognosis of CD5+ DLBCL patients may be related to CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The efficacy of the traditional rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen is unsatisfactory in CD5+ DLBCL patients. Despite supporting evidence from retrospective studies, it is currently unclear whether dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) can improve outcomes in this population. Several new drugs, such as Bruton tyrosine kinase inhibitors (BTKi), BCL-2 inhibitors, and CXCR4 antagonists, as well as immunotherapy, may help to improve the prognosis of CD5+ DLBCL patients, but additional clinical explorations are needed to determine the optimal therapeutic strategy for this disease.

Drug Repurposing for COVID-19 by Constructing a Comorbidity Network with Central Nervous System Disorders.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug-target network and dynamic network-based drug-repurposing analysis, ubiquitin-carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.

Progression patterns, resistant mechanisms and subsequent therapy for ALK-positive NSCLC in the era of second-generation ALK-TKIs

BackgroundIn the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC).MethodsPatients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.ResultsThe incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15–0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18–1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.ConclusionsFirst-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient’s overall physical health and personal preferences.

BIOM-01. PROGNOSTIC IMPLICATIONS OF SMALL CELL LUNG CANCER (SCLC) TRANSCRIPTIONAL SUBTYPING FOR CENTRAL NERVOUS SYSTEM (CNS) METASTASES

Abstract BACKGROUND Small cell lung cancer (SCLC) is characterized by a high propensity for brain metastases (BM) and is associated with a poor prognosis. Subtypes characterized by high versus low neuroendocrine states (expressing ASCL1 or NEUROD1) have been identified. This study aims to evaluate the influence of transcription factor-defined SCLC subtypes on the incidence and outcomes of BM. METHODS We identified 164 patients with SCLC based on their ASCL1 and NEUROD1 expression status by immunohistochemistry. Four transcriptional subtypes were defined: ASCL1+/NEUROD1- (A+/N-), ASCL1+/NEUROD1+ (A+/N+), ASCL1-/NEUROD1+ (A-/N+), and ASCL1-/NEUROD1- (A-/N-). Cumulative incidence competing risk analyses examined the incidence of central nervous system (CNS) progression. Cox proportional hazards models were utilized to assess both overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS Out of 164 patients, the majority fell into either A+/N- or A+/N+ subtypes (n = 62, n = 63, respectively). BM were detected at the time of diagnosis in 12% (20/164) of patients, while 18% (29/164) developed BM later. In two distinct cohorts of patients (initially free from BM and with de novo BM at diagnosis), the 12-month cumulative incidence of CNS progression was numerically highest for the A+/N- subtype (HR = 11.8, 95%CI: 4.7-22.4, and HR = 44, 95%CI: 10.5-74.7, respectively). OS in both A+/N- and A-/N+ subtypes was worse compared to the A+/N+ subtype (HR = 1.62, 95%CI: 1.03-2.56, and HR = 1.63, 95%CI: 1.06-2.60, respectively). Similarly, CNS-PFS was poorer in same A+/N- and A-/N+ subtypes (HR = 3.10, 95%CI: 1.39-6.93, and HR = 3.38. 95% CI: 1.49-7.67) when compared to A+/N+. CONCLUSIONS This study is the first to explore CNS-specific outcomes based on transcription factor SCLC subtypes. Among patients without BM at SCLC diagnosis, those exclusively expressing ASCL1 or NEUROD1 demonstrated poorer outcomes than those with co-expression. Further investigation is warranted to elucidate the implications of SCLC subtyping, ultimately facilitating tailored disease management.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Novel therapeutic delivery for neurodegenerative diseases: Strategies to overcome CNS barriers

The incidence of central nervous system (CNS) diseases is expected to rise significantly due to increasing lifespan and changing population demographics. Among CNS diseases, neurodegenerative diseases (ND’s) entail a significant challenge since they frequently involve neuronal loss and age-related progressive deterioration in brain function. Although the mechanisms and pathogenesis of neuronal disorders including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease (HD) have been extensively studied, effective treatment strategies remain limited. Drug delivery to the CNS is particularly challenging and poses a significant obstacle in the management of neurodegeneration. The present review focuses on the challenges associated with neuronal disorders, especially concerning the delivery of macro molecules containing proteins and nucleic acid. Additionally, we highlight opportunities to enhance therapeutic delivery for the treatment of ND’s. As our understanding of the biological aspects of ND’s continues to grow, there is a growing potential for therapeutic interventions. Therefore, these delivery strategies play a vital role for the future transition of CNS therapies from research labs to clinical practices.

Voiding Dysfunction Due to Urethral Sphincter Dysfunction Might Be an Early Neurological Presentation of Central Nervous System Disorders in Aged Patients.

To investigate the incidence of central nervous system (CNS) diseases in adult patients with voiding dysfunction and videourodynamics (VUDS) proven urethral sphincter dysfunction. This retrospective analysis reviewed the medical charts of patients aged > 60 years who underwent VUDS for non-prostatic voiding dysfunction from 2006 to 2021. A chart review was performed to search for the occurrence and treatment of CNS diseases after the VUDS examination up to 2022. The diagnosis of CNS disease, such as cerebrovascular accidents (CVA), Parkinson's disease (PD), and dementia, by neurologists was also retrieved from the charts. Based on the VUDS findings, patients were divided into the following subgroups: dysfunctional voiding (DV), poor relaxation of the external sphincter (PRES), and hypersensitive bladder (HSB) and coordinated sphincter subgroups. The incidence of CVA, PD, and dementia in each subgroup was recorded and compared among them using one-way analysis of variance (ANOVA). A total of 306 patients were included. VUDS examinations revealed DV in 87 patients, PRES in 108, and HSB in 111. Among them, 36 (11.8%) patients had CNS disease, including CVA in 23 (7.5%), PD in 4 (1.3%), and dementia in 9 (2.9%). Among the three subgroups, the DV group had the highest incidence rate of CNS disease (n = 16, 18.4%), followed by PRES (n = 12, 11.1%) and HSB (n = 8, 7.2%). However, no significant difference was noted in the incidence of CNS disease across the three subgroups. Nevertheless, the incidence of CNS disease was higher in patients with DV and PRES than that in the general population. The incidence of CNS diseases was high in patients aged > 60 years with voiding dysfunction due to urethral sphincter dysfunction. Patients with VUDS-confirmed DV had the highest incidence of CNS disease among the three subgroups.

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones-AFF1, MLLT1, and MLLT3-which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5-6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

990P Osimertinib for RT-naïve CNS metastasis of EGFR mutation-positive NSCLC: Phase II OCEAN study (LOGIK 1603/WJOG 9116L), part of the first-line cohort

Non-small cell lung cancer (NSCLC) with EGFR mutations exhibits a higher incidence of central nervous system (CNS) metastasis. Although radiotherapy (RT) is a standard treatment for CNS metastasis, it delays the start of systemic chemotherapy, and whole brain RT carries a risk of cognitive dysfunction. The aim of the study was to assess osimertinib for patients with RT-naïve CNS metastasis of EGFR mutations positive NSCLC. This study was two-cohort trial, we previously reported about 'T790M cohort', and here we report the results of '1st-line cohort'.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.

Simple SummaryComparisons between the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs) in treating HER2-positive breast cancer brain metastasis (BCBM) patients have not previously been conducted. We performed a systematic review and Bayesian-based network meta-analysis to pool the estimates of progression-free survival, overall survival, and incidence of central nervous system (CNS) disease progression. The current study indicated that both T-DXd and T-DM1 presented better efficacy than TKIs regarding survival outcomes. Treatments containing neratinib or T-DM1 tended to rank the best in reducing the recurrent rate of CNS. Our study provides more evidence for the clinical decision making for patients with HER2-positive BCBM. More high-quality studies with standardized entry criteria and comparable CNS-related endpoints are warranted in the future.HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician’s choice of treatment (HR 0.17; 95% CrI 0.03–0.82) or afatinib (HR 0.14; 95% CrI 0.02–1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.

Comparison of Extracorporeal Life Support Anticoagulation Using Activated Clotting Time Only to a Multimodal Approach in Pediatric Patients.

To evaluate an institutional practice change from an extracorporeal life support (ECLS) anticoagulation monitoring strategy of activated clotting time (ACT) alone to a multimodal strategy including ACT, activated partial thrombin time, heparin anti-factor-Xa, and thromboelastography. This was a retrospective review of patients younger than 18 years on ECLS and heparin between January 2014 and June 2020 at a single institution. Twenty-seven patients used an ACT-directed strategy and 25 used a multimodal strategy. The ACT-directed group was on ECLS for a shorter median duration than the multimodal group (136 versus 164 hours; p = 0.046). There was a non-significant increase in major hemorrhage (85.1% versus 60%; p = 0.061) and a significantly higher incidence of central nervous system (CNS) hemorrhage in the ACT-directed group (29.6% versus 0%; p = 0.004). Rates of thrombosis were similar, with a median of 3 circuit changes per group (p = 0.921). The ACT-directed group had larger median heparin doses (55 versus 34 units/kg/hr; p < 0.001), required more dose adjustments per day (3.8 versus 1.7; p < 0.001), and had higher rates of heparin doses >50 units/kg/hr (62.9% versus 16%; p = 0.001). More anticoagulation parameters were supratherapeutic (p = 0.015) and fewer were therapeutic (p < 0.001) in the ACT-directed group. Patients with a multimodal strategy for monitoring anticoagulation during ECLS had lower rates of CNS hemorrhage and decreased need for large heparin doses of >50 units/kg/hr without an increase in clotting complications, compared with ACT-directed anticoagulation. Multimodal anticoagulation monitoring appears superior to ACT-only strategies and may reduce heparin exposure and risk of hemorrhagic complications for pediatric patients on ECLS.

Efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen for prevention of seizure recurrence during the same fever episode in children with suspected simple febrile seizures.

This study was undertaken to evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS). This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children's hospital. Children aged 6months to 60months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs. Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (.3-.5mg/kg for up to two doses) was administered to 88 of 316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk = .29, 95% confidence interval [CI] = .09-.93, p=.03). The adjusted odds ratio of diazepam administration against recurrence was .23 (95% CI = .07-.78, p=.02). None of the patients had a CNS pathology. No severe adverse events occurred, although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs. 18.7%, p=.04). The median medical cost was US $199 (interquartile range [IQR] = 86-244) for the group receiving both medications and US $202 (IQR = 114-242) for the group receiving as-needed acetaminophen alone. Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected SFS.

International variations in central nervous system incidence in children and adolescents.

International variations in central nervous system incidence in children and adolescents.

A randomized, controlled, phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus ADT alone in metastatic hormone-sensitive prostate cancer (ARANOTE).

TPS200 Background: Previous randomized, phase 3 trials have shown the efficacy of adding docetaxel, abiraterone acetate, enzalutamide, or apalutamide to ADT in improving overall survival and/or radiologic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, these combinations are associated with an increased risk of adverse events (eg, fatigue, rash, and cardiovascular events). Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor. In the ARAMIS study, darolutamide has been shown to significantly reduce the risk of death by 31% and have a favorable safety profile in men with nonmetastatic castration-resistant prostate cancer. It has a low incidence of central nervous system−related adverse events, which may be explained by its distinct low blood−brain barrier penetration. Darolutamide has also been shown to have a low potential for drug−drug interactions, allowing flexibility with concomitant medications. ARANOTE will evaluate the efficacy and safety of darolutamide plus ADT in patients with mHSPC (NCT04736199). Methods: ARANOTE is an international, multicenter (ex-US), randomized, double-blind, placebo-controlled, phase 3 study in patients with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease by conventional imaging (eg, computed tomography or magnetic resonance imaging) who started ADT ≤12 weeks before randomization. In total, 555 patients will be randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus ADT. Patients will be stratified by the presence of visceral metastases, assessed by central review, and prior local therapy. Patients will be evaluated every 12 weeks for efficacy, safety, and quality of life (using the FACT-P questionnaire) during treatment and active follow-up post treatment. For long-term follow-up, patients will be contacted by telephone every 12 weeks. The primary endpoint is rPFS; secondary endpoints include overall survival, time to castration-resistant prostate cancer, time to prostate-specific antigen progression, and safety. Recruitment is ongoing, and the first patient first visit was on February 23, 2021. The estimated study completion date is September 2025. Clinical trial information: NCT04736199.

The efficacy of EGFR-tyrosine kinase inhibitor in non-small cell lung cancer patients with synchronous brain metastasis: a real-world study.

Background/AimsThe optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains to be determined.MethodsA retrospective review was conducted on 77 NSCLC patients with synchronous BM who underwent first-line EGFR-tyrosine kinase inhibitor (TKI) Tx. The outcomes of patients were analyzed according to the clinicopathological characteristics including local Tx modalities.ResultsFifty-nine patients underwent local Tx for BM (gamma knife surgery [GKS], 37; whole brain radiotherapy [WBRT], 18; others, four) concurrently or sequentially with EGFR-TKI. Patients treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all patients were 9 and 19 months, respectively. In 60 patients with follow-up brain imaging, the median time to CNS progression was 15 months. Patients with EGFR exon 19 deletion had a significantly longer median OS than those with other mutations including L858R (23 months vs. 17 months). Other clinical characteristics, including CNS symptoms, number of BM, and the use of local Tx were not associated with OS, as well as PFS. In terms of the local optimal Tx modality, no difference was found between GKS and WBRT in the OS and PFS.ConclusionsThis study suggests that EGFR-TKI may result in a favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Antibiotic Prophylaxis and Incidence of Infection with External Ventricular Drains and Intra-Cranial Pressure Monitors.

Objectives: Guidelines do not recommend extended antibiotic prophylaxis for external ventricular drains (EVD) or intra-cranial pressure (ICP) monitors. The study objective was to determine if infection rates are different for patients receiving antibiotic prophylaxis for EVD or ICP monitors. Patients and Methods: This single-center retrospective cohort reviewed intensive care unit patients who had an EVD or ICP monitor placed. Patients receiving antibiotic prophylaxis were compared with those who did not receive prophylaxis. The primary end point was incidence of central nervous system (CNS) infection. Results: Overall, 228 patients were included, 120 of whom received prophylaxis and 108 who did not receive prophylaxis. The primary end point of CNS infection was not different between groups (18 [17%] vs. 23 [19%]; p = 0.6236). Conclusions: Antibiotic prophylaxis was not associated with a decreased incidence of CNS infection in patients with EVD or ICP monitors. Evaluation of antibiotic use in this patient population is warranted to prevent resistance and adverse drug effects.

Clinical impact of central nervous system-directed therapies on intravascular large B-cell lymphoma: A single institution's experience.

Intravascular large B‐cell lymphoma (IVLBCL) is a rare subtype of B‐cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS‐directed therapy or standard therapy alone. CNS‐directed therapy was associated with a significantly better 2‐year CNS‐free survival (100% vs. 63%, p = 0.0191), despite no significant effects on progression‐free or overall survival. Further studies should assess CNS‐focused treatment in patients with IVLBCL with or without primary CNS involvement.

Association Between Maternal Hormonal Contraception Use and Central Nervous System Tumors in Children

The incidence of central nervous system (CNS) tumors in children appears to be increasing, yet few risk factors are established. There is limited information regarding whether maternal hormonal contraception use increases this risk. To examine the association between maternal hormonal contraception use and CNS tumors in children (<20 years). In this nationwide cohort study based on population-based registry data, 1 185 063 children born in Denmark between January 1, 1996, and December 31, 2014, were followed up for a diagnosis of a CNS tumor (final follow-up on December 31, 2018). Maternal hormonal contraception use was analyzed according to any use, regimen (combined/progestin only), and route of administration (oral/nonoral), categorized as recent use (≤3 months before start and during pregnancy), previous use (>3 months before start of pregnancy), and no use. For injections, implants, and intrauterine devices that are used for a different time period, the categorization was appropriately altered. Hazard ratio (HR) and incidence rate difference (IRD) of CNS tumors diagnosed at younger than 20 years. After 15 335 990 person-years of follow-up (mean follow-up, 12.9 years), 725 children were diagnosed with a CNS tumor. The mean age at diagnosis was 7 years, and 342 (47.2%) of the diagnosed children were female. The adjusted incidence rate of CNS tumors per 100 000 person-years was 5.0 for children born to mothers with recent hormonal contraception use (n = 136 022), 4.5 for children born to mothers with previous use (n = 778 843), and 5.3 for children born to mothers with no use (n = 270 198). The corresponding HRs were 0.95 ([95% CI, 0.74-1.23]; 84 children with CNS tumors; IRD, -0.3 [95% CI, -1.6 to 1.0]) for recent use and 0.86 ([95% CI, 0.72-1.02]; 421 children with CNS tumors; IRD, -0.8 [95% CI, -1.7 to 0.0]) for previous use, compared with no use. No statistically significant associations were found for recent or previous use of oral combined, nonoral combined, oral progestin only, or nonoral products compared with no use of hormonal contraception. Among Danish children, there was no statistically significant association between any maternal hormonal contraception use and CNS tumor risk.