Senataxin Mutation Reveals How R-Loops Promote Transcription by Blocking DNA Methylation at Gene Promoters.

R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor ß (TGF-ß), is reduced; that then leads to the activation of the TGF-ß pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins.

Diagnostic and Therapeutic Updates in Leptomeningeal Disease.

PURPOSE OF REVIEW: Leptomeningeal disease (LMD) is a devastating complication of advanced metastatic cancer associated with a poor prognosis and limited treatment options. This study reviews the current understanding of the clinical presentation, pathogenesis, diagnosis, and treatment of LMD. We highlight opportunities for advances in this disease. RECENT FINDINGS: In recent years, the use of soluble CSF biomarkers has expanded, suggesting improved sensitivity over traditional cytology, identification of targetable mutations, and potential utility for monitoring disease burden. Recent studies of targeted small molecules and intrathecal based therapies have demonstrated an increase in overall and progression-free survival. In addition, there are several ongoing trials evaluating immunotherapy in LMD. Though overall prognosis of LMD remains poor, studies suggest a potential role for soluble CSF biomarkers in diagnosis and management and demonstrate promising findings in patient outcomes with targeted therapies for specific solid tumors. Despite these advances, there continues to be a gap of knowledge in this disease, emphasizing the importance of inclusion of LMD patients in clinical trials.

A Single-Institution Retrospective Series of SARS-CoV-2 Infection in Adult Glioma Patients.

A subset of cancer patients is particularly vulnerable to SARS-CoV-2 infection; however, real-world outcomes-based data on primary central nervous system tumor patients is sparse. This retrospective series describes a cohort of adult glioma patients seen at Stanford Cancer Center between January 1, 2020, and June 30, 2022 who contracted SARS-CoV-2, which, to our knowledge, currently represents the largest single-institution comprehensive analysis of this patient population. We performed a retrospective search of patients seen in the Stanford Neuro-Oncology clinic, identifying 29 cases of COVID-19 amongst glioma patients and extracted clinical data via individual chart review. At the time of COVID-19 diagnosis, 15 patients had been vaccinated against SARS-CoV-2, 8 patients were taking dexamethasone, and 8 were undergoing cancer-specific treatment. Obesity, prior tobacco use, and diabetes were the most common comorbidities. Cough, sore throat, and congestion were the most common symptoms. Five patients were admitted to the hospital and two received COVID-19-specific treatment. None died from COVID-related causes or complications. Our data suggest that glioma patients seen at Stanford Cancer Center do not experience an exceptionally high COVID-19 infectivity, hospitalization, or mortality rate, especially when compared to other vulnerable populations such as lung cancer patients. High vaccination rates, adherence to COVID-19 guidelines, and low prevalence of comorbidities may have contributed to these results.

Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging.

Objective: The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC. Materials and methods: Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment. Results: We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%). Conclusions: At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

Guillain-Barré Syndrome with Rapid Onset and Autonomic Dysfunction Following First Dose of Pfizer-BioNTech COVID-19 Vaccine: A Case Report.

Guillain-Barre syndrome (GBS) is an immune-mediated, often post-infectious illness manifesting as an acute, characteristically monophasic, polyradiculoneuropathy. We present a case of GBS with autonomic involvement following an mRNA-based vaccine against SARS-COV2 (Pfizer/BioNTech mRNA-BNT162b2). A 58-year-old woman presented with fatigue, distal extremity paresthesias, and severe back pain within 3 days after receiving her first vaccine dose. She developed worsening back pain and paresthesias in distal extremities which prompted her initial presentation to the hospital. By the third week post-vaccine, she developed increasing gait unsteadiness, progression of paresthesias, and new autonomic symptoms including presyncopal episodes and constipation. Neurological exam showed bilateral distal predominant lower extremity weakness, decreased sensation in a length-dependent pattern, and areflexia. EMG/NCS showed a diffuse sensorimotor polyneuropathy with mixed demyelinating and axonal features consistent with GBS. She was treated with 2 g/kg of IVIG over 3 days and also received prednisone 60 mg daily for 3 days for severe back pain, with improvement of symptoms. This possible association with mRNA-based vaccination expands the potential triggers for an autoimmune-based attack on the peripheral nervous system.

CNS Neurotoxicity of Antiretrovirals.

The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.

Isolated Leptomeningeal Progression in a Patient with NTRK Fusion+ Uterine Sarcoma: A Case Report.

While neurotrophic tropomyosin receptor kinase (NTRK) fusions represent rare oncogenic drivers (<1% of solid cancers), the recent approval of NTRK inhibitors (larotrectinib and entrectinib) led to dramatic responses in patients with NTRK fusion+ tumors. Both drugs have phase I data, demonstrating efficacy in the central nervous system (CNS), including both primary brain tumors and brain metastases. We present a 29-year-old woman who was diagnosed with NTRK3-SPECC1L fusion+ undifferentiated uterine sarcoma and underwent resection, chemotherapy, and radiotherapy. Two years later, lung metastases were discovered. She was started on larotrectinib with complete response. She remained stable on larotrectinib until she presented with altered mental status and seizures. MRI demonstrated leptomeningeal enhancement, but because leptomeningeal progression from sarcoma is exceedingly rare and her symptoms improved dramatically with antiepileptics, these findings were initially attributed to seizures. After 2 unrevealing lumbar punctures and stable systemic imaging, a brain biopsy demonstrated metastatic sarcoma, still showing NTRK positivity. She underwent whole brain radiotherapy and was switched to entrectinib, but had clinical progression 1 month later and transitioned to hospice. This case demonstrates the efficacy of NTRK inhibitors in rare and aggressive cancer but highlights that these patients can develop isolated CNS progression even in the setting of CNS-penetrant drugs. CNS progression can occur if there is incomplete CNS drug penetration, discordance in molecular profiles between CNS and systemic disease, or acquired NTRK inhibitor resistance. In this case, CNS disease maintained the NTRK fusion status, but either inadequate CNS penetration or development of a resistance gene may explain the isolated CNS progression.

Smoking As a Risk Factor for Postcraniotomy 30-Day Mortality.

BACKGROUND: There is limited information on the impact of smoking on postcraniotomy mortality. In this study we used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to examine this issue. METHODS: We identified 16,280 postcraniotomy patients in the ACS-NSQIP database. Indications for surgery were categorized by vascular, trauma, epilepsy, malignant tumor, and benign tumor. Univariate and multivariable logistic regression analyses were used to identify risk factors associated with mortality. RESULTS: In the ACS-NSQIP dataset, postcraniotomy mortality within 30 days of surgery was 5.03%. An area under the curve analysis indicated 30 pack-years as the optimal discriminating threshold for risk stratification in terms of 30-day postcraniotomy mortality. Using this threshold, multivariate analyses revealed 3 variables that were closely associated with 30-day post-craniotomy mortality: male gender (P = 0.002), indication for operation (P < 0.001), and a smoking history of ≥30 pack-years (P < 0.001). In subsequent stratified analyses, smoking-associated mortality risk was observed only in males (odds ratio of 2.33 comparing males with ≥30 and <30 pack-years of smoking history; 97.5% confidence interval 1.36-4.03). When the analysis was further stratified by surgical indications, the mortality association with smoking was found only in male patients who underwent craniotomy as treatment for neurovascular diseases (odds ratio 3.88, 97.5% confidence interval 1.39-11.65). Such an association was not seen in patients who underwent craniotomy for traumatic brain injury, malignant tumors, benign tumors, or epilepsy. CONCLUSIONS: This study identified ≥30 pack-years as a risk factor for male patients undergoing craniotomy as treatment for neurovascular diseases.

Management and Survival Patterns of Patients with Gliomatosis Cerebri: A SEER-Based Analysis.

OBJECTIVE: We used the SEER (Surveillance Epidemiology and End Results) database (1999-2010) to analyze the clinical practice patterns and overall survival in patients with gliomatosis cerebri (GC), or glioma involving 3 or more lobes of the cerebrum. METHODS: We identified 111 patients (age ≥18 years) with clinically or microscopically diagnosed GC in the SEER database. Analyses were performed to determine clinical practice patterns for these patients and whether these practices were associated with survival. RESULTS: Fifty-eight percent of the 111 patients with GC received microscopic confirmation of their diagnosis. Of the remaining patients, 40% were diagnosed via imaging or laboratory tests, and 2% had unknown methods of diagnosis. Seven percent of patients who did not have microscopic confirmation of their diagnosis received radiation therapy. Radiation therapy and surgery were not associated with survival. The only variable significantly associated with overall survival was age at diagnosis. Patients aged 18-50 years showed improved survival relative to patients aged >50 years (median survival, 11 and 6 months, respectively; P = 0.03). For patients aged >50 years, improved overall survival was observed in the post-temozolomide era (2005-2010) relative to those treated in the pre-temozolomide era (1999-2004) (median survival, 9 and 4 months, respectively; P = 0.005). CONCLUSIONS: In the SEER database, ∼40% of the patients with glioma with imaging findings of GC do not receive microscopic confirmation of their diagnosis. We propose that tissue confirmation is warranted in patients with GC, because genomic analysis of these specimens may provide insights that will contribute to meaningful therapeutic intervention.

Sexual Reassignment Fails to Prevent Kennedy's Disease.

Spinal and bulbar muscular atrophy is caused by polyglutamine expansion in the androgen receptor. As an X-linked disease dependent on androgens, symptoms and findings are only fully manifest in males. Here we describe a 40-year-old male-to-female transgender SBMA patient who developed full disease manifestations despite undetectable levels of androgens. We used cell culture and animal models to show that spironolactone, the anti-androgen she had taken for 15 years, promotes nuclear localization and toxicity of the mutant protein, which may explain the disease manifestations in this patient.

Mouse intracerebral hemorrhage models produce different degrees of initial and delayed damage, axonal sprouting, and recovery.

The mechanisms of delayed damage and recovery after intracerebral hemorrhage (ICH) remain poorly defined. Two rodent models of ICH are commonly used: injection of the enzyme collagenase (cICH) and injection of autologous blood (bICH). In mice, we compared the effects of these two models on initial and delayed tissue damage, motor system connections, and behavioral recovery. There is no difference in lesion size between models. Injection of autologous blood causes greater mass effect and early mortality. However, cICH produces greater edema, inflammation, and cell death. Injection of the enzyme collagenase causes greater loss of cortical connections and secondary shrinkage of the striatum. Intracerebral hemorrhage occurs within the motor system connections of the striatum. Mapping of the projections of the forelimb motor area shows a significant sprouting in motor cortex projections only in cICH. Both models of ICH produce deficits in forelimb motor control. Behavioral recovery occurs by 5 weeks in cICH and 9 weeks in bICH. In summary, cICH and bICH differ in almost every facet of initial and delayed stroke pathophysiology, with cICH producing greater initial and secondary tissue damage and greater motor system axonal sprouting than bICH. Motor recovery occurs in both models, suggesting that motor system axonal sprouting in cICH is not causally associated with recovery.