New Breakthroughs in the Diagnosis of Leptomeningeal Carcinomatosis: A Review of Liquid Biopsies of Cerebrospinal Fluid.

Leptomeningeal carcinomatosis represents a terminal stage and is a devastating complication of cancer. Despite its high incidence, current diagnostic methods fail to accurately detect this condition in a timely manner. This failure to diagnose leads to the refusal of treatment and the absence of clinical trials, hampering the development of new therapy strategies. The use of liquid biopsy is revolutionizing the field of diagnostic oncology. The dynamic and non-invasive detection of tumor markers has enormous potential in cancer diagnostics and treatment. Leptomeningeal carcinomatosis is a condition where invasive tissue biopsy is not part of the routine diagnostic analysis, making liquid biopsy an essential diagnostic tool. Several elements in cerebrospinal fluid (CSF) have been investigated as potential targets of liquid biopsy, including free circulating tumor cells, free circulating nucleic acids, proteins, exosomes, and even non-tumor cells as part of the dynamic tumor microenvironment. This review aims to summarize current breakthroughs in the research on liquid biopsy, including the latest breakthroughs in the identification of tumor cells and nucleic acids, and give an overview of future directions in the diagnosis of leptomeningeal carcinomatosis.

Navigating Post-Operative Outcomes: A Comprehensive Reframing of an Original Graded Prognostic Assessment in Patients with Brain Metastases.

BACKGROUND: Graded Prognostic Assessment (GPA) has been proposed for various brain metastases (BMs) tailored to the primary histology and molecular profiles. However, it does not consider whether patients have been operated on or not and does not include surgical outcomes as prognostic factors. The residual tumor burden (RTB) is a strong predictor of overall survival. We validated the GPA score and introduced "volumetric GPA" in the largest cohort of operated patients and further explored the role of RTB as an additional prognostic factor. METHODS: A total of 630 patients with BMs between 2007 and 2020 were included. The four GPA components were analyzed. The validity of the original score was assessed using Cox regression, and a modified index incorporating RTB was developed by comparing the accuracy, sensitivity, specificity, F1-score, and AUC parameters. RESULTS: GPA categories showed an association with survival: age (p < 0.001, hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.5-3.3), Karnofsky performance status (KPS) (p < 0.001, HR 1.3, 95% CI 1.2-1.5), number of BMs (p = 0.019, HR 1.4, 95% CI 1.1-1.8), and the presence of extracranial manifestation (p < 0.001, HR 3, 95% CI 1.6-2.5). The median survival for GPA 0-1 was 4 months; for GPA 1.5-2, it was 12 months; for GPA 2.5-3, it was 21 months; and for GPA 3.5-4, it was 38 months (p < 0.001). RTB was identified as an independent prognostic factor. A cut-off of 2 cm3 was used for further analysis, which showed a median survival of 6 months (95% CI 4-8) vs. 13 months (95% CI 11-14, p < 0.001) for patients with RTB > 2 cm3 and <2 cm3, respectively. RTB was added as an additional component for a modified volumetric GPA score. The survival rates with the modified GPA score were: GPA 0-1: 4 months, GPA 1.5-2: 7 months, GPA 2.5-3: 18 months, and GPA 3.5-4: 34 months. Both scores showed good stratification, with the new score showed a trend towards better discrimination in patients with more favorable prognoses. CONCLUSION: The prognostic value of the original GPA was confirmed in our cohort of patients who underwent surgery for BM. The RTB was identified as a parameter of high prognostic significance and was incorporated into an updated "volumetric GPA". This score provides a novel tool for prognosis and clinical decision making in patients undergoing surgery. This method may be useful for stratification and patient selection for further treatment and in future clinical trials.

Neurological Outcome and Respiratory Insufficiency in Intramedullary Tumors of the Upper Cervical Spine.

Background and Objectives: Intramedullary spinal cord tumors (IMSCT) are rare entities. A location in the upper cervical spine as a highly eloquent region carries the risk of postoperative neurological deficits, such as tetraparesis or respiratory dysfunction. Evidence for respiratory dysfunction is scarce. This study aimed to describe these highly eloquent tumors' early and late postoperative clinical course. Materials and Methods: This is a single-center retrospective cohort study. We included 35 patients with IMSCT at levels of the craniocervical junction to C4 who underwent surgical treatment between 2008 and 2022. The authors analyzed the patients' preoperative status, tumor- and surgery-specific characteristics, and follow-up functional status. Results: The study cohort included twenty-two patients with grade II ependymoma (62.9%), two low-grade astrocytomas (5.7%), two glioblastomas (5.7%), six hemangioblastomas (17.1%), two metastases (5.7%), and one patient with partially intramedullary schwannoma (2.9%). Gross total resection was achieved in 76% of patients. Early dorsal column-related symptoms (gait ataxia and sensory loss) and motor deterioration occurred in 64% and 44% of patients. At a follow-up of 3.27 ± 3.83 years, 43% and 33% of patients still exhibited postoperative sensory and motor deterioration, respectively. The median McCormick Scale grade was 2 in the preoperative and late postoperative periods, respectively. Only three patients (8.6%) developed respiratory dysfunction, of whom, two patients, both with malignant IMSCT, required prolonged invasive ventilation. Conclusions: More than 60% of the patients with IMSCT in the upper cervical cord developed new neurological deficits in the immediate postoperative period, and more than 40% are permanent. However, these deficits are not disabling in most cases since most patients maintain functional independence as observed by unchanged low McCormick scores. The rate of respiratory insufficiency is relatively low and seems to be influenced by the rapid neurological deterioration in high-grade tumors.

Enhancing outcomes: neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - a comprehensive survival analysis.

Background: A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival. Methods: Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor. Results: A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20-60 vs. 50; range, 10-60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197-0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263-0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610-13.677, p < 0.001]. Conclusion: Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment.

A microRNA signature that correlates with cognition and is a target against cognitive decline.

While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

Exercise as a model to identify microRNAs linked to human cognition: a role for microRNA-409 and microRNA-501.

MicroRNAs have been linked to synaptic plasticity and memory function and are emerging as potential biomarkers and therapeutic targets for cognitive diseases. Most of these data stem from the analysis of model systems or postmortem tissue from patients which mainly represents an advanced stage of pathology. Due to the in-accessibility of human brain tissue upon experimental manipulation, it is still challenging to identify microRNAs relevant to human cognition, which is however a key step for future translational studies. Here, we employ exercise as an experimental model for memory enhancement in healthy humans with the aim to identify microRNAs linked to memory function. By analyzing the circulating smallRNAome we find a cluster of 18 microRNAs that are highly correlated to cognition. MicroRNA-409-5p and microRNA-501-3p were the most significantly regulated candidates. Functional analysis revealed that the two microRNAs are important for neuronal integrity, synaptic plasticity, and morphology. In conclusion, we provide a novel approach to identify microRNAs linked to human memory function.

Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties.

BACKGROUND: The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-κB can be converted into a tumor suppressor by the non-psychotropic cannabinoid cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study, we performed pharmacological assays, gene expression profiling, biochemical, and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM datasets. RESULTS: We found that CBD promotes DNA binding of the NF-κB subunit RELA and simultaneously prevents RELA phosphorylation on serine-311, a key residue that permits genetic transactivation. Strikingly, sustained DNA binding by RELA-lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen species (ROS), while high ROS content in other tumors blocked CBD-induced hGSC death. Consequently, ROS levels served as a predictive biomarker for CBD-sensitive tumors. CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NF-κB into a tumor suppressor and suggests a promising repurposing option for GBM therapy.

Epigenetic gene expression links heart failure to memory impairment.

In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

Learning Curve and Early Results of Interlaminar and Transforaminal Full-Endoscopic Resection of Lumbar Disc Herniations.

Background Full-endoscopic spinal surgery is an evolving technique. A laborious learning phase is inevitable due to the complexity of the orientation and instrumentation. The goal of the present study is to evaluate a single surgeon's learning curve and early outcomes in full-endoscopic resection of lumbar disc herniations. Methods This was a prospective non-controlled single-surgeon cohort study. In 54 patients with 57 herniations, 41 interlaminar and 16 transforaminal resections were performed. Surgery time, severity of adhesive process in the spinal canal, complication rates and clinical outcomes (VAS, ODI, custom questionnaire, recurrence and re-operation rate) were assessed. Results In the interlaminar group, operative time has decreased from 60 ± 20 min in the first 20 operations to 45 ± 14 min in the following 17 (p=0.023). In the transforaminal group, operative time has decreased from 60 ± 16 min in the first 7 operations to 41 ± 12 min in following 9 (p=0.023). Severe adhesive process in spinal canal was associated with duration of symptoms greater than 2 years, longer surgery and higher risk of surgical complications. Four recurrent disc herniations were re-operated using full-endoscopic technique. VAS, ODI and pain medications significantly decreased in both groups and in re-operated patients. Conclusion The plateau of the learning curve and good short-term clinical results of full-endoscopic interlaminar and transforaminal surgery may be achieved after twenty operations, given extensive previous experience in microsurgery. Risk of complications at the learning phase may be decreased by excluding the patients with symptoms lasting over two years.

The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence.

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence. Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated. Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity (n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density (p = 0.03) and proliferation rate (p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012-1.07), p = 0.046). Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting.

Predictors of ventricular tension pneumocephalus after posterior fossa surgery in the sitting position.

BACKGROUND: Ventricular pneumocephalus is a rare but potentially life-threatening complication of cranial surgery in the sitting position. OBJECTIVE: The objective of the study is to assess the incidence and risk factors of postoperative ventricular pneumocephalus. METHODS: We performed a retrospective chart review of 307 consecutive patients (147 men, 160 women) treated at our institution by intracranial surgery in the sitting position from January 2010 to October 2014. Ventricular air entrapment with lack of arousal or neurologic deterioration requiring external ventriculostomy (EVD) was defined as ventricular tension pneumocephalus (VTP). Demographic variables were recorded along with radiological and clinical data. The occurrence of pneumocephalus was correlated with patient-related and surgical variables. RESULTS: VTP was observed in 12 cases (3.9%). These patients had higher intraventricular air volumes (48.5 cm3 (CI 95% [29.06-67.86])) compared to asymptomatic patients (7.4 cm3 (CI 95% [5.43-9.48])). Opening of the fourth ventricle was the most potent predictor of VTP (OR = 34.7, CI 95% [4.4-273.5], p = 0.001). In patients undergoing no additional treatment for pneumocephalus, ventricular air volume declined to an average of 41.7% of the initial postoperative volume on postoperative day 3. CONCLUSIONS: Entrapment of intracranial and particularly ventricular air requiring emergent EVD occurred in 3.9% cases of intracranial surgery in the sitting position. Especially the opening of the fourth ventricle was associated with the development of VTP, which should warrant particularly diligent postoperative observation of these patients. In cases without neurological symptoms, the rate of spontaneous air resorption is sufficiently high to warrant expectant management.

Perception of Obesity in the Latino Population: Implications for Weight Loss Clinical Trials.

Ethnic minorities in the United States have a higher prevalence of obesity, with higher levels reported in Latinos/Hispanics. A qualitative study was done to understand perceptions of obesity and identify factors that may enhance the attractiveness of a behavioral weight-loss intervention in the Latino community. Weight loss trials designed to target the Latino/Hispanic population may benefit by considering the Latino/Hispanic perception of the problem, the barriers to weight loss, and for study participation that may be specific to this population.

The Latino Health Project: pilot testing a culturally adapted behavioral weight loss intervention in obese and overweight Latino adults.

OBJECTIVE: To pilot test a culturally adapted behavioral weight loss intervention in obese and overweight Latino adults. DESIGN: Pilot study. SETTING: Latino community organization in Durham, North Carolina. PARTICIPANTS: Overweight and obese, self-identified Latinos > or =18 years old. INTERVENTION: Intervention consisted of 20 weekly group sessions (90-120 minutes each) incorporating motivational interviewing techniques. The intervention goal was weight loss by adopting the Dietary Approach to Stop Hypertension (DASH) dietary pattern, increasing physical activity, and reducing caloric intake. The cultural adaptation included foods and physical activities commonly used in the Latino culture, using a Spanish-speaking interventionist, and conducting the intervention at a local Latino community organization. MAIN OUTCOME MEASURES: Weight, body mass index (BMI), blood pressure, dietary pattern, and physical activity were measured at baseline and at 20 weeks. RESULTS: A total of 56 participants are included in the final analysis. The average weight loss was 5.1 lbs (95% CI -8.7 to -1.5; P = .006); and there was a reduction in BMI of 1.3 kg/m2 (95% CI -2.2 to -0.5; P =.002) at 20 weeks. Systolic blood pressure decreased by 2.6 mm Hg (95% CI -4.7 to -0.6; P = .013). CONCLUSION: A culturally adapted behavioral intervention for the treatment of overweight and obesity is potentially effective in a diverse group of Latino adults.

Hypertension Improvement Project (HIP) Latino: results of a pilot study of lifestyle intervention for lowering blood pressure in Latino adults.

OBJECTIVES: To assess the feasibility of a culturally tailored behavioral intervention for improving hypertension-related health behaviors in Hispanic/Latino adults. DESIGN: Feasibility pilot study in a community health center and a Latino organization in Durham, North Carolina. INTERVENTION: The culturally adapted behavioral intervention consisted of six weekly group sessions incorporating motivational interviewing techniques. Goals included weight loss if overweight, adoption of the Dietary Approaches to Stop Hypertension dietary pattern, and increased physical activity. Participants were also encouraged to monitor their daily intake of fruits, vegetables, dairy and fat, and to record physical activity. Cultural adaptations included conducting the study in familiar places, using Spanish-speaking interventionist, culturally appropriate food choices, and physical activity. MAIN OUTCOMES: Systolic blood pressure (BP), weight, body mass index (BMI), exercise, and dietary pattern were measured at baseline and at 6 weeks follow-up. Qualitative evaluations of the recruitment process and the intervention were also conducted. RESULTS: There were 64 potential participants identified via healthcare provider referrals (33%), printed media (23%), and direct contact (44%). Seventeen participants completed the intervention and had main outcome data available. Participants 'strongly agreed/agreed' that the group sessions provided them with the tools they needed to achieve weight loss, BP control, and the possibility of sustaining the lifestyle changes after completing the intervention. At the end of the intervention, all physiological, diet, and exercise outcomes were more favorable, with the exception of fat. After 6 weeks, systolic BP decreased an average of -10.4+/-10.6 mmHg, weight decreased 1.5+/-3.2 lbs, BMI decreased 0.3+/-0.5, and physical activity increased 40 minutes per week. CONCLUSION: Our findings suggest that lifestyle interventions for preventing and treating hypertension are feasible and potentially effective in the Hispanic/Latino population.

Inovacao educacional: grandezas e miserias da ideologia

O trabalho questiona o papel da ideologia no campo da inovacao educacional, em tres niveis (conceptualizacao, critica e acao educacional inovadora), em tres niveis (conceptualizacao, critica e acao educacional inovadora) e em termos das respectivas grande e miserias.

Inovacao educacional e ideologia: grandezas e miserias de uma recolocacao

O trabalho da continuacao ao debate sobre a questao da ideologia e da inovacao educacional. Analisa aspectos positivos e negativos da recolocacao feita em numero anterior dos Cadernos de Pesquisas.