Abstract
Leptomeningeal (LM) metastases or dural spread by adult high-grade astrocytomas are problematic; it is unclear which tumor types are predisposed to spread and at what time intervals from ...original diagnosis. We reviewed our recent experience with these tumor types with LM or dural spread, all of which had assessments that allowed CNS World Health Organization, 5th Edition classification. Following a database search, 2018–present, 10 patients were identified: 4 glioblastomas, IDH-wildtype, WHO grade 4; 4 astrocytomas, IDH-mutant, WHO grade 4; 1 high-grade astrocytoma with piloid features (HGAP) proven by DNA methylation, and 1 high-grade astrocytic tumor that fell closest to the HGAP category by DNA methylation. Most had LM dissemination; 2 had dural spread. Intervals from initial tumor diagnosis to LM spread for 4 astrocytomas, IDH-mutant were 1, 6, 7, and 14 years. Two glioblastomas, IDH-wildtype had dural spread at the time of diagnosis; 1 had a 6-year interval to metastasis; and 1 had a 3-month interval to LM spread. The definite HGAP showed an interval of 7 years to metastasis and the possible HGAP had LM spread recognized at the time of initial diagnosis. All adult high-grade astrocytic tumor types are capable of LM or dural spread, including HGAP.
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the ...temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
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•Longitudinal glioma evolution follows an IDH mutation-dependent trajectory•Hypermutation and CDKN2A deletions underlie increased proliferation at recurrence•Recurrent IDH-wild-type neoplastic cells up-regulate neuronal signaling programs•Mesenchymal transitions associate with distinct myeloid cell interactions
Integrating longitudinal transcriptomic and genomic data from paired diffuse glioma samples with complementary single-cell RNA-seq and multiplex immunofluorescence datasets reveals recurrence-associated genetic and microenvironmental changes that are dependent on IDH mutation status.
Breast cancer brain metastases (BM) affect younger women disproportionally, including those lacking estrogen receptor (ER), progesterone receptor, and HER2 (known as triple-negative breast cancer; ...TNBC). Previous studies in preclinical models showed that pre-menopausal levels of estradiol (E2) promote TNBC-BM through incompletely understood mechanisms involving reactive astrocytes. Herein, a novel mechanism involving E2-dependent upregulation of brain-derived neurotrophic factor (BDNF) in astrocytes, and subsequent activation of tumor cell tropomyosin kinase receptor B (TrkB), is identified. E2 increased experimental BM of TNBC 4T1BR5 and E0771 cells by 21 and 3.6 fold, respectively, compared to E2-depleted mice. ERα
reactive astrocytes were found at early and late stages of BM, and E2 upregulated BDNF in ER
reactive astrocytes in vitro and in vivo. TrkB was expressed in TNBC brain-trophic cell lines, BM-patient-derived xenografts, and breast cancer BM. Conditioned media from E2-treated astrocytes (CM-E2) activated TrkB and downstream AKT, ERK, and PLC-γ signaling in TNBC cells, increasing their invasiveness and tumor-initiating capability in vitro. The promotion of BM by E2-activated astrocytes was found to be more complex, involving feedback loops and other receptor tyrosine kinases. In 4T1BR5 cells, there was a positive feedback loop whereby astrocytic BDNF induced cancer cell BDNF translation. Upregulation of cancer cell BDNF was required to promote full invasiveness of 4T1BR5 in response to CM-E2, and was observed in brain metastatic cells in E2-treated mice in vivo. Moreover, the non-competitive BDNF/TrkB inhibitor ANA-12 reduced E2-induced 4T1BR5 BM to levels similar to OVX mice. BDNF also activated EGFR in TrkB
EGFR
TNBC cells, suggesting that E2 action through astrocytes activates redundant pathways promoting BM. These findings have important therapeutic implications, as they provide a rationale to use E2-depletion therapies or TrkB inhibitors to prevent or delay development of BM in younger women.
Stroke-induced cerebral ischemia is a major cause of death and disability. The disruption of blood flow results in neuronal and glial cell death leading to brain injury. Reperfusion restores oxygen ...to the affected tissue, but can also cause damage through an enhanced oxidative stress and inflammatory response. This study examines mitochondrial transfer from MSC to neurons and the role it plays in neuronal preservation after oxidant injury. We observed the transfer of mitochondria from MSC to mouse neurons in vitro following hydrogen peroxide exposure. The observed transfer was dependent on cell-to-cell contact and led to increased neuronal survival and improved metabolism. A number of pro-inflammatory and mitochondrial motility genes were upregulated in neurons after hydrogen peroxide exposure. This included Miro1 and TNFAIP2, linking inflammation and mitochondrial transfer to oxidant injury. Increasing Miro1 expression in MSC improved the metabolic benefit of mitochondrial transfer after neuronal oxidant injury. Decreasing Miro1 expression had the opposite effect, decreasing the metabolic benefit of MSC co-culture. MSC transfer of mitochondria to oxidant-damaged neurons may help improve neuronal preservation and functional recovery after stroke.
Acute traumatic spinal cord injury (SCI) is marked by the enhanced production of local cytokines and pro-inflammatory substances that induce gliosis and prevent reinnervation. The transplantation of ...stem cells is a promising treatment strategy for SCI. In order to facilitate functional recovery, we employed stem cell therapy alone or in combination with curcumin, a naturally-occurring anti-inflammatory component of turmeric (Curcuma longa), which potently inhibits NF-κB. Spinal cord contusion following laminectomy (T9-10) was performed using a weight drop apparatus (10 g over a 12.5 or 25 mm distance, representing moderate or severe SCI, respectively) in Sprague-Dawley rats. Neural stem cells (NSC) were isolated from subventricular zone (SVZ) and transplanted at the site of injury with or without curcumin treatment. Functional recovery was assessed by BBB score and body weight gain measured up to 6 weeks following SCI. At the conclusion of the study, the mass of soleus muscle was correlated with BBB score and body weight. Stem cell therapy improved recovery from moderate SCI, however, it had a limited effect on recovery after severe SCI. Curcumin stimulated NSC proliferation in vitro, and in combination with stem cell therapy, induced profound recovery from severe SCI as evidenced by improved functional locomotor recovery, increased body weight, and soleus muscle mass. These findings demonstrate that curcumin in conjunction with stem cell therapy synergistically improves recovery from severe SCI. Furthermore, our results indicate that the effect of curcumin extends beyond its known anti-inflammatory properties to the regulation of stem cell proliferation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gliomas account for 26.5% of all primary central nervous system tumors. Recent studies have used diffusion tensor imaging (DTI) to extract white matter fibers and the diffusion coefficients derived ...from MR processing to provide useful, non-invasive insights into the extent of tumor invasion, axonal integrity, and gross differentiation of glioma from metastasis. Here, we extend this work by examining whether a tract-based analysis can improve non-invasive localization of tumor impact on white matter integrity. This study retrospectively analyzed preoperative magnetic resonance sequences highlighting contrast enhancement and DTI scans of 13 subjects that were biopsy-confirmed to have either high or low-grade glioma. We reconstructed the corticospinal tract and superior longitudinal fasciculus by applying atlas-based regions of interest to fibers derived from whole-brain deterministic streamline tractography. Within-subject comparison of hemispheric diffusion coefficients (e.g., fractional anisotropy and mean diffusivity) indicated higher levels of white matter degradation in the ipsilesional hemisphere. Novel application of along-tract analyses revealed that tracts traversing the tumor region showed significant white matter degradation compared to the contralesional hemisphere and ipsilesional tracts displaced by the tumor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
BACKGROUND
Epilepsy surgery is well established as safe and successful for children with temporal lobe epilepsy (TLE). Despite evidence from available data, there remains some reluctance to ...refer children with medically refractory epilepsy for preoperative evaluation and workup for possible surgery.
OBJECTIVE
To present the largest case series of pediatric (TLE) patients thus far, in order to better understand the predictability of preoperative evaluation on seizure outcome, and to better understand longitudinal outcomes in a large pediatric cohort.
METHODS
One hundred eighty-three pediatric patients with TLE who underwent surgical treatment between 1988 and 2012 were retrospectively reviewed. Preoperative seizure history, noninvasive and invasive preoperative evaluation, surgical results, pathological results, long-term seizure outcomes, and complications were evaluated. A review of pediatric TLE in the literature was also undertaken to better understand reported complications and long-term outcomes.
RESULTS
Mean follow-up was 42 mo (range 12-152 mo); 155 patients had good seizure outcomes (Engel I/II; 84.8%) and 28 patients had poor seizure outcomes (Engel III/IV; 15.2%); 145 patients were Engel I (78.8%). Only 10 patients did not have worthwhile improvement (Engel class IV; 5.4%). A review of the literature identified 2089 unique cases of pediatric TLE. Satisfactory seizure outcomes occurred in 1629 patients (79%) with unsatisfactory outcomes in 433 patients (21%).
CONCLUSION
Pediatric patients benefit from surgery for medically refractory TLE with an acceptable safety profile regardless of histopathological diagnosis, seizure frequency, or seizure type. Seizure freedom appears to have extensive durability in a significant proportion of surgically treated patients.
Transcallosal microscopic and endoscopic excisions are both well established approaches to colloid cyst resection; however, there has been no clear consensus regarding the favored approach. We ...performed a systematic review comparing the transcallosal microscopic and endoscopic transcortical approaches for colloid cyst excision.
We performed a systematic review from 2000–2018 of patients undergoing colloid cyst excision via a microscopic transcallosal or endoscopic transcortical approach where the surgical intent was gross total resection. Studies that included multiple approaches were included if the reported results were stratified by approach.
The microsurgical transcallosal approach had a higher rate of gross total resection when compared with endoscopic excision (96% for transcallosal vs. 78.5% endoscopic; P < 0.0001). There was also a lower recurrence rate with the transcallosal approach (0.98% vs. 2.16%; P = 0.0036); however, there was no difference in reoperation rates with similar length of follow-up (0.33% transcallosal, 0.61% endoscopic; P = 1.000). Endoscopy had lower overall morbidity when compared with transcallosal approaches (8.7% vs. 18.6%; P = 0.0001), including statistically significant lower rates of infection, infarct, and seizures in the endoscopic cohort. Rates of permanent memory deficit were similar (6.55% transcallosal vs. 4.5% endoscopic; P = 0.52). Shunt dependency was 9.8% after transcallosal excision versus 3.5% after endoscopic excision (P = 0.0002).
Modern series of colloid cyst excision continue to favor transcallosal approaches in achieving gross total resection. Nevertheless, endoscopic techniques have significantly reduced morbidity compared to transcallosal approaches, including lower rates of infection, infarct, and seizure. Endoscopic approaches also have a statistically significant decreased rate of shunt dependency—arguably the most important primary endpoint of surgery. With improving endoscopic technology and mastery of the technique, endoscopic excision is maturing into a standard first-line approach for colloid cyst excision.
In the treatment of brain tumors, surgical intervention remains a common and effective therapeutic option. Recent advances in neuroimaging have provided neurosurgeons with new tools to overcome the ...challenge of differentiating healthy tissue from tumor-infiltrated tissue, with the aim of increasing the likelihood of maximizing the extent of resection volume while minimizing injury to functionally important regions. Novel applications of diffusion tensor imaging (DTI), and DTI-derived tractography (DDT) have demonstrated that preoperative, non-invasive mapping of eloquent cortical regions and functionally relevant white matter tracts (WMT) is critical during surgical planning to reduce postoperative deficits, which can decrease quality of life and overall survival. In this review, we summarize the latest developments of applying DTI and tractography in the context of resective surgery and highlight its utility within each stage of the neurosurgical workflow: preoperative planning and intraoperative management to improve postoperative outcomes.
Neuronavigation has become a crucial tool in the surgical management of CNS pathology in higher-income countries, but has yet to be implemented in most low- and middle-income countries (LMICs) due to ...cost constraints. In these resource-limited settings, neurosurgeons typically rely on their understanding of neuroanatomy and preoperative imaging to help guide them through a particular operation, making surgery more challenging for the surgeon and a higher risk for the patient. Alternatives to assist the surgeon improve the safety and efficacy of neurosurgery are important for the expansion of subspecialty neurosurgery in LMICs. A low-cost and efficacious alternative may be the use of intraoperative neurosurgical ultrasound. The authors analyze the preliminary results of the introduction of intraoperative ultrasound in an LMIC setting.
After a training program in intraoperative ultrasound including courses conducted in Dar es Salaam, Tanzania, and Aurora, Colorado, neurosurgeons at the Muhimbili Orthopaedic and Neurosurgical Institute began its independent use. The initial experience is reported from the first 24 prospective cases in which intraoperative ultrasound was used. When possible, ultrasound findings were recorded and compared with postoperative imaging findings in order to establish accuracy of intraoperative interpretation.
Of 24 cases of intraoperative ultrasound that were reported, 29.2% were spine surgeries and 70.8% were cranial. The majority were tumor cases (95.8%). Lesions were identified through the dura mater in all 24 cases, with 20.8% requiring extension of craniotomy or laminectomy due to inadequate exposure. Postoperative imaging (typically CT) was only performed in 11 cases, but all 11 matched the findings on post-dural closure ultrasound.
The use of intraoperative ultrasound, which is affordable and available locally, is changing neurosurgical care in Tanzania. Ultimately, expanding the use of intraoperative B-mode ultrasound in Tanzania and other LMICs may help improve neurosurgical care in these countries in an affordable manner.