Treatment Of Brain Tumors Research Articles

REVOLUTIONIZING CANCER TREATMENT: THE ROLE OF NANOTECHNOLOGY IN MODERN ONCOLOGY

Cancer is one of the deadliest diseases of our time, affecting millions of people worldwide. Despite the significant progress made in cancer treatment over the past few decades, conventional cancer therapies such as chemotherapy, radiation, and surgery have their limitations, including toxicity, drug resistance, and damage to healthy cells and tissues. Therefore, researchers are constantly exploring new avenues for cancer treatment that are safer, more effective, and less invasive. One such avenue is the use of nanotechnology. Nanotechnology involves the manipulation and control of matter at the nanoscale, which is approximately one billionth of a meter. This technology has the potential to revolutionize cancer treatment by offering more targeted and precise therapy. Nanoparticles, for instance, can be engineered to target cancer cells specifically and deliver drugs or other therapeutic agents directly to them, minimizing damage to healthy cells. In this research, we aim to explore the current state of nanotechnology in modern oncology, its potential applications, and its limitations. We review the recent advancements in nanotechnology-based cancer therapy, including the development of targeted nanoparticles for drug delivery, imaging, and theranostics. One of the main advantages of using nanotechnology for cancer treatment is its ability to bypass the blood-brain barrier, allowing for the delivery of therapeutic agents to the brain. This opens up new avenues for the treatment of brain tumors, which are notoriously difficult to treat due to the barrier. Another potential application of nanotechnology in cancer treatment is the use of nanorobots that can be programmed to seek out and destroy cancer cells. These nanorobots can be designed to carry payloads of therapeutic agents or deliver hyperthermia to destroy cancer cells. Despite the many advantages of nanotechnology in cancer treatment, there are also challenges and limitations that need to be addressed. For instance, the toxicity and biocompatibility of nanoparticles need to be carefully evaluated to minimize potential harm to healthy cells and tissues.In conclusion, the role of nanotechnology in modern oncology has the potential to revolutionize cancer treatment. It offers more targeted and precise therapy, and can potentially overcome the limitations of conventional cancer therapies. However, further research is needed to fully explore the potential of nanotechnology in cancer treatment and to address the challenges and limitations associated with it. In conclusion, the role of nanotechnology in modern oncology has the potential to revolutionize cancer treatment. It offers more targeted and precise therapy, and can potentially overcome the limitations of conventional cancer therapies. However, further research is needed to fully explore the potential of nanotechnology in cancer treatment and to address the challenges and limitations associated with it.

Cyclic Ruthenium-Peptide Conjugates as Integrin-Targeting Phototherapeutic Prodrugs for the Treatment of Brain Tumors.

To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Ph2phen)2(OH2)2]2+, was conjugated to the RGD-containing Ac-MRGDH-NH2 peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[1]Cl2 and Δ-[1]Cl2. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made [1]Cl2 amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin (Kd = 0.061 μM for the binding of Λ-[1]Cl2 to αIIbβ3), which resulted in the receptor-mediated uptake of the conjugate in vitro. Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of [1]Cl2 were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, in vivo studies in a subcutaneous U87MG glioblastoma mice model showed that [1]Cl2 efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex [2]Cl2. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer in vivo.

Neurotoxicity from Old and New Radiation Treatments for Brain Tumors.

Research regarding the mechanisms of brain damage following radiation treatments for brain tumors has increased over the years, thus providing a deeper insight into the pathobiological mechanisms and suggesting new approaches to minimize this damage. This review has discussed the different factors that are known to influence the risk of damage to the brain (mainly cognitive disturbances) from radiation. These include patient and tumor characteristics, the use of whole-brain radiotherapy versus particle therapy (protons, carbon ions), and stereotactic radiotherapy in various modalities. Additionally, biological mechanisms behind neuroprotection have been elucidated.

Nanoparticle Strategies to Improve the Delivery of Anticancer Drugs across the Blood-Brain Barrier to Treat Brain Tumors.

Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors' exquisitely sensitive location and the body's own defense mechanisms (e.g., the brain-CSF barrier and blood-brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Here, we will cover the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.

Oncolytic Virotherapy for High-Grade Glioma and Current Evidence and Factors to Consider for Incorporation into Clinical Practice.

Brain tumor incidence is on the rise, and glioblastoma comprises the majority of primary tumors. Despite maximal safe resection and adjuvant chemoradiation, median survival for high-grade glioma remains poor. For this reason, it is important to develop and incorporate new treatment strategies. Oncolytic virotherapy has emerged as a viable new therapeutic entity to fill this gap. Preclinical research has shown oncolytic virotherapy to be a robust and effective treatment option for brain tumors, and clinical trials for both adult and pediatric high-grade glioma are underway. The unique and protected environment of the nervous system, in part due to the blood-brain barrier, prevents traditional systemic therapies from achieving adequate penetration. Brain tumors are also heterogenous in nature due to their diverse molecular profiles, further complicating systemic treatment efforts. Oncolytic viruses may serve to fill this gap in brain tumor treatment given their amenability to genetic modification and ability to target unique tumor epitopes. In addition, direct inoculation of the oncolytic virus agent to the tumor bed following surgical resection absolves risk of systemic side effects and ensures adequate delivery. As virotherapy transitions from bench to bedside, it is important to discuss factors to make this transition more seamless. In this article, we describe the current clinical evidence as it pertains to oncolytic virotherapy and the treatment of brain tumors as well as factors to consider for its incorporation into neurosurgical workflow.

Manajemen Anestesi pada Kraniotomi Pengangkatan Tumor Meningioma dengan Riwayat Operasi Kliping Aneurisma: Studi Kasus

The co-existence of brain tumors with cerebral aneurysms is extremely rare, with an estimated incidence of 0,5-4,5%. The priority for surgical treatment of these two pathologies is not clear, where surgery on a cerebral aneurysm is sometimes performed initially before surgical removal of brain tumor. Treatment of brain tumors in patients with a history of clipping aneurysm has its own challenges in the field of anesthesia, where anesthetic action has the goal of reducing the risk of aneurysm rupture, preventing cerebral ischemia, and optimizing systemic function while facilitating surgical procedures. This case study reports on a 58-year-old woman who underwent surgical removal of a meningioma tumor with a history of aneurysm clipping. Aneurysm clipping surgery was performed 3 months before brain tumor removal. Patient with clinical headache and blurred vision in the right eye, without other neurological deficits. Anesthetic management is carried out with the target of preventing further increase in intracranial pressure, with adequate analgesia, proper brain relaxation techniques, and prevention of hypercapnia, hypocapnia, and hypoxia. In addition, blood pressure must be maintained by preventing hypotension or hypertension. At the end of the operation, the patient was extubated and transffered to the intensive care unit. On postoperative examination the patient was conscious, without seizures, and without neurological deficits.

The Symptomatic Improvement of Metastatic Brain Tumor Patients Based on Clinical and Distress Thermometer in Adjunctive Psychotherapy

Background: Along with the increasing incidence of primary cancer, metastatic brain tumors are becoming more common. Metastatic brain tumor patients go through a great deal of distress. Therefore, providing adequate standard therapy can alleviate patients’ clinical symptoms and improve their overall quality of life. This study aimed to investigate the role of symptomatic treatments and adjunctive psychotherapy in patients with metastatic brain tumors. Methods: We conducted a randomized, single-blind, parallel design without matching and pragmatic clinical trial at Cipto Mangunkusumo Hospital from August 2019 – June 2020. A total of 30 metastatic brain tumor patients were divided into 2 groups: (1) The treatment group which received a combination of symptomatic and adjunctive psychotherapy, and (2) The control group which was given symptomatic therapy only. The patients’ distress level was evaluated using a distress thermometer (DT). Data analysis was carried out using the Chi-square test, Fisher exact’s, and binominal test.Results: All patients in the treatment group experienced a significant improvement in overall DT scores before and after adjunctive psychotherapy (p=0.01). Symptomatic therapy alleviates headaches and seizures significantly by 100% with or without psychotherapy. Conclusions: The standard symptomatic treatment of metastatic brain tumors can alleviate clinical symptoms in both groups, especially for headaches and seizures. An adjunctive psychotherapy may significantly improve the overall DT.

Exploring the Power of Deep Learning: Fine-Tuned Vision Transformer for Accurate and Efficient Brain Tumor Detection in MRI Scans.

A brain tumor is a significant health concern that directly or indirectly affects thousands of people worldwide. The early and accurate detection of brain tumors is vital to the successful treatment of brain tumors and the improved quality of life of the patient. There are several imaging techniques used for brain tumor detection. Among these techniques, the most common are MRI and CT scans. To overcome the limitations associated with these traditional techniques, computer-aided analysis of brain images has gained attention in recent years as a promising approach for accurate and reliable brain tumor detection. In this study, we proposed a fine-tuned vision transformer model that uses advanced image processing and deep learning techniques to accurately identify the presence of brain tumors in the input data images. The proposed model FT-ViT involves several stages, including the processing of data, patch processing, concatenation, feature selection and learning, and fine tuning. Upon training the model on the CE-MRI dataset containing 5712 brain tumor images, the model could accurately identify the tumors. The FT-Vit model achieved an accuracy of 98.13%. The proposed method offers high accuracy and can significantly reduce the workload of radiologists, making it a practical approach in medical science. However, further research can be conducted to diagnose more complex and rare types of tumors with more accuracy and reliability.

ATRT-18. ELUCIDATING THE ETMR MICROENVIRONMENT USING SPATIAL MULTI-OMICS TECHNOLOGIES

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants under 4 years of age and is associated with an extremely poor prognosis. A bottleneck in the development of new and curative treatments for ETMR stems from our limited understanding of the spatiotemporal biological heterogeneity within patient tumor samples and a lack of preclinical models that adequately reflect the entire biological spectrum. Novel lipid-based therapeutics that encompass ganglioside-directed immunotherapy, targeting lipid metabolism and membrane lipid therapy, have shown efficacy in the treatment of brain tumors but have yet to be evaluated in the treatment of ETMR. We carried out mass spectrometry imaging on ETMR patient samples to identify the histology-specific accumulation of lipids within the diverse cell populations of the tumor microenvironment. Our preliminary studies identified the accumulation of glycosphingolipids, cardiolipins, phosphatidylinositols, and ceramide-1-phosphates within tumor cells, including the characteristic multilayered rosettes, and within different microvascular proliferations. All data were correlated to histopathology and Ki67 proliferation index. We next evaluated the lipid profiles in the patient-derived ETMR cell line, BT183, compared to control neural stem cells (NSCs), grown as 3D tumorspheres and neurospheres, respectively. From this data we identified lipids that accumulated in our patient samples and the ETMR cell line but were significantly reduced or not detected in the control NSCs. Analysis aimed at a systems biology approach to study the ETMR microenvironment using imaging mass cytometry for multiplex IHC and spatial transcriptomics to correlate lipidomic phenotype to distinct cell populations within the microenvironment are ongoing. Preclinical model development based on these findings and drug screening of therapeutics targeting these lipidomic pathways are also ongoing.

IMMU-11. PRECLINICAL HIGH-RISK PEDIATRIC BRAIN TUMOR MODELS FOR IMMUNOTHERAPY: HURDLES AND THE WAY FORWARD

Abstract Despite recent therapeutic advancements in the treatment of pediatric brain tumors, high-risk brain tumors (pHRBT) remain the leading cause of cancer-related deaths in children. In recent years, immunotherapy has become a viable treatment option for several cancers including brain tumors. However, several factors have limited the use of immunotherapy in the treatment of pHRBT. For example, an "immunologically cold" tumor environment has been predominantly implicated in the failure of checkpoint inhibitors (ICIs) as monotherapy in pHRBT. Nevertheless, priming the effects of ICIs with epigenetic modulators through a process called “viral mimicry” that induces the expression of human endogenous retroviruses has the potential to enhance immunotherapy by sparking a T-cell mediated immune response. However, the inadequate understanding of the limitations of the preclinical models has prevented the development of efficient immunotherapy strategies for pHRBT. Although several studies and reviews have compiled some limitations of the available models, a hands-on experience using preclinical models for ICIs testing has not been fully communicated. Here, we share our bedside to bench experience with syngeneic and humanized mouse models of DIPG, ATRT, and medulloblastoma using ICIs therapy in conjunction with an epigenetic alteration. We will present and discuss the limitations of mouse models for the development of immunotherapies for pHRBT. For instance, our results indicated that the baseline levels of MHC-I expression in patients’ DIPG tumors were comparable to matched normal tissue. However, these levels were significantly lower in mouse DIPG tumors. To compensate for this difference, we treated mice with IFN-γ in combination with an epigenetic modulator. Surprisingly, the addition of INF-γ had a negative effect on animal overall survival compared to the treatment with the epigenetic modulator alone. Together, our experience demonstrated the importance of suitability assessment of current models for developing and translating successful immunotherapy strategies to treat pHRBT.

XRT-05. LITHIUM PREVENTS RADIATION-INDUCED HIPPOCAMPAL MICROGLIA SENESCENCE IN A MOUSE MODEL OF PEDIATRIC CRANIAL RADIOTHERAPY

Abstract Radiotherapy is essential in the treatment of high-grade brain tumors. While often lifesaving, it typically results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating, especially in pediatric patients. Although the survival rates have improved dramatically, there are currently no treatments or preventive strategies available to ameliorate the late cognitive complications. Lithium (Li), long used to treat patients with bipolar affective disorders, has been shown to reduce irradiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their division. However, except for these anti-apoptotic and pro-neurogenic effects, there is limited understanding of how Li exerts its actions in the brain. This work aimed to further elucidate the mechanisms behind the protective action of Li in the irradiated young brain. To this end, post-natal day (PD) 21 C57BL6/J mice were intraperitoneally injected with lithium chloride (4 mmol/kg) and subsequently kept on a Li carbonate diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. At PD25, the animals were subjected to a single dose of 8 Gy whole brain irradiation, and 6 weeks after irradiation, they were sacrificed, and their hippocampi were harvested for single-cell RNA sequencing and RT-qPCR. The attained results showed that irradiation induced hippocampal microglia senescence, as judged by the increased expression of the senescence-associated genes Cdkn1a, Cdkn2, Ccl12, C/Ebp and others in this cellular population. Conversely, Li prevented microglia senescence by activating the Bcl2 family of genes, as confirmed by the lower expression of the abovementioned senescence-associated genes in the Li-treated animals. These results provide the first step towards understanding the action of Li in the brain and confirm its potential to become the first pharmacological treatment for irradiation-induced late cognitive effects.

BIOL-10. MOUSE MODELING OF PEDIATRIC MYCN GLIOMA REVEALS INTRATUMORAL HETEROGENEITY INCLUDING NEURONAL AND OLIGODENDROGLIAL LINEAGE SIGNATURES

Abstract Pediatric glioma of the subclass MYCN are highly aggressive tumors with a median age at diagnosis of 8 years and a median survival of only 14 months. Molecularly, they frequently carry MYCN amplifications, TP53 mutations or both of these alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and both biological as well as clinical details have not been fully addressed. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Therefore, we generated a genetically engineered model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice, which carry a loss of Trp53 and show aberrant MYCN expression in neural precursors of the central nervous system. All such mice developed aggressive forebrain tumors early in lifetime that mimic their human counterparts regarding histology, DNA methylation, and gene expression. Single cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. To find new treatment options, we performed in vitro high-throughput drug screening on both, mouse and human tumor cells. Among 640 investigated anticancer compounds, Doxorubicin, Irinotecan, and Etoposide effectively suppressed the growth of tumor cells. As FDA-approved chemotherapeutics, these compounds are used for the treatment of other pediatric brain tumors. Repurposing them for the treatment of MYCN-driven high grade glioma could achieve a rapid transition to glioma treatment. We believe that our model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.

P.102 Weighing the risks and benefits of perioperative steroids in the surgical treatment of malignant brain tumours

Background: Steroids are widely used in medicine because of their anti-inflammatory and immunosuppressive properties; however, they have numerous adverse effects. In neuro-oncology, dexamethasone is the first-line treatment for vasogenic edema caused by malignant brain tumours. This retrospective chart review investigated the risks and benefits of perioperative steroids in the surgical treatment of malignant brain tumours. Methods: All patients (age ≥ 18 years) who underwent a craniotomy for the treatment of a malignant brain tumour at Windsor Regional Hospital between 2012 and 2020 were assessed for eligibility for this retrospective study. Baseline patient characteristics, cumulative perioperative steroid dose, and postoperative outcomes were recorded from electronic medical records (n = 362). Statistical analysis was performed using SPSS. Results: Patients who received a higher cumulative perioperative steroid dose (≥ 80 mg) had a significantly higher rate of postoperative complications compared to those who received a lower dose. These included wound dehiscence, postoperative brain edema on imaging, unplanned return to the operating room, and readmission within 30 days. Conclusions: Steroids are important medications in neuro-oncology, but they are not without potential complications. The findings of this study highlight the need for careful consideration when using steroids in patients undergoing surgical treatment of a malignant brain tumour.

OUTC-03. IMPACT OF TREATMENT EXPOSURES AND SOCIOECONOMIC STATUS ON NEUROCOGNITIVE PERFORMANCE IN CHILDREN WITH BRAIN TUMORS

Abstract PURPOSE To investigate the impact of treatment exposures and socioeconomic status on neurocognitive performance in children with brain tumors. METHODS Eligible patients included those diagnosed with a brain tumor at <22 years of age with ≥ 1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age standardized measures of intellectual function. Neurocognitive outcomes included Wechsler indices of full-scale intelligent quotient (IQ), working memory (WM), and processing speed (PS). Neurocognitive decline was defined as a negative slope. Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models. RESULTS Eligible patients (n=152) had a mean neurocognitive follow-up of 50.2 months and median age at diagnosis of 9.6 years. PS was most frequently impaired in patients (37.5%) followed by IQ (20.6%) and WM (16.5%). Patients with public insurance had eight-fold increased odds of impaired IQ compared to those with private insurance (Odds Ratio [OR]: 7.59, p<0.001). Patients treated with CSI had eight-fold increased odds of impaired IQ (OR: 7.86, p=0.003) and almost six-fold increased odds of impaired WM (OR: 5.66, p=0.028) compared to those treated without RT. After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, p=0.012). Patients treated with both chemotherapy and RT demonstrated the greatest decline whereas those treated without either demonstrated no decline in any of the neurocognitive measures. CONCLUSION After treatment for pediatric brain tumors, public insurance, an indicator of low socioeconomic status, was associated with impairment in IQ with a large effect size similar to that of CSI. Chemotherapy was associated with decline in IQ with a small effect size. Combined chemotherapy and RT had additive effects on neurocognitive decline in IQ, WM, and PS.

Potential roles of transformers in brain tumor diagnosis and treatment

AbstractBrain tumor (BT) is one of many malignancies that have substantially enhanced global human morbidity and mortality rates. Early detection and characterization of glioma are essential for effective preventive strategies. Currently, the use of Transformers, a deep learning model for BT diagnosis and treatment, is attracting significant attention. The transformer self‐attention mechanism automatically learns the associations between input data for efficient processing and analysis. Research indicates that Transformers could play an essential role in the BT segmentation of magnetic resonance imaging (MRI) images, the MRI and histopathology‐based grading of brain cancer, BT molecular expression prediction, the classification of primary brain metastasis sites, voxel‐level dose and BT radiotherapy outcome prediction, synergistic prediction, and the pathway deconvolution of drug combinations. In this review, the feasibility, accuracy, and applicability of various algorithms are systematically analyzed and their prospects are discussed. Overall, this review aimed to discuss and provide an overview of the increasing applications of Transformers in real‐time BT detection and therapy, indicating their broad prospects and potential. In the future, Transformers are expected to be increasingly used for the diagnosis and subsequent treatment of BT because of the continuous development and improvement of Transformer‐based deep learning technology. However, more work is required to investigate their properties for anomaly detection, medical image classification, network design development, and application to other medical data.

Carbon Dots in Treatment of Pediatric Brain Tumors: Past, Present, and Future Directions.

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood-brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and micellar molecules of varying structures and compositions, have been investigated as a potential therapy to circumvent some of these inherent challenges. Carbon dots (CDs) have recently gained popularity as a novel nanoparticle with theranostic properties. This carbon-based modality is highly modifiable, allowing for conjugation to drugs, as well as tumor-specific ligands in an effort to more effectively target cancerous cells and reduce peripheral toxicity. CDs are being studied pre-clinically. The ClinicalTrials.gov site was queried using the search terms: brain tumor and nanoparticle, liposome, micelle, dendrimer, quantum dot, or carbon dot. At the time of this review, 36 studies were found, 6 of which included pediatric patients. Two of the six studies investigated nanoparticle drug formulations, whereas the other four studies were on varying liposomal nanoparticle formulations for the treatment of pediatric brain tumors. Here, we reviewed the context of CDs within the broader realm of nanoparticles, their development, promising pre-clinical potential, and proposed future translational utility.

The Use of Stereotactic Radiosurgery to Treat Functional Disorders: A Topic Discussion

Stereotactic radiosurgery (SRS) is a well-known modality for the treatment of malignant brain tumors. SRS, however, can also be used to treat non-malignant functional disorders such as epilepsy, tremor, trigeminal neuralgia (TN), obsessive compulsive disorder (OCD), and intractable pain among others. Given the limited prospective data guiding treatment of these benign disorders, this article serves as a consolidated discussion of the application of SRS for functional ailments, hopefully serving as a reference for those considering application of this technique in clinical practice.

Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling–dependent neurogenesis in the embryonic neural tube

The balance between neural stem cell proliferation and neuronal differentiation is paramount for the appropriate development of the nervous system. Sonic hedgehog (Shh) is known to sequentially promote cell proliferation and specification of neuronal phenotypes, but the signaling mechanisms responsible for the developmental switch from mitogenic to neurogenic have remained unclear. Here, we show that Shh enhances Ca2+ activity at the neural cell primary cilium of developing Xenopus laevis embryos through Ca2+ influx via transient receptor potential cation channel subfamily C member 3 (TRPC3) and release from intracellular stores in a developmental stage-dependent manner. This ciliary Ca2+ activity in turn antagonizes canonical, proliferative Shh signaling in neural stem cells by down-regulating Sox2 expression and up-regulating expression of neurogenic genes, enabling neuronal differentiation. These discoveries indicate that the Shh-Ca2+-dependent switch in neural cell ciliary signaling triggers the switch in Shh action from canonical-mitogenic to neurogenic. The molecular mechanisms identified in this neurogenic signaling axis are potential targets for the treatment of brain tumors and neurodevelopmental disorders.

Advances in Focused Ultrasound for the Treatment of Brain Tumors

Employing the full arsenal of therapeutics to treat brain tumors is limited by the relative impermeability of the blood–brain and blood–tumor barriers. In physiologic states, the blood–brain barrier serves a protective role by passively and actively excluding neurotoxic compounds; however, this functionality limits the penetrance of therapeutics into the tumor microenvironment. Focused ultrasound technology provides a method for overcoming the blood–brain and blood–tumor barriers through ultrasound frequency to transiently permeabilize or disrupt these barriers. Concomitant delivery of therapeutics has allowed for previously impermeable agents to reach the tumor microenvironment. This review details the advances in focused ultrasound in both preclinical models and clinical studies, with a focus on its safety profile. We then turn towards future directions in focused ultrasound-mediated therapies for brain tumors.

Perfusion-Weighted Imaging: The Use of a Novel Perfusion Scoring Criteria to Improve the Assessment of Brain Tumor Recurrence versus Treatment Effects.

Imaging surveillance of contrast-enhancing lesions after the treatment of malignant brain tumors with radiation is plagued by an inability to reliably distinguish between tumor recurrence and treatment effects. Magnetic resonance perfusion-weighted imaging (PWI)-among other advanced brain tumor imaging modalities-is a useful adjunctive tool for distinguishing between these two entities but can be clinically unreliable, leading to the need for tissue sampling to confirm diagnosis. This may be partially because clinical PWI interpretation is non-standardized and no grading criteria are used for assessment, leading to interpretation discrepancies. This variance in the interpretation of PWI and its subsequent effect on the predictive value has not been studied. Our objective is to propose structured perfusion scoring criteria and determine their effect on the clinical value of PWI. Patients treated at a single institution between 2012 and 2022 who had prior irradiated malignant brain tumors and subsequent progression of contrast-enhancing lesions determined by PWI were retrospectively studied from CTORE (CNS Tumor Outcomes Registry at Emory). PWI was given two separate qualitative scores (high, intermediate, or low perfusion). The first (control) was assigned by a neuroradiologist in the radiology report in the course of interpretation with no additional instruction. The second (experimental) was assigned by a neuroradiologist with additional experience in brain tumor interpretation using a novel perfusion scoring rubric. The perfusion assessments were divided into three categories, each directly corresponding to the pathology-reported classification of residual tumor content. The interpretation accuracy in predicting the true tumor percentage, our primary outcome, was assessed through Chi-squared analysis, and inter-rater reliability was assessed using Cohen's Kappa. Our 55-patient cohort had a mean age of 53.5 ± 12.2 years. The percentage agreement between the two scores was 57.4% (κ: 0.271). Upon conducting the Chi-squared analysis, we found an association with the experimental group reads (p-value: 0.014) but no association with the control group reads (p-value: 0.734) in predicting tumor recurrence versus treatment effects. With our study, we showed that having an objective perfusion scoring rubric aids in improved PWI interpretation. Although PWI is a powerful tool for CNS lesion diagnosis, methodological radiology evaluation greatly improves the accurate assessment and characterization of tumor recurrence versus treatment effects by all neuroradiologists. Further work should focus on standardizing and validating scoring rubrics for PWI evaluation in tumor patients to improve diagnostic accuracy.