Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review.

Glioblastoma (GBM) is the most common and malignant tumour of the central nervous system. Recent appreciation of the heterogeneity amongst these tumours not only changed the WHO classification approach, but also created the need for developing novel and personalised therapies. This systematic review aims to highlight recent advancements in understanding the molecular pathogenesis of the GBM and discuss related novel treatment targets. A systematic search of the literature in the PubMed library was performed following the PRISMA guidelines for molecular pathogenesis and therapeutic advances. Original and meta-analyses studies from the last ten years were reviewed using pre-determined search terms. The results included articles relevant to GBM development focusing on the aberrancy in cell signaling pathways and intracellular events. Theragnostic targets and vaccination to treat GBM were also explored. The molecular pathophysiology of GBM is complex. Our systematic review suggests targeting therapy at the stemness, p53 mediated pathways and immune modulation. Exciting novel immune therapy involving dendritic cell vaccines, B-cell vaccines and viral vectors may be the future of treating GBM.

Nanotechnology in neurosurgery: a systematic review.

BACKGROUND: The application of nanotechnology in medicine encompasses an interdisciplinary field of sciences for the diagnosis, treatment, and monitoring of medical conditions. This study aims to systematically review and summarize the advances of nanotechnology applicable to neurosurgery. METHODS: We performed a PubMed advanced search of reports exploring the advances of nanotechnology and nanomedicine relating to diagnosis, treatment, or both, in neurosurgery, for the last decade. The search was performed according to PRISMA guidelines, and the following data were extracted from each paper: title; authors; article type; PMID; DOI; year of publication; in vitro, in vivo model; nanomedical, nanotechnological material; nanofield; neurosurgical field; the application of the system; and main conclusions of the study. RESULTS: A total of 78 original studies were included in this review. The results were organized into the following categories: functional neurosurgery, head trauma, neurodegenerative diseases, neuro-oncology, spinal surgery and peripheral nerves, vascular neurosurgery, and studies that apply to more than one field. A further categorization applied in terms of nanomedical field such as neuroimaging, neuro-nanotechnology, neuroregeneration, theranostics, and neuro-nanotherapy. CONCLUSION: In reviewing the literature, significant advances in imaging and treatment of central nervous system diseases are underway and are expected to reach clinical practice in the next decade by the application of the rapidly evolving nanotechnology techniques.

Crocus sativus L. Causes a Non Apoptotic Calpain Dependent Death in C6 Rat Glioma Cells, Exhibiting a Synergistic Effect with Temozolomide.

Crocus sativus L., a dietary herb, has been used for various diseases including cancer. This is an in vitro study investigating the antineoplastic effect of the extract of the plant against C6 glioma rat cell line. The mechanism of cellular death and the synergistic effect of the extract with the alkylating agent temozolomide (TMZ) were investigated. Cellular viability was examined in various concentrations of the extract alone or in combination with TMZ. Apoptosis was determined with flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and autophagy by western blotting of the light chain 3 (LC3)-II. Cellular viability was reduced after exposure to the extract with half maximal inhibition concentration at 3 mg/ml. Flow cytometry and TUNEL assay suggested that the extract does not induce apoptosis. Moreover, their combination increased the ratio dead/apoptotic cells 10-fold (P < 0.001). LC3-II protein levels reduced after Crocus extract while this effect was reversed when the calpain inhibitor MDL28170 was added, suggesting a calpain-dependent death possibly through autophagy. We concluded that the extract of Crocus increases dead cell number after 48 h of exposure. Our results suggest that the cell undergoes calpain-dependent programmed cell death while co-exposure to Crocus extract and TMZ enhances the antineoplastic effect of the latter.

Primary Ewing sarcoma of the axis-C2: A case report and the review of the literature.

INTRODUCTION: Neck pain and torticollis are common symptoms in the pediatric population that rarely requires further investigation. However, in case symptoms persist, then a more meticulously approach should be considered. Underlying conditions such as infections, neck injury, autoimmune disorders or even cervical spine cancer should be excluded from diagnosis. Cervical spine cancer is a rare neurosurgical entity in the pediatric population and even rarer is atlantoaxial Ewing's sarcoma. In this report, we present a rare case of primary Ewing's sarcoma of the axis. CASE REPORT: A 3.5-year-old female with progressive neck pain and intermittent episodes of torticollis was referred to our outpatient clinic. Imaging studies revealed a malignant tumor located on C2 vertebra. Diagnosis of Ewing's Sarcoma was confirmed via open biopsy and the patient was treated with Euro-EWING 99 chemotherapy. CONCLUSION: Pediatric neck pain and/or torticollis should raise high suspicion for malignancy of cervical spine. Modern diagnostic means and techniques can assist in the screening and diagnosis of these tumors.

Personalizing Deep Brain Stimulation Therapy for Parkinson's Disease With Whole-Brain MRI Radiomics and Machine Learning.

Background Deep brain stimulation (DBS) is a well-recognised treatment for advanced Parkinson's disease (PD) patients. Structural brain alterations of the white matter can correlate with disease progression and act as a biomarker for DBS therapy outcomes. This study aims to develop a machine learning-driven predictive model for DBS patient selection using whole-brain white matter radiomics and common clinical variables. Methodology A total of 120 PD patients underwent DBS of the subthalamic nucleus. Their therapy effect was assessed at the one-year follow-up with the Unified Parkinson's Disease Rating Scale-part III (UPDRSIII) motor component. Radiomics analysis of whole-brain white matter was performed with PyRadiomics. The following machine learning methods were used: logistic regression (LR), support vector machine, naïve Bayes, K-nearest neighbours, and random forest (RF) to allow prediction of clinically meaningful UPRDSIII motor response before and after. Clinical variables were also added to the model to improve accuracy. Results The RF model showed the best performance on the final whole dataset with an area under the curve (AUC) of 0.99, accuracy of 0.95, sensitivity of 0.93, and specificity of 0.97. At the same time, the LR model showed an AUC of 0.93, accuracy of 0.88, sensitivity of 0.84, and specificity of 0.91. Conclusions Machine learning models can be used in clinical decision support tools which can deliver true personalised therapy recommendations for PD patients. Clinicians and engineers should choose between best-performing, less interpretable models vs. most interpretable, lesser-performing models. Larger clinical trials would allow to build trust among clinicians and patients to widely use these AI tools in the future.

Predicting impact of Deep Brain Stimulation on Non-motor symptoms of Parkinson's disease.

This is the largest study on Radiomics analysis looking into the impact of Deep Brain Stimulation on Non-Motor Symptoms (NMS) of Parkinson's disease. Preoperative brain white matter radiomics of 120 patients integrated with clinical variables were used to predict the DBS effect on NMS after 1 year from the surgery. Patients were classified "suboptimal" vs "good" based on a 10% or more improvement in NMS score. The combined Radiomics-Clinical Random Forrest (RF) model achieved an AUC of 0.96, Accuracy of 0.91, Sensitivity of 0.94 and Specificity of 0.88. The Youden's index showed optimal threshold for the RF of 0.535. The confusion matrix of the RF classifier gave a TPR of 0.92 and a FPR of 0.03. This corresponds to a PPV of 0.93 and a NPV of 0.93. The predictive models can be easily interpreted and after careful large-scale validation be integrated in assisting clinicians and patients to make informed decisions.Clinical Relevance- This paper shows the lesser studied positive impact of Deep Brain Stimulation on Non motor symptoms of Parkinson's disease while allows clinicians to predict non responders to the therapy.

Re-irradiation of Pediatric Medulloblastoma: A Case Report and Systematic Review.

Despite the optimal treatment given to children with medulloblastoma, many relapses are seen after combining treatments. Re-irradiation is part of salvage therapy for children who relapse and might provide long-term disease control. Nevertheless, it is challenging because there is a concern about exceeding radiation tolerances and late treatment toxicities. Re-irradiation is an option for many brain tumors, including medulloblastoma in children. This study presents a case of recurrent medulloblastoma treated with re-irradiation. A systematic review of the literature provided up-to-date data on the re-irradiation of medulloblastoma in children. This study aims to contribute to the scarce literature on the treatment strategy, which may help improve patients' outcomes.

The 100 Most Cited Papers About Brain Metastases.

BACKGROUND: A vast amount of articles centered on brain metastases have been published. OBJECTIVE: To present the 100 most-cited articles dedicated to brain metastasis and to accomplish a broad literature review. METHODS: In December 2019, we performed a title-focused search using the Thomson Reuters Web of Science database to identify the most cited articles centered on brain metastatic disease. Our search query term was based on using the following algorithm: "brain metastases" OR "brain metastasis" OR "brain metastatic disease" OR "cerebral metastases" OR "cerebral metastasis" OR "cerebral metastatic disease." Afterward, we reviewed the results to certify that they were relevant to the purposes of our research protocol. The 100 most cited papers were chosen and further analyzed. RESULTS: Our search resulted in 11,579 articles, published from 1975 until the completion of our survey. The most cited article, by Patchell et al., was published in 1990, with 1862 citations, and an average of 62.07 citations per year, whereas the last in our list, by Gaspar et al., was published in 2010, with 195 total citations, and an average of 19.50 citations per year. Countries with the highest-cited articles included the United States (75 records), followed by Canada (16 records). CONCLUSIONS: We discovered the top 100 most-cited articles centered on brain metastasis, all of which show a potentially increased level of interest, because they are meaningful scientific reports. In addition, we reviewed the historical development and advances in brain metastasis research and relevant points of interest, alongside the relevant contributions of different authors, fields of special interest, and countries. Many of the most cited articles were written by authors whose specialty was not neurosurgery or by neurosurgeons who were supported by colleagues from other medical fields. As a consequence, many of these articles were not published in neurosurgery-dedicated journals.

The 100 most cited papers about pediatric traumatic brain injury: a bibliometric analysis.

BACKGROUND: The high incidence of traumatic brain injury (TBI) in children, combined with the challenges in diagnosis and treatment options, the difficulty of predicting the outcome of each case, and also the wide variety of possibly lifelong complications, has led to an extraordinary number of published papers regarding this topic. This bibliometric analysis is aimed at identifying and reviewing the 100 most cited papers in the most challenging and trending aspects of pediatric traumatic brain injury. METHODS: A search was performed using the Web of Science database in October 2018. Results were organized by citation number, and the 100 most cited papers were further reviewed and analyzed. RESULTS: Our search resulted in 2754 published papers from 1975 until October 2018, of which 1783 (64.74%) had been published in the last decade (2010-2018). The 100 most cited papers about traumatic brain injury in children have an average citation of 140.59 and have been published in 44 different journals. Four hundred thirty-five authors have contributed to these prominent articles, most of them from the USA. CONCLUSIONS: By reviewing those highly cited papers, we sought to offer significant help not only for studying this challenging field but also for designing new studies.

Postoperative Tetraplegia to a Child after Cerebellar Pilocytic Astrocytoma Excision at Prone Position: Case Report and Literature Review.

BACKGROUND Various factors have been implicated in the pathogenesis of infarction after posterior fossa surgery such as venous air embolism, patient's position (seated or prone), hyperflexion of the neck, excessive spinal cord traction, cervical canal stenosis, and systemic arterial hypotension. The main aim of this case report was to elucidate a case in which hydrogen peroxide was implicated in a major and systemic complication after a neurosurgical procedure. CASE REPORT We describe the case of a 5-year-old female patient who was admitted to our hospital because of a cerebellar hemispheric astrocytoma associated with obstructive hydrocephalus and accompanied by 2 syringomyelic cavities in the cervicothoracic portion of the spinal cord. Immediately after gross total resection of the lesion, impaired mobility of the upper and lower extremities was observed, a finding that was not consistent with intraoperative neurophysiologic monitoring data. Hydrogen peroxide had been judiciously used to irrigate the resection tumor cavity. In the next few postoperative days, the patient suffered from transient diabetes insipidus and hyperpyrexia, indicative of hypothalamic injury. CONCLUSIONS Neurological evaluation of the patient, after stabilization of her medical condition, revealed residual spasticity of upper and lower extremities, rendering her able to mobilize via the aid of wheelchair only. The most possible pathophysiologic explanation of her neurological deterioration, including hypothalamic dysfunction, was analyzed. The role of hydrogen peroxide as a source of free radical formation, and its co-responsibility for vascular platelet aggregation and vasoconstriction was considered, upon case review, the main responsible etiologic factor.

Fetal subependymal giant cell astrocytoma: A case report and review of the literature.

BACKGROUND: Subependymal giant cell astrocytomas (SEGAs) appear approximately in 10% of patients with tuberous sclerosis. These tumors are most commonly diagnosed in childhood and adolescence, with in utero diagnosed SEGAs being an extremely rare entity. CASE DESCRIPTION: We present the case of a congenital SEGA detected in an antenatal ultrasound and further investigated with fetal magnetic resonance imaging (MRI) scans at 22 and 32 weeks of gestational age. At 9 days of age, the child underwent craniotomy and partial excision of the tumor, followed by a second more extensive operation 13 days later. The patient was subsequently administered mammalian target of rapamycin inhibitor (everolimus). CONCLUSION: In the latest follow-up MRI, at the age of two, the SEGA remained unchanged. Management of these tumors in neonates is challenging, mainly due to high morbidity and mortality of surgical treatment in these ages.

Antithrombotics in intracerebral hemorrhage in the era of novel agents and antidotes: A review.

BACKGROUND: Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin-novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. OBJECTIVE: The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents. Moreover, this review attempts to provide guidelines concerning the termination, inversion, and of course resumption of antithrombotic therapy. METHODS AND MATERIALS: We reviewed the most recently presented available data for patients who dealt with intracerebral hemorrhagic events while on antithrombotic agents (due to atrial fibrillation, prosthetic mechanical valves or recent/recurrent deep vein thrombosis). Furthermore, we examined and compared the thromboembolic risk, the bleeding risk, as well as the re-bleeding risk in two groups: patients receiving antithrombotic therapy versus patients not on antithrombotic therapy. CONCLUSION: Antithrombotic therapy is of great importance when indicated, though it does not come without crucial side-effects, such as ICH. Optimal timing of withdrawal, reversal, and resumption of antithrombotic treatment should be determined by a multidisciplinary team consisting of a stroke specialist, a cardiologist, and a neurosurgeon, who will individually approach the needs and risks of each patient.

Giant intracranial congenital hemangiopericytoma/solitary fibrous tumor: A case report and literature review.

BACKGROUND: Hemangiopericytoma and solitary fibrous tumor (HPC/SFT) are considered to be one category according to the WHO 2016 classification of central nervous system tumors. HPC/SFT are subdivided into infantile (congenital) and adult type. Both are extremely rare entities, with little knowledge about etiology, prognosis, and optimal therapeutic strategy. CASE DESCRIPTION: A 10-day-old girl was referred to our neurosurgical department due to hypotonia, palsy of the right oculomotor nerve, and prominent frontal fontanel. Imaging studies revealed a large occupying mass in the right middle cerebral fossa and the suprasellar cisterns. Only a subtotal resection of the tumor was possible, and postoperatively, she underwent chemotherapy (CHx). After a 3-year follow-up, the girl has minimum neurologic signs and receives no medications, and she can walk when she is supported. CONCLUSION: Congenital HPC/SFT is considered to have a benign behavior with a good prognosis. Treatment with gross total resection, when it is feasible, is the key to a good prognosis and low rates of recurrence. However, there is no consensus on the therapeutic strategy of a HPC/SFT, which is difficult to be completely resected. Literature lacks a therapeutic algorithm for these tumors, and thus, more clinical studies are needed to reach a consensus.

Colchicine in Neurosurgery.

BACKGROUND: Colchicine is an ancient drug. Many uses have been reported in medical books and reports through the centuries. Currently the understanding of its mechanism of action has opened new horizons to its use. OBJECTIVE: This article aims to discuss the use of colchicine in various neurosurgical conditions. METHODS: A pubmed database and clinical trials search was performed, using the key words "colchicine", "Neurosurgery", "low back pain", "stroke" and glioma". RESULTS: Various reports were found contemplating the use of colchicine in chronic low-back pain. The effect of the drug on neutrophil chemotaxis and its role as an anti-inflammatory agent has been the main argument upon which such use of colchicine has been structured. These characteristics have been the key to initiate colchicine as a preventive agent in vascular conditions. Furthermore, as colchicine is an antimitotic drug, it is currently being studied as a potential anti-glioma agent. However, the narrow therapeutic index of the drug is a discouraging factor in clinical application of colchicine in these entities. Therefore, colchicine derivatives that can exert the same effectiveness in lower doses are being studied, forming a new direction in colchicine use. CONCLUSION: Colchicine is a drug that over the years has shown promising results in certain neurosurgical entities. Its derivatives or potential colchicine-like agents might have a more significant place in neurosurgical practice.

Paediatric gliomas: diagnosis, molecular biology and management.

Paediatric gliomas represent the most common brain tumour in children. Early diagnosis and treatment greatly improve survival. Histological grade is the most significant classification system affecting treatment planning and prognosis. Paediatric gliomas depend on pathways and genes responsible for mitotic activity and cell proliferation as well as angiogenesis (MAPK, VEGF, EFGR pathways). Symptoms such as focal neurologic deficit or seizures can facilitate diagnosis, but they are not always present and therefore diagnosis is occasionally delayed. Imaging has adequate diagnostic accuracy (surpassing 90%), and novel imaging techniques such as MR spectroscopy and PET increase only slightly this percentage. Low grade gliomas (LGG) can be approached conservatively but most authors suggest surgical excision. High grade gliomas (HGG) are always operated with exception of specific contradictions including butterfly or extensive dominant hemisphere gliomas. Surgical excision is universally followed by radiotherapy and chemotherapy, which slightly increase survival. Inoperable cases can be managed with or without radiosurgery depending on location and size, with adjunctive use of radiotherapy and chemotherapy. Surgical excision must be aggressive and gross total resection (GTR) should be attempted, if possible, since it can triple survival. Radiosurgery is effective on smaller tumours of <2 cm2. Surgical excision is always the treatment of choice, but glioma recurrences, and residual tumours in non-critical locations are candidates for radiosurgery especially if tumour volume is low. Management of recurrences includes surgery, radiosurgery and chemoradiotherapy and it should be individualized according to location and size. In combination with molecular targeted therapeutic schemes, glioma management will be immensely improved in the next years.

Pediatric Nonmissile Penetrating Head Injury: Case Series and Literature Review.

BACKGROUND: Pediatric nonmissile penetrating head injury (NMPHI) is usually accidental attributed mainly to the softer skulls of growing children. However, it is a rare entity, and therefore no consensus exists regarding treatment to effectively prevent immediate and long-term complications. Throughout the literature, these injuries are mostly discussed in case reviews and case series in the general population. No data originating from randomized studies are available because of ethical and practical limitations. METHODS: We retrospectively studied and present 5 cases of children with NMPHI treated in the last 6 years in the Neurosurgery Department of Children's Hospital "Aghia Sofia". We performed a review of the literature in PubMed, using the key words "non-missile," "penetrating head injury," and "pediatric." We included case reports and case series involving pediatric cases since 2008 and selected older reports as well as certain literature reviews focusing on analysis of complications and treatment suggestions. We compared reported practice in various institutions with suggestions from the literature. RESULTS: In the last year, 4 literature reviews were published suggesting treatment algorithms of NMPHIs. Surgery timing and method as well as anticonvulsant and antibiotic therapy still remain debatable. The only review concentrating on pediatric populations dates back to 1994, based on patient outcome studies from the 1980s. In our review, treatment steps were similar among various institutions and resembled recently suggested algorithms, with better treatment outcomes than originally reported 30 years ago.

Primitive synovial sarcoma of suboccipital region in child.

Synovial sarcoma (SS) most commonly affects the lower limbs of males in the third to fifth decades of life, with masses of the head and neck accounting for 3-10% of all cases, mainly as a metastatic lesion. The lack of specific symptoms and radiological features in addition to the diversity of their microscopic aspects may cause confusion in the diagnosis; hence, knowledge of the unusual locations of SSs is very important. The immunohistochemistry, and more recently the cytogenetic studies, contribute to the differential diagnosis. We report the case of a 12-year-old girl with a rare primary SS in the suboccipital region, which underwent complete surgical resection.

Pediatric infratentorial subdural empyema: A case report.

BACKGROUND: Infratentorial subdural empyemas in children are extremely rare and potentially lethal intracranial infections. Delay in diagnosis and therapy is associated with increased morbidity and mortality. CASE DESCRIPTION: A 4-year-old boy presented with cerebellar signs following a failed treatment of otitis media. Imaging studies revealed a subdural empyema and left transverse and sigmoid sinus thrombosis. The empyema was evacuated operatively and antibiotic treatment was initiated and administered for 6 weeks. The patient recovered fully and was discharged 4 weeks following the evacuation of the empyema. CONCLUSION: While prompt identification and treatment of subdural infratentorial empyemas are crucial for favorable outcomes, their diagnosis in children might be initially missed. This is, in part because they are so rare and in part, because imaging artifacts arising from the complex posterior fossa anatomy may obscure their presence in the computer tomography (CT) scan. Therefore, high level of suspicion is necessary, given the appropriate history and clinical presentation. In children, this is a recent history of protracted otitis media and central nervous system symptomatology-cerebellar or other.

Spinal synovial cysts. A case series and current treatment options.

Synovial cysts constitute an uncommon degenerative lesion of the spine. They are usually asymptomatic but they may also cause symptoms of variable severity. The authors present three cases of such cysts, two in the lumbar region of a 55-year-old female and a 66 year old female and one in the cervical region of a 56-year-old male patient. All patients presented with radiculopathy. Magnetic Resonance Images revealed a cystic lesion at the L4/5 level in the first case, at L5/S1 level in the second case and at the C7/T1 junction level in the third case. Treatment has been microsurgical resection of all cysts with no post-operative complications and an excellent outcome. A discussion of current management options for this unusual disease is presented and a decision making flow chart is proposed.

Epilepsy and Neurosurgery: Historical Highlights.

Epilepsy has been known since antiquity and trepanation has been documented as a therapeutic option. The Greek born physician Aretaeus of Cappadocia (2nd century BC) was the first to recommend trepanation for the treatment of refractory epilepsy to drugs, pointing out the efficacy of the method (Fig. 1). Trepanation was practiced throughout the Middle Ages, as it is proved by the book of "Quattuor Magistri" and during Renaissance as well. In 19th century, Sir Victor Alexander Horsley (1857-1916), combining analysis of clinical presentation with cortical stimulation, performed a series of craniotomies for the treatment of epilepsy Fig. 2. In the following years the advent of electrophysiology and neurosurgery provided a fertile ground for further progress in epilepsy surgery such as the preoperative use of electroencephalography (EEG) to determine the epileptogenic zone by Otfrid Foerster (1873-1941); the research of Wilder Graves Penfield (1891-1976) in Montreal Neurological Institute and the use of stereoelectroencephalography (SEEG) by the neurosurgeon Jean Talairach (1911-2007) and the neurologist Jean Bancaud (1921-1994)) Fig. 3. Nowadays, epilepsy surgery remains a valuable therapeutic option in cases of drug resistant epilepsy.