Idiopathic normal pressure hydrocephalus diagnosis: Quantitative and qualitative score predicting outcome of extended lumbar drainage.

Image 1.

DKK3 Expression in Glioblastoma: Correlations with Biomolecular Markers.

Glioblastoma is the most common malignant primary tumor of the CNS. The prognosis is dismal, with a median survival of 15 months. Surgical treatment followed by adjuvant therapies such as radiotherapy and chemotherapy characterize the classical strategy. The WNT pathway plays a key role in cellular proliferation, differentiation, and invasion. The DKK3 protein, capable of acting as a tumor suppressor, also appears to be able to modulate the WNT pathway. We performed, in a series of 40 patients, immunohistochemical and Western blot evaluations of DKK3 to better understand how the expression of this protein can influence clinical behavior. We used a statistical analysis, with correlations between the expression of DKK3 and overall survival, age, sex, Ki-67, p53, and MGMT and IDH status. We also correlated our data with information included in the cBioPortal database. In our analyses, DKK3 expression, in both immunohistochemistry and Western blot analyses, was reduced or absent in many cases, showing downregulation. To date, no clinical study exists in the literature that reports a potential correlation between IDH and MGMT status and the WNT pathway through the expression of DKK3. Modulation of this pathway through the expression of DKK3 could represent a new tailored therapeutic strategy in the treatment of glioblastoma.

Impact of Heavy Metals on Glioma Tumorigenesis.

Recently, an increase in the incidence of brain tumors has been observed in the most industrialized countries. This event triggered considerable interest in the study of heavy metals and their presence in the environment (air, water, soil, and food). It is probable that their accumulation in the body could lead to a high risk of the onset of numerous pathologies, including brain tumors, in humans. Heavy metals are capable of generating reactive oxygen, which plays a key role in various pathological mechanisms. Alteration of the homeostasis of heavy metals could cause the overproduction of reactive oxygen species and induce DNA damage, lipid peroxidation, and the alteration of proteins. A large number of studies have shown that iron, cadmium, lead, nickel, chromium, and mercury levels were significantly elevated in patients affected by gliomas. In this study, we try to highlight a possible correlation between the most frequently encountered heavy metals, their presence in the environment, their sources, and glioma tumorigenesis. We also report on the review of the relevant literature.

Novel Advances in Treatment of Meningiomas: Prognostic and Therapeutic Implications.

Meningiomas are the most frequent histotypes of tumors of the central nervous system. Their incidence is approximately 35% of all primary brain tumors. Although they have the status of benign lesions, meningiomas are often associated with a decreased quality of life due to focal neurological deficits that may be related. The optimal treatment is total resection. Histological grading is the most important prognostic factor. Recently, molecular alterations have been identified that are specifically related to particular phenotypes and, probably, are also responsible for grading, site, and prognostic trend. Meningiomas recur in 10-25% of cases. In these cases, and in patients with atypical or anaplastic meningiomas, the methods of approach are relatively insufficient. To date, data on the molecular biology, genetics, and epigenetics of meningiomas are insufficient. To achieve an optimal treatment strategy, it is necessary to identify the mechanisms that regulate tumor formation and progression. Combination therapies affecting multiple molecular targets are currently opening up and have significant promise as adjuvant therapeutic options. We review the most recent literature to identify studies investigating recent therapeutic treatments recently used for meningiomas.

Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis of these in patients is still very unfavorable. The limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors, are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood-brain barrier, which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, a penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, a large surface area, and easy modification with molecules, which render them as suitable candidates for deliver drugs. In this review, we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas and discuss the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

Molecular Investigation of DKK3 in Cerebral Ischemic/Reperfusion Injury.

Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. Its role in the mechanisms of cellular degeneration and protection is still unknown. The aim of our work is to investigate the endogenous activation of the DKK3 pathway in a model of transient occlusion of the middle cerebral artery in rats. In particular, the animals were subjected to 1 h of ischemia followed by different reperfusion times (1 h, 6 h, 12 h and 24 h) to evaluate the downstream pathway and the time course of its activation. Western blot analysis showed increased Dkk3 expression in animals with the highest time of reperfusion. The increased levels of Dkk3 were accompanied by reduced Wnt3a, Frz1 and PIWI1a expression in the cytosol while FOXM1 and ß-catenin decreased in the nucleus. These molecular changes led to an increase in the apoptotic pathway, as showed by the increased expression of Caspase 3 and Bax and the reduced levels of Bcl-2, and to a decrease in neurogenesis, as shown by the decreased expression of Tbr2, Ngn2 and Pax6. In the second part of the study, we decided to employ curcumin, an activator of the Wnt/ß-catenin signaling, to investigate its effect on Dkk3. In particular, curcumin was administered 1 and 6 h after ischemia, and animals were sacrificed 24 h later when the expression of Dkk3 was higher. Our data displayed that curcumin administration decreased Dkk3 expression, and increased Wnt3a, Frz1 and PIWI1a levels. Well in line with these data, curcumin administration increased nuclear ß-catenin and FOXM1 expression. The down-regulation of Dkk3 by curcumin led to reduced apoptosis and increased neurogenesis. Summarizing, our results showed that Dkk3 acts as an inhibitor of Wnt/ß-catenin signaling during cerebral ischemia. Additionally, its inhibition and the contextual activation of the Wnt/ß-catenin pathway are protective against ischemic stroke.

The Role of Nanotechnologies in Brain Tumors.

The treatment of glioma remains one of the most interesting topics in neurooncology. Glioblastoma multiforme is the most aggressive and prevalent malignant brain tumor. Nowadays, technologies and new tools are helping the neurosurgeons to define a tailored surgery. However, there are few pharmaceutical strategies in operated and nonoperated patients. There are still few anticancer drugs approved by FDA and EMA. Moreover, these drugs are not so effective and have a lot of side effects due to their toxicity. Nanoparticles are a new strategy which could help to create and carry new drugs. In fact, NPs improve the pharmacokinetic properties of anticancer drugs, reduce side-effects, and increase drug half-life and its selectivity. Nanoparticle drug delivery system has been studied for targeting different molecular biomarkers and signaling pathways. Furthermore, the first problem of anticancer drugs in the treatment of gliomas is penetrating the blood brain barrier which represents an insurmountable wall for most of synthetic and natural particles. In the last 15 years, a lot of researches tried to design a perfect nanoparticle both able to cross blood-brain barrier and to selectively target glioma cells, unfortunately, without great results. In vivo human trials are still ongoing and many of them have already failed. In this chapter we evaluate the effectiveness of nanotechnologies in the treatment of brain tumors. There is not yet, currently, a nanoparticle drug designed for the treatment of gliomas approved by FDA and EMA. Advancements in discovery of molecular characteristics of tumors lead to the development of targeted nanoparticles that are tested in numerous in vitro and in vivo studies on gliomas. Novel and repurposed drugs, as well as novel drug combinations, have also been already studied but those are not included in this chapter because the carried drugs (active substances) are not included among the approved anticancer drug used in the treatment of gliomas.

The Role of Nanotechnology in Spinal Cord Tumors.

The efficacy of current multimodal therapeutic strategies in spinal cord tumors is limited by the lack of specific therapies. Importantly, sufficient amount of therapeutic materials should be concentrated in tumors in order to be efficient. Overcoming the blood-brain barrier is the major obstacle for chemotherapeutics, which cannot reach the tumor bed in efficacious doses. The intrinsic properties of nanoparticles make them suitable for activating numerous processes both at the cellular and subcellular levels, making them good candidates to be used for different purposes in medicine. Furthermore, the adaptability characteristic of NPs may enable them to pass through the blood-brain barrier and transport different pharmacological compounds. Nanoparticle systems provide prolonged drug delivery directly to the tumor or by functionalizing the material surface with peptides and ligands allowing the drug-loaded material to specifically target the tumor cells. In this chapter, various preclinical and/or clinical studies in treatment of spinal cord tumors are discussed.

Treatment of Chiari III Malformation in Infant with 4K 3D ORBEYE Exoscope.

Chiari malformation (CM)-III is the rarest anomaly among CMs.1 Treatment of choice is surgical repair,2 although poor outcome and postoperative mortality has been reported.3 Surgical timing is still debated.4,5 We present the case of a male infant with a prenatal diagnosis of encephalocele. Presentation was characterized by hemodynamic instability, horizontal nystagmus, and left shoulder dystocia due to caesarean section, with a 64 mm × 49 mm × 76 mm soft, fluctuant, and translucent suboccipital-cervical sac. Magnetic resonance imaging revealed a median occipital bone defect with the meningoencephalic sac communicating with the vermian cistern and the fourth ventricle, moderate hydrocephalus, reduction of the posterior cranial fossa volume, hypoplasia of cerebellar hemispheric, vermian structures, and corpus callosum hypoplasia. The patient underwent surgery on day 4 with the use of a 4K 3D ORBEYE exoscope (Video 1). Surgery consisted of disengagement of nervous structures and repair of the neurocutaneous defect, followed on day 12 by a ventriculoperitoneal shunt with a programmable valve. The procedures were well tolerated. At the 14-month follow-up visit he was in range with growth charts (weight, height, and cranic circumference) and gained the physiologic stages of growth. He had no motor impairment but still present were convergent strabismus and mild left C5-C6 radiculopathy, secondary to shoulder dystocia. This is the first case reported in the literature of CM-III treated with the 4K 3D ORBEYE exoscope. Advantages of the exoscope were ergonomic positions for operative staff, possibility for the team to assist in the 4K 3D view, especially in cases with a narrow operative field, with a clear and detailed vision, although a learning curve is required6 to become a valid alternative in pediatric neurosurgery.

Cisternostomy for malignant middle cerebral artery infarction: proposed pathophysiological mechanisms and preliminary results.

BACKGROUND: The ischaemic stroke of the territory of the middle cerebral artery represents an event burdened by high mortality and severe morbidity. The proposed medical treatments do not always prove effective. Decompressive craniectomy allows the ischaemic tissue to shift through the surgical defect rather than to the unaffected regions of the brain, thus avoiding secondary damage due to increased intracranial pressure. In this study, we propose a novel treatment for these patients characterised by surgical fenestration of the cisterns of the skull base. METHODS: We have treated 16 patients affected by malignant middle cerebral artery ischaemia and treated with cisternostomy between August 2018 and December 2019. The clinical history, neurological examination findings and neuroradiological studies (brain CT, CT angiography, MRI) were performed to diagnose stroke. Clinical examination was recorded on admission and preoperatively using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. RESULTS: The study included 16 patients, 10 males and 6 females. The mean age at surgery was 60.1 years (range 19-73). Surgical procedure was performed in all patients. The patients underwent immediate postoperative CT scan and were in the early hours evaluated in sedation window. In total, we recorded two deaths (12.5%). A functional outcome between mRS 0-3, defined as favourable, was observed in 9 (64.2%) patients 9 months after discharge. A functional outcome between mRS 4-6, defined as poor, was observed in 5 (35.7%) patients 9 months after discharge. CONCLUSIONS: The obtained clinical results appear, however, substantially overlapping to decompressive craniectomy. Cisternostomy results in a favourable functional outcome after 9 months. This proposed technique permits that the patient no longer should be undergone cranioplasty thus avoiding the possible complications related to this procedure. The results are certainly interesting but higher case numbers are needed to reach definitive conclusions.

Unusual Case of Posterior Fossa Extradural Hematoma in a Child: Review of the Literature.

INTRODUCTION: Posterior fossa extradural hematoma (PFEH) is a rare pathology often due to nuchal region trauma. In children, PFEH causes rapid decline of the neurological status also for brain stem compression. Early brain computed tomography (CT) scan is necessary suspicious for PFEH. Most patients need surgical evacuation. CASE PRESENTATION: In this article, we present a 5-year-old patient arrived for meningitis that came out in favor of PFEH after an accurate history record. DISCUSSION/CONCLUSION: Accurate anamnestic records, especially in pediatric patients, prevent from misleading clinic and neurological presentation. Brain CT scan is an indispensable diagnostic tool in order to promptly recognize and treat PFEH considering that rapid cognitive impairment of patients raises the risk of mortality and morbidity.

The Value of Preoperative Planning Based on Navigated Transcranical Magnetic Stimulation for Surgical Treatment of Brain Metastases Located in the Perisylvian Area.

BACKGROUND: Brain metastases are the most common neoplasms in adults. When brain metastases are located in eloquent areas, their treatment still seems controversial and not clearly defined. It is therefore essential to provide correct preoperative planning to better define extension and characterization of brain metastasis. METHODS: We retrospectively looked for the tumor database of our institution, patients with single brain metastasis, located in the sylvian area, who underwent resection with the support of intraoperative neurophysiologic monitoring between 2008 and 2018. RESULTS: We retrieved data for 30 adults, each with a single brain metastasis that was located in the sylvian area, including the insula and the lower portion of the motor cortex. Neuronavigation and the intraoperative visualization of the navigated transcranial magnetic stimulation-based reconstruction of functional networks were used to delineate the ideal trajectory toward the lesion. The Karnofsky Performance Status significantly improved in the postoperative period. CONCLUSIONS: The correct planning of brain metastasis allows more secure removal of the neoplastic lesion, avoiding and/or reducing the appearance of neurologic deficits. Navigated transcranial magnetic stimulation represents a new method that can promote a more complete and safer resection of the metastatic lesion in eloquent areas. An optimal surgical result, in the absence of postoperative neurologic deficits, allows the patient to undertake adjuvant therapy able to prolong survival.

Minimally invasive posterior fossa decompression with duraplasty in Chiari malformation type I with and without syringomyelia.

BACKGROUND: Posterior fossa decompression (PFD), with and without duraplasty, represents a valid treatment in Chiari malformation Type I (CM-I) with and without syringomyelia. Despite a large amount of series reported in literature, several controversies exist regarding the optimal surgical approach yet. In this study, we report our experience in the treatment of CM-I, with and without syringomyelia, highlighting how the application of some technical refinements could lead to a good outcome and a lesser rate of complications. METHODS: Twenty-six patients with CM-I, with and without syringomyelia, underwent PFD through a 3 cm × 3 cm craniectomy with the removal of the most median third of the posterior arch of C1 and duraplasty. Signs and symptoms included sensory deficits, motor deficits, neck pain, paresthesias, headache, dizziness, lower cranial nerve deficits, and urinary incontinence. Postoperative magnetic resonance (MR) was performed in all patients. RESULTS: Signs and symptoms improved in 76.9% of cases. Postoperative MR revealed a repositioning of cerebellar tonsils and the restoration of cerebrospinal fluid circulation. In our experience, the rate of complication was 23% (fistula, worsening of symptoms, and respiratory impairment). CONCLUSION: PFD through a 3 cm × 3 cm craniectomy and the removal of the most median third of posterior arch of C1 with duraplasty represents a feasible and valid surgical alternative to treat patients with CM-I, with and without syringomyelia, achieving a good outcome and a low rate of complications.

TLR-4/Wnt modulation as new therapeutic strategy in the treatment of glioblastomas.

PURPOSE: Glioblastomas are highly aggressive brain tumors. Various pathways are involved in gliomagenesis, among which the Wingless (Wnt) signaling. Dickkopf protein-related protein 3 (Dkk-3) interacts with proteins of Wnt pathwayas inhibitor. The Wnt signaling contributes to activity of the claudins, that are critical components of tight junctions, whose expression was altered selectively in cerebral microvessels of glioblastoma. The aim of this study was to determine the role of Wnt pathways in the regulation of tumor growth, apoptosis process by targeting Dkk-3, tight junctions alteration involving claudin-5, suggesting possible therapeutic interactions involving Wnt/Toll-like receptors (TLRs) pathways. RESULTS: We showed a significant decreasing of Dkk-3 and claudin-5 in human glioblastoma cell lines, as well as in U-87 MG xenograft tumors and in glioblastoma human patient's tissues, with an involvement of the apoptosis process. Also, an interesting TLR-4/Wnt modulation highlighted that the absence of TLR-4 determined resistance to the tumor onset. CONCLUSIONS: We concluded that combined modulation of Wnt/Dkk-3/claudin-5 and TLR-4 pathways, simultaneously targeting apoptosis and survival signaling defects, might shift the balance from tumor growth stasis to cytotoxic therapeutic responses, flowing in greater therapeutic benefits. METHODS: In the present study we investigated the expression of Dkk-3, claudin-5, apoptosis markers and TLR-4 receptor protein levels in in vitro studies on U-138MG, A-172, LN-18 and LN-229 human glioblastoma cell lines, and in vivo study using TLR-4 KO mice and in glioblastoma human patient's tissues.

Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas.

Meningiomas are the most common tumors of the central nervous system, where the incidence is around 25% of all primary brain tumors. The optimal treatment is represented by total resection accompanied by the removal of the dura mater and bone when infiltrated by the tumor. The histological grading is the most important prognostic factor in the outcome. However, recurrences do occur in a significant proportion (10-25%) of cases, representing the most relevant clinical complication. Molecular therapies are providing to give different opportunities in the development of new treatments. The Dickkopf-related family of proteins includes four secretory proteins. The expression of the REIC/Dkk-3 gene is down-regulated in many tumor cell lines and could contribute to the immunomodulatory properties of the tissue microenvironment. An important role in carcinogenesis is played by Dickkopf protein-related protein 3, which is involved in embryonic development through its interaction and modulation of the pathway of the Wnt signal transduction. The mutations of this pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The claudin-5, is an integral membrane protein, which regulate the permeability of the blood-brain barrier. In various pathological processes, including inflammation, trauma and tumor, claudin 5 regulate the change in endothelial or epithelial permeability, therefore, modification in claudin-5 expression may play a role in malignant transformation. The aim of our study is to demonstrate the role of Dkk-3 and claudin-5 in the pathogenesis of meningiomas. A more correct identification of the role of these proteins might suggest interesting and new molecular targets for future therapeutic protocols.

Ossified Intracranial Meningiomas: Description of the First Series of Cases and Review of the Literature.

BACKGROUND: Metaplastic meningiomas are characterized by mesenchymal differentiation with formation of bone, cartilage, fat, or xanthomatous elements. However the presence of extensive areas of ossification is rare in meningiomas. In addition, intracranial location of ossified meningiomas is uncommon. Surgical management represents the optimal treatment for ossified meningiomas, but ossification may interfere with surgery and condition outcome. METHODS: By reviewing patient records and contacting patients, families, and referring physicians, the following information was gathered: age, sex, tumor location, clinical presentation, preoperative and postoperative functional status, and surgical data. Each surgical specimen had been formalin-fixed, paraffin-embedded, and cut into parallel 4-µm-thick sections for histological evaluation. RESULTS: Our literature search identified 8 cases, all of whom had undergone surgical treatment. Histopathological analysis revealed the presence of disorganized bone spicules with solitary oval osteocytic nuclei and lined by osteoblasts, with clear evidence of bone tissue in at least 50% of tumor tissue. CONCLUSIONS: Here we present the largest series, to our knowledge, of surgically treated intracranial ossified meningiomas reported to date. The mechanism of ossification in these meningiomas remains unclear, and various hypotheses have been formulated. Complete lesion removal, or subtotal debulking in those cases characterized by tenacious adherences to vascular structures and/or critical areas, may represent the optimal treatment.

ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies.

Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas.

Innovative Therapeutic Strategies in the Treatment of Meningioma.

Few medical options are available for progressive/recurrent and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. We review the more recent literature to recognize studies investigating recent medical and chemotherapeutic agents that have been experienced or are currently being tested for meningiomas. Combination therapies affecting multiple molecular targets are currently opening up and present significant promise as adjuvant therapeutic options. However, there is an evident need for new molecular studies in order to better understand the biology of meningiomas and, thus, to identify new and more specific therapeutic targets.

Gliomas with intratumoral abscess formation: Description of new cases, review of the literature, and the role of (99m)TC-Leukoscan.

Abscess formation within a brain tumor is uncommon. Intrasellar or parasellar tumors are the most common neoplasms that develop such complications. Cerebral gliomas with abscesses are extremely rare. In this paper three rare cases of glioma associated with abscess formation are described. The diagnosis of brain tumor associated with abscess is particularly difficult by conventional neuroradiological studies. (99m)Tc-labeled sulesomab can be useful in the diagnosis of brain tumors with intratumoral abscesses. There are no precise guidelines for the diagnosis and treatment of cerebral gliomas associated with abscesses formation for the low number of cases reported to date. Appropriate treatment, aimed at radical surgery, and a suitable antibiotic-protocol, deferring adjuvant postoperative therapy, is associated with a more favorable outcome. A review of the pertinent literature is also performed.