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The management of brain edema in brain tumors
Abstract
This review focuses on pathophysiology, clinical signs, and imaging of brain edema associated with intracranial tumors and its treatment. Brain edema in brain tumors is the result of leakage of plasma into the parenchyma through dysfunctional cerebral capillaries. The latter type of edema (ie, vasogenic edema) and the role of other types in brain tumors is discussed. Vascular endothelial growth factor-induced dysfunction of tight junction proteins probably plays an important role in the formation of edema. Corticosteroids are the mainstay of treatment of brain edema. When possible, corticosteroids should be used in a low dose (eg, 4 mg dexamethasone daily) to avoid serious side effects such as myopathy or diabetes. Higher doses of dexamethasone (16 mg/day or more), sometimes together with osmotherapy (mannitol, glycerol) or surgery, may be used in emergency situations. On tapering, one should be aware of the possible development of corticosteroid dependency or withdrawal effects.Novel therapies include vascular endothelial growth factor receptor inhibitors and corticotropin releasing factor, which should undergo further clinical testing before they can be recommended in practice.
... The intensity of pain is often associated with the size and location of the tumour, the amount of oedema surrounding the tumour and presence of midline shift [6,13]. Brain tumour related oedema is primarily extracellular and results from increased capillary permeability and pressure gradient, which lead to plasma leak into the brain parenchyma [17]. A. Any headache fulfilling criterion C B. Intracranial neoplasia has been diagnosed C. Evidence of causation demonstrated by one or more of the following: ...
... Dexamethasone is routinely administered in dosage of 4 mg/day or 16 mg/day in 4 equal doses [19]. Dexamethasone has shown to be approximately six times as potent as prednisone and reaches full effect within 24 to 72 hours [17]. ...
... In cases of severe oedema, osmotherapy with mannitol or glycerol may also be employed. A standard dose of 20% mannitol solution (1g/kg) effectively reduces intracranial pressure by 30 to 60% for 2-4 hour [17]. However, studies show that osmotherapy usefulness in tumour related brain oedema is uncertain. ...
Introduction. Brain tumours constitute approximately 1% of all newly diagnosed cancers. Their manifestation typically involves headache, neurological impairment, focal onset seizures and syndromes related to tumour location. Severe headache presents as a prevailing symptom and occurs in over 50% of patients. Brain tumour associated headache exerts significant effect on quality of life in cancer patients. The following article aims to provide a comprehensive overview of most common and promising brain tumour related headache treatment strategies. State of knowledge. Headache in brain tumour patients arises from traction or displacement of intracranial pain-sensitive structures, such as vascular tissue, dura mater or periosteum. This can be caused by tumour’s mass itself, by tumour associated oedema or as a sequela of anti-tumour treatment. Most common therapeutic modalities include tumour surgical resection, cerebral oedema management, radiotherapeutic interventions and administration of analgesic agents. Complete removal of the tumour stands as the most effective approach, often bringing substantial alleviation in majority of cases. Conclusion. Headache affects the majority of individuals afflicted by brain tumours. Not all patients are suitable candidates for the resection of the underlying neoplasm. In such instances, the application of alternative approaches might be beneficial. Ongoing and future investigations may enhance the development of novel treatment strategies, possibly influencing the well-being of cancer patients, especially within palliative care area.
... In contrast, significantly more adverse events occurred in other primary sites, suggesting that the incidence of ISEs varies by histological type. The development of neurological symptoms is related to not only the mass effect of the tumor but also various factors, including peritumoral vasogenic edema [9,30,31]. For example, vasogenic edema is thought to be caused by the breakdown of the blood-brain barrier and the subsequent increase in interstitial fluid. ...
... Vasogenic edema is mediated by molecular factors such as VEGF [31,32]. Irradiation to tumors may influence these molecular expressions and enhance peritumoral edema [33]; thus, the occurrence of acute toxicities after SRT may differ by histological type and their molecular expressions. ...
... We observed that corticosteroid administration reduced the incidence of ISEs in patients with pre-treatment neurological symptoms. The use of corticosteroids for symptoms caused by brain tumors is widely accepted [31,35]. However, physicians may avoid administering corticosteroids to patients scheduled to receive immunotherapy even if they are symptomatic because of concerns that corticosteroids may decrease the effectiveness of immunotherapy [36]. ...
Background
Data on acute toxicities after stereotactic radiotherapy (SRT) for brain metastases, including multiple and large lesions, are lacking. We aimed to evaluate the incidence and nature of toxicities immediately after SRT using a linear accelerator.
Methods
This retrospective study reviewed the medical records of 315 patients with brain metastases treated with SRT at our institution between May 2019 and February 2022. In total, 439 SRT sessions were performed for 2161 brain metastases. The outcome of interest was immediate side effects (ISEs), defined as new or worsening symptoms occurring during SRT or within 14 days after the end of SRT.
Results
Grade ≥ 2 and ≥ 3 ISEs occurred in 16 (3.6%) and 7 (1.6%) cases, respectively. Among 63 treatments for 10 or more lesions (range: 10–40), 1 (1.6%) ISE occurred. Among 22 treatments for lesions with a maximum tumor volume of > 10 cc, 2 (9.1%) ISEs occurred. Grade ≥ 3 ISEs included 1, 4, 1, and 1 cases of grade 3 nausea, grade 3 new-onset partial and generalized seizures, grade 3 obstructive hydrocephalus, and grade 5 intracranial hemorrhage, respectively. ISEs were more common in patients with a larger maximum tumor volume, primary sites other than lung and breast cancer, and pre-treatment neurological symptoms.
Conclusion
SRT using a linear accelerator for brain metastases, including multiple and large lesions, is safe, with a low incidence of ISEs. Serious complications immediately after SRT are rare but possible; therefore, careful follow-up is necessary after treatment initiation.
... This increase in permeability is mainly attributed to the release of vascular endothelial growth factor (VEGF) by glioma cells under hypoxic stress. Possible effects of VEGF on the BBB are fenestration of the endothelium and disruption of the tight junctions between endothelial cells [23,24]. Other factors are suspected to promote the development of vasogenic oedema such as expression of aquaporin-4 (AQP4) [22,24], increased levels of leukotriene C4 in tumour tissues [23], or secretion products of infiltrating macrophages [23]. ...
... Possible effects of VEGF on the BBB are fenestration of the endothelium and disruption of the tight junctions between endothelial cells [23,24]. Other factors are suspected to promote the development of vasogenic oedema such as expression of aquaporin-4 (AQP4) [22,24], increased levels of leukotriene C4 in tumour tissues [23], or secretion products of infiltrating macrophages [23]. All of these factors have in common to reflect alterations of the micro-environment subsequent to the tumour invasion. ...
... Possible effects of VEGF on the BBB are fenestration of the endothelium and disruption of the tight junctions between endothelial cells [23,24]. Other factors are suspected to promote the development of vasogenic oedema such as expression of aquaporin-4 (AQP4) [22,24], increased levels of leukotriene C4 in tumour tissues [23], or secretion products of infiltrating macrophages [23]. All of these factors have in common to reflect alterations of the micro-environment subsequent to the tumour invasion. ...
Gliomas are the most common primary brain tumours and are associated with poor prognosis. Among them, diffuse gliomas – which include their most aggressive form glioblastoma (GBM) – are known to be highly infiltrative. The diagnosis and follow-up of gliomas rely on positron emission tomography (PET) and magnetic resonance imaging (MRI). However, these imaging techniques do not currently allow to assess the whole extent of such infiltrative tumours nor to anticipate their preferred invasion patterns, leading to sub-optimal treatment planning. Mathematical tumour growth modelling has been proposed to address this problem. Reaction-diffusion tumour growth models, which are probably the most commonly used for diffuse gliomas growth modelling, propose to capture the proliferation and migration of glioma cells by means of a partial differential equation. Although the potential of such models has been shown in many works for patient follow-up and therapy planning, only few limited clinical applications have seemed to emerge from these works.
This thesis aims at revisiting reaction-diffusion tumour growth models using state-of-the-art medical imaging and data processing technologies, with the objective of integrating multi-parametric PET/MRI data to further personalise the model. Brain tissue segmentation on MR images is first addressed with the aim of defining a patient-specific domain to solve the model. A previously proposed method to derive a tumour cell diffusion tensor from the water diffusion tensor assessed by diffusion-tensor imaging (DTI) is then implemented to guide the anisotropic migration of tumour cells along white matter tracts. The use of dynamic [S-methyl-11C]methionine ([11C]MET) PET is also investigated to derive patient-specific proliferation potential maps for the model. These investigations lead to the development of a microscopic compartmental model for amino acid PET tracer transport in gliomas. Based on the compartmental model results, a novel methodology is proposed to extract parametric maps from dynamic [11C]MET PET data using principal component analysis (PCA). The problem of estimating the initial conditions of the model from MR images is then addressed by means of a translational MRI/histology study in a case of non-operated GBM. Numerical solving strategies based on the widely used finite difference and finite element methods are finally implemented and compared.
All these developments are embedded within a common framework allowing to study glioma growth in silico and providing a solid basis for further research in this field. However, commonly accepted hypothesis relating the outlines of abnormalities visible on MRI to tumour cell density iso-contours have been invalidated by the translational study carried out, leaving opened the questions of the initialisation and the validation of the model. Furthermore, the analysis of the temporal evolution of real multi-treated glioma patients demonstrates the limitations of the formulated model. These latter statements highlight current obstacles to the clinical application of reaction-diffusion tumour growth models and pave the way to further improvements.
... 23 First, vasogenic edema is most commonly associated with tumors in the brain due to the hyperpermeable cerebral vasculatures. 24 As a result, solutes and osmolytes from serum leak into the brain parenchyma, which secondarily draws fluids into the same area, resulting in cerebral edema, mass effect, or both. 24 The downstream neuronal dysfunctions include localized seizure, vascular compression, weakness, language impairment, and/or vision loss as well as generalized multifocal seizures, syndrome of inappropriate secretion of antidiuretic hormone, neurocognitive deficits involving multiple cognitive domains, or a combination of these deficits. ...
... 24 As a result, solutes and osmolytes from serum leak into the brain parenchyma, which secondarily draws fluids into the same area, resulting in cerebral edema, mass effect, or both. 24 The downstream neuronal dysfunctions include localized seizure, vascular compression, weakness, language impairment, and/or vision loss as well as generalized multifocal seizures, syndrome of inappropriate secretion of antidiuretic hormone, neurocognitive deficits involving multiple cognitive domains, or a combination of these deficits. Second, cytotoxic edema is a disorder of bioenergetics, and this is associated with loss of ATPase function resulting in cellular edema due to inability of the cell to maintain electrolyte balance; 25 cellular swelling is the principal consequence. ...
Tumor treating fields (TTFields) are nonionizing alternating electric fields that have anticancer properties. After the initial approval for use in patients with recurrent glioblastoma in 2011 and newly diagnosed glioblastomas in 2015, they are now being tested in those with advanced lung cancer, ovarian carcinoma, and pancreatic cancer. Unlike ionizing radiation therapy, TTFields have nonlinear propagation characteristics; therefore, it is difficult for clinicians to recognize intuitively the location where these fields have the most impact. However, finite element analysis offers a means of delineating TTFields in the human body. Our analyses in the brain, pelvis, and thorax revealed that cerebrospinal fluid, edema, urine, ascites, pleural fluid, and necrotic core within a tumor greatly influence their distribution within these body cavities. Our observations thus provided a unified framework on the role of these compartmentalized fluids in influencing the propagation of TTFields.
... Brain edema is defined as an expansion of the brain volume due to increased water and sodium content [9]. Though the exact mechanism involved in the development of PTBE is not clearly understood, there are several factors directly included in PTBE pathophysiology such as tumor size, localization, histological grade, venous thrombosis, vascularization, gender, hormone receptor expression, growth factor expression, and microcortical invasion [10,11]. ...
... Meningiomas account for 14-19% of all primary intracranial tumors in adults, occur most commonly in females, and are the most common tumors of the sphenoid wing region [9,12]. In this study, most of the patients (41.5%) were in the age category of 50-69 years which correlated with other studies [13]. ...
Sphenoidal meningiomas constitute 18% of intracranial masses, and still present a difficult surgical challenge. PTBE has been associated with several complications and future recurrence. This study aims to evaluate the outcome of the operatively treated sphenoid wing meningiomas in relation to PTBE as a prognostic factor in a series of 65 patients. The clinical materials of 65 patients with SWM treated microsurgically between 2007 and 2020 were analyzed retrospectively. Follow-up ranged from 6 to 156 months (median, 86). Clinical outcomes include postoperative major neurological deficit, quality of life using KPS, recurrence, and mortality rates. The mean age of patients was 53.9 years (range 20–74), males 24.6% and females75.4%. An edema index (EI) of 1 (40%) was considered as absent edema, and EI > 1 (60%) indicated present edema. Total resection (Simpson I–II) was achieved in 64.6% and subtotal (Simpson IV) in 13.8%. Postoperative complications included vision impairment in 3 patients, motor weakness 6, third nerve palsy 6, intraoperative bleeding and edema 5, and MCA infarct 2, recurrence in 17% and 7.7% died. In univariate analysis, we found that the PTBE is one of the serious risk factors in the immediate surgical outcomes and complication, though more data is needed to support this claim, while having a negative effect on postoperative KPS at short-term follow up (χ² = 6.44, p = 0.011). PTBE was associated with decline in KPS and quality of life in the early postoperative period (three months) while showing no significant effect at long-term outcomes.
... Antaño nos enseñaron a clasifi car patologías específi cas a algún tipo de edema (por ejemplo, isquemia cerebral aguda con edema citotóxico), hoy en día es un error suponer que no puedan coexistir dos o más tipos de edema en cualquier patología cerebral. 15 La BHE es parte fundamental en el tejido nervioso, ya que es un fi ltro para moléculas tóxicas y permeable a sustancias Lesión temporal derecha (reforzamiento con medio de contraste). ...
... 32 Una gran variedad de esteroides sintéticos se encuentran disponibles para su uso terapéutico, en comparación con el cortisol, se caracterizan por diferentes propiedades farmacodinámicas y farmacocinéticas. 15,33 A pesar del uso generalizado de la dexametasona para el manejo del edema cerebral peritumoral, no existe acuerdo respecto a la dosis, tiempo de tratamiento y esquema de reducción. 34 La administración de 4 mg/día de dexametasona para el tratamiento del edema cerebral peritumoral tiene el mismo grado de mejoría (evaluado por Karnofsky) que la administración de 16 mg/día después de una semana de tratamiento en pacientes sin signos de herniación inminente. ...
Steroids have been used since 1960, and even though they are associated with potential side effects, they play a decisive role in treating cerebral edema associated with primary or secondary brain tumors. On the other hand, steroids play a very important role within the initial management, considering that most tumors trigger vasogenic edema. We present the case of a 48-year-old woman with deviation of the labial commissure, left hemicorporal hemiparesis and somnolence secondary to a right temporal tumor; she was treated with dexamethasone 8 mg intravenously every eight hours, with the improvement of signs and symptoms (reversal of left fasciocorporal hemiparesis and improvement of the state of consciousness). Due to its pharmacological properties, dexamethasone is considered the steroid of choice for the treatment of peritumoral cerebral edema; it has a minimal mineralocorticoid effect, high potency and a longer half-life than the rest, although any other steroid could be effective if administered in equivalent doses. Currently, the dose, treatment time and ideal reduction scheme regarding the use of dexamethasone in the patient with cerebral peritumoral edema have not been defined, and the recommendations found are very different.
... Mannitol and hyperosmotic saline increase intravascular colloid osmotic pressure, leading to the withdrawal of water from the brain tissue. The intravenous administration of these agents can effectively alleviate brain pressure within minutes to half an hour [1,67]. However, it is essential to note that osmotherapy is intended for emergency situations and that its effects are temporary, lasting only a few hours [1,23]. ...
Treating malignant glioma is challenging owing to its highly invasive potential in healthy brain tissue and the formation of intense surrounding edema. Peritumoral edema in gliomas can lead to severe symptoms including neurological dysfunction and brain herniation. For the past 50 years, the standard treatment for peritumoral edema has been steroid therapy. However, the discovery of cerebral lymphatic vessels a decade ago prompted a re-evaluation of the mechanisms involved in brain fluid regulation and the formation of cerebral edema. This review aimed to describe the clinical features of peritumoral edema in gliomas. The mechanisms currently known to cause glioma-related edema are summarized, the limitations in current cerebral edema therapies are discussed, and the prospects for future cerebral edema therapies are presented. Further research concerning edema surrounding gliomas is needed to enhance patient prognosis and improve treatment efficacy.
... It cannot be denied that the vasogenic component is the major player in the progression of HGGs. In most cases, disruption of the blood-brain barrier and increased vascular permeability are responsible for the described fluid accumulation (38). This results in impaired oxygen transport, which increases the symptoms elicited by the edema (39). ...
Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced neurodegeneration has been identified as glutamate. Glutamate promotes cell growth and proliferation in variety of tumor types. Intriguently, glutamate is also an excitatory neurotransmitter and evokes neuronal cell death at high concentrations. Even though glutamate signaling at the receptor and its downstream effectors has been extensively investigated at the molecular level, there has been little insight into how glutamate enters the tumor microenvironment and impacts on metabolic equilibration until recently. Surprisingly, the 12 transmembrane spanning tranporter xCT (SLC7A11) appeared to be a major player in this process, mediating glutamate secretion and ferroptosis. Also, PPARγ is associated with ferroptosis in neurodegeneration, thereby destroying neurons and causing brain swelling. Although these data are intriguing, tumor-associated edema has so far been quoted as of vasogenic origin. Hence, glutamate and PPARγ biology in the process of glioma-induced brain swelling is conceptually challenging. By inhibiting xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated. This review sheds light on the role of glutamate in brain tumors presenting the conceptual challenge that xCT disruption causes ferroptosis activation in malignant brain tumors. Thus, interfering with glutamate takes center stage in forming the basis of a metabolic equilibration approach.
... Psychological support is also included in palliative care as it addresses the symptoms like depression, especially at the end-of-life stage. 22. A 63-year-old male patient is seen for grade 2 meningioma and he has been using high-dose corticosteroids (dexamethasone) for the past 6 months. ...
Palliative care via multidisciplinary programs is used to focus on patients’ necessities and assist in reducing their burden by providing the best available support to the patient. Palliative care is an important aspect of dealing with patients suffering from incurable tumors with poor prognoses. Though certain issues that neuro-oncology patients face at the end of life are similar to numerous other cancer forms, there is a subset of challenging complications that are distinctive to neuro-oncology patients. The end-of-life stage for Neuro-Oncology patients tends to have an unusual route than the overall cancer patients. Thus, continuous re-evaluation of the patient’s needs is important since the patient’s needs may change with the progression of the disease. This chapter on palliative care aims to test the knowledge of the reader on the subject with the help of 33 questions.
Keywords: Palliative treatment, Palliative care, Palliative surgery, Steroids, Anticonvulsants
... Radiation necrosis and edema are closely associated. Indeed, researchers have determined that the greater the edema surrounding the lesion, as observed with magnetic resonance imaging (MRI), the greater the positive predictive value that the observed changes are due to radiation necrosis [3,4]. ...
Introduction
Radiosurgery is a treatment in which a high dose of ionizing radiation is administered to a small field with high-precision techniques, and is a common treatment for tumors and other diagnoses. A typical complication is the development of radiation-induced edema that can progress to radiation necrosis in some cases. The administration of corticosteroids has been used empirically as a prophylaxis in patients who will be treated by stereotactic radiosurgery with intracranial tumors and other pathologies with the intention to prevent radiation-induced edema and or necrosis.
Objective
The aim of our study is to describe the actual use of corticosteroids in hospitals that perform stereotactic radiosurgery treatments in Latin America and Spain through a survey applied to neurosurgeons and radiation oncologists and expose the implications of the results, as well as to analyze the available literature on it.
Methods
We designed a questionnaire of 15 items related to the use of corticosteroids as prophylaxis in patients who will be treated with radiosurgery. The questionnaire was answered by 121 Ibero-Latin Americans through Google Drive considering a database from the Iberolatinoamerican Radiosurgery Association.
Results
We found that the preference for the use of corticosteroids as prophylaxis for radiosurgery is associated with informal training in radiosurgery, and it was more used by radiation oncologists compared to neurosurgeons (p=0.023). Side effects can exceed the benefit of its use.
Conclusions
There is practically no literature on the use of corticosteroids as prophylaxis for radiation necrosis in stereotactic radiosurgery. This is a controversial inter- and intra-specialty issue, and its empirical use has a relatively high prevalence, making us reconsider the value of experience in a medical environment that should be fundamentally guided by evidence-based medicine.
... Synthetic corticoste roids that were administered in this study included methylprednisolone (SoluMedrol) or dexamethasone (Decadron). While dexamethasone is widely used in neurosurgical practice (e.g., in the management of edema in brain tumors 16 ), its use in the management of acute traumatic SCI is not well supported based on the current level of evidence. A recent AO Spine survey, however, found that 32.2% (n = 82) of spine care professionals who administer steroids to patients with acute SCIs (n = 255) would choose Dexamethasone. ...
Immunomodulatory therapeutics represent a potential neuroprotective strategy for the management of acute spinal cord injury (SCI). One of the most intensely debated neuroprotective drugs has been methylprednisolone sodium succinate (MPSS). MPSS was initially investigated for its role in mitigating lipid peroxidation. More recently, the anti-inflammatory/immunomodulatory properties of MPSS have been increasingly appreciated. Over the past two decades, several systematic reviews and clinical practice guidelines related to MPSS use in SCI have been published. The goal of this study was to investigate the temporal changes in the use of steroids at North American Clinical Trials Network (NACTN) centers and to correlate these with the evolution in published literature and guidelines. Data on patients enrolled from 2008 - 2018 in the prospective, multicenter NACTN registry, and in whom information related to the use of steroids was available, were analyzed. Patients were stratified as to whether they received steroids or not. The primary outcome was the change in the rate of steroid use per year between 2008 and 2018. Secondary outcomes included cardiac, gastrointestinal & genitourinary (GIGU), pulmonary and dermatologic complications. We identified 608 patients, of whom 171 (28.1%) were given steroids. In 2008 and 2009, the prevailing paradigm across NACTN centers was in favor of steroid administration and as such 70% (n=56) of patients received steroids in 2008 and 71.9% (n=46) in 2009. An abrupt practice reversal was observed in 2010, whereby only 19.7% of patients (n=14) received steroids, a trend that continued over subsequent years. Increasing literature in the 2000s arguing against the use of steroids culminated in the 2013 CNS/AANS practice guidelines for the management of acute SCI. These guidelines recommended against the use of MPSS for the treatment of acute SCI. Over the following years (2013-2018), steroids continued to be an uncommonly used therapeutic option in NACTN centers (range 3.9-16.9%). Patients receiving steroids had significantly higher rates of pulmonary complications (87%, n=147) compared to those not receiving steroids (73%, n=265; p=0.0003). However, compared to patients receiving steroids, those who did not receive steroids had significantly higher rates of cardiac (40%, [n=146] versus 23%, [n=39]; p=0.0001) and gastrointestinal/genitourinary complications (55%, [n=189], versus 31%, [n=52]; p<0.0001). The 2013 AANS/CNS guidelines and preceding literature appeared to have an impact on dramatically lowering the rates of corticosteroid use for acute SCI in NACTN sites after 2009. Of note, this analysis may not reflect the impact of the 2017 AO Spine Clinical Practice guidelines, which suggested the use of methylprednisolone as a valid practice option for acute SCI, especially for cervical injuries. Enhanced patient involvement in the clinical decision-making process and opportunities to personalize SCI management exist in reference to the use of MPSS in acute SCI.
... Glucocorticoids are commonly used to treat inflammation for a myriad of diseases; in glioma patients, synthetic glucocorticoids such as dexamethasone (DEX) are used to treat swelling of the brain [5]. Despite their benefits, exogenous glucocorticoids like DEX give rise to highly variable responses among people, and patients may experience adverse events. ...
Background
Identifying blood-based DNA methylation patterns is a minimally invasive way to detect biomarkers in predicting age, characteristics of certain diseases and conditions, as well as responses to immunotherapies. As microarray platforms continue to evolve and increase the scope of CpGs measured, new discoveries based on the most recent platform version and how they compare to available data from the previous versions of the platform are unknown. The neutrophil dexamethasone methylation index (NDMI 850) is a blood-based DNA methylation biomarker built on the Illumina MethylationEPIC (850K) array that measures epigenetic responses to dexamethasone (DEX), a synthetic glucocorticoid often administered for inflammation. Here, we compare the NDMI 850 to one we built using data from the Illumina Methylation 450K (NDMI 450).
Results
The NDMI 450 consisted of 22 loci, 15 of which were present on the NDMI 850. In adult whole blood samples, the linear composite scores from NDMI 450 and NDMI 850 were highly correlated and had equivalent predictive accuracy for detecting DEX exposure among adult glioma patients and non-glioma adult controls. However, the NDMI 450 scores of newborn cord blood were significantly lower than NDMI 850 in samples measured with both assays.
Conclusions
We developed an algorithm that reproduces the DNA methylation glucocorticoid response score using 450K data, increasing the accessibility for researchers to assess this biomarker in archived or publicly available datasets that use the 450K version of the Illumina BeadChip array. However, the NDMI850 and NDMI450 do not give similar results in cord blood, and due to data availability limitations, results from sample types of newborn cord blood should be interpreted with care.
... P < 0.05), we can find that TTFields treatment with the dose of dexamethasone ≤ 4.1 mg has a longer OS than the group with the dose of dexamethasone > 4.1 mg. As we all know, dexamethasone, a kind of synthetic corticosteroids, is routinely administered to patients with intracranial tumors to alleviate the cerebral edema and provide symptomatic relief [36]. It is also the first-line agents to combat immune-related adverse events [37]. ...
TTFields is a novel treating modality of glioblastoma (GBM) which can significantly prolong the overall survival (OS) of newly diagnosed or recurrent glioblastoma. Some researchers have revealed that a variety of factors can affect the efficacy of TTFields. So, we review the available literature about the influencing factors on efficacy of TTFields and then choose two experimentally supported factors: the dose of dexamethasone and compliance of TTFields to perform a meta-analysis. The PubMed, Embase, and the Cochrane Library are searched. Five articles are identified between 2014 and 2017. Three articles are about the compliance of TTFields. Two articles are about the dose of dexamethasone. The Newcastle-Ottawa Quality Assessment Scale (NOS) is used as an assessment tool to evaluate the methodological quality of all included trials. The scale’s range varies from 0 to 9 stars. According to the Cochrane Handbook for Systematic Reviews of Interventions, articles are graded in six items to evaluate the risk of bias. Two reviewers rate the studies independently and the final decision is reached by consensus.
Our data shows that the median OS is conspicuously longer in the TTFields group in which the dose of dexamethasone is ≤ 4.1 mg, WMD = 9.23 [95% CI 5.69–12.78]; P < 0.05). And the patients whose compliance of TTFields treatment ≥ 75% (≥ 18 h per day) have a significant lower overall survival risk than the patients whose compliance of TTFields treatment < 75% (HR = 0.57 [95% CI 0.46–0.70]; P < 0.00001).TTFields is a safe and efficient novel treatment modality. The dose of dexamethasone ≤ 4.1 mg of TTFields treatment and the compliance of TTFields treatment ≥ 75%, ≥ 18 h per day are beneficial to the prognosis of the glioblastoma patients.
... Immunosuppressive activity is the basis for the use of glucocorticosteroids to abolish immune reactions after tissue and organ transplants [141]. An absolute indication for immediate glucocorticosteroid therapy is life-threatening disease, e.g., anaphylactic shock [142] and edema of the brain [143]. ...
Interest in the use of mesoporous materials as carriers of medicinal substances has been steadily increasing in the last two decades. Mesoporous carriers have application in the preparation of delivery systems for drugs from various therapeutic groups; however, their use as the carriers of anti-inflammatory agents is particularly marked. This review article, with about 170 references, summarizes the achievements in the application of mesoporous materials as the carriers of anti-inflammatory agents in recent years. This article will discuss a variety of mesoporous carriers as well as the characteristics of their porous structure that determine further use of these materials in the field of medical applications. Special attention will be paid to the progress observed in the construction of stimuli-responsive drug carriers and systems providing site-specific drug delivery. Subsequently, a review of the literature devoted to the use of mesoporous matrices as the carriers of anti-inflammatory drugs was carried out.
... Patients receiving corticosteroids in the palliative care setting, especially those with metastatic cancer, can have specific indications such as brain metastases, bone metastases, or spinal cord compression as well as non-specific indications such as fatigue, anorexia, or nausea [5][6][7][8][9][10]. The strength of evidence for each indication varies, but the specific cancer-related indications are better supported than the non-specific indications [11][12][13][14][15][16][17][18]. The anti-inflammatory effect of corticosteroids and their potential as analgesics is well-reported [7,18]. ...
Purpose
Dexamethasone is a commonly prescribed corticosteroid by both palliative care physicians and radiation oncologists for the treatment of metastatic cancer pain. However, clinical evidence for dexamethasone dose and efficacy is lacking, and prescribing between these different specialties may be influenced by other factors. This study investigates the dexamethasone prescriptions of palliative care physicians and radiation oncologists for cancer pain and their prescription rationales.
Methods
Palliative care physicians and radiation oncologists in British Columbia, Canada, were surveyed on their preferred dexamethasone prescription in response to 4 case vignettes of patients with metastatic cancer and asked to choose a rationale from a list of options which were then categorized as “habit-based,” “results-based,” or “evidence-based.” Response frequencies between the specialties were compared with odds ratios.
Results
The total daily dose and duration of dexamethasone prescriptions were similar between the specialties. Palliative care physicians were significantly more likely than radiation oncologists to prescribe a single daily dose of dexamethasone rather than a divided dose (OR 3.3 [95% CI 2.0–5.5]). This significant difference persisted when separately analyzing results at different total daily doses. Both specialties were more likely to select habit-based rationales rather than evidence-based rationales, with no significant difference between specialties.
Conclusion
These findings show that dexamethasone prescriptions are habit-based and that prescribing habits are different between palliative care physicians and radiation oncologists. Interventions based on these findings could potentially prevent unequal patient care. Further qualitative investigations of physician perceptions are indicated to better understand habit-based corticosteroid prescribing patterns.
... In preoperative treatment planning, the CTV will be defined as tumor plus peripheral edema because the edema is thought to harbor microscopic disease [24]. On the other hand, in post-operative verification, the newly enlarged edematous area is thought to be caused by surgical operation and implanted seeds [25], so it should not be included in the target volume. MR imaging is more accurate than CT imaging in identifying the boundary between tumor and edema [26,27] and MR-based fusion images are more suitable for TPS. ...
Purpose:
To calculate and evaluate postimplant dosimetry (PID) with CT-MR fusion technique after brain tumor brachytherapy and compare the result with CT-based PID.
Methods and materials:
16 brain tumor patients received MR-guided intervention with Iodine-125 (125I) seed implantation entered this preliminary study for PID evaluation. Registration and fusion of CT and MR images of the same patients were performed one day after operation. Seeds identification and targets delineation were carried out on CT, MR, and CT-MR fusion images, each. The number and location of seeds on MR or CT- MR fusion images were compared with those of actually implanted seeds. Clinical target volume (CTV) and dosimetric parameters such as %D90, %V100 and external V100 were measured and calculated. In addition, the correlation of the fusion to CT CTV ratio and other factors were analyzed.
Results:
The numbers of fusion seeds were not significantly different compared with reference seeds (t =1.76, p >0.05). The difference between reference seeds numbers and truly extracted MR seeds numbers was statistically significant (t =3.91, p <0.05). All dosimetric parameters showed significant differences between the two techniques (p <0.05). The mean CTV delineated on fusion images was 34.3 ± 33.6, smaller than that on CT images. The mean values of external V100, %V100 and %D90 on fusion images were larger than those on CT images. Correlation analysis showed that the fusion-CT V100 ratio was positively and significantly correlated with the fusion-CT volume ratio.
Conclusions:
This preliminary study indicated that CT-MR fusion-based PID exhibited good accuracy for 125I brain tumor brachytherapy dosimetry when compared to CT-based PID and merits further research to establish best-outcome protocols.
... However, these features were enriched for biological processes in immune response and apoptosis from spatial immunoprofiling while the abundance and phenotype of tumor infiltration lymphocytes are closely linked with clinical survival [8,27]. That reflected the regulation of gene expression such as autophagy gene in necrosis [28], vascular endothelial growth factor gene in peritumoral tissue [29], and angiogenesis gene in edema [30,31] with pathological and molecular features of GBM [32]. Moreover, aquaporin 4 (AQP4) contributes to extended tumor cell migration, possibly passing through increasing water permeability and implication of AQP4 in tumor edema [33,34]. ...
Simple Summary
Glioblastomas carry a poor prognosis and usually presents with heterogeneous regions in the brain tumor. Multi-parametric MR images can show morphological characteristics. Radiomics features refer to the extraction of a large number of quantitative measurements that describe the geometry, intensity, and texture which were extracted from contrast-enhanced T1-weighted images from anatomical MRI and metabolic features from PET. It also provides a qualitative image interpretation as well as cellular, molecular, and tumor properties. Thus, it derives additional information about the entire tumor volume which is generally of irregular shape and size from routinely evaluated “non-invasive” imaging biomarkers techniques. We demonstrated volumetric habitats and signatures in necrosis, solid tumor, peritumoral tissue, and edema with key biological processes and phenotype features. This provides physicians with key information on how the disease is progressing in the brain and can also give an indication of how well treatment is working.
Abstract
Glioblastoma (GBM) is a fast-growing and aggressive brain tumor of the central nervous system. It encroaches on brain tissue with heterogeneous regions of a necrotic core, solid part, peritumoral tissue, and edema. This study provided qualitative image interpretation in GBM subregions and radiomics features in quantitative usage of image analysis, as well as ratios of these tumor components. The aim of this study was to assess the potential of multi-parametric MR fingerprinting with volumetric tumor phenotype and radiomic features to underlie biological process and prognostic status of patients with cerebral gliomas. Based on efficiently classified and retrieved cerebral multi-parametric MRI, all data were analyzed to derive volume-based data of the entire tumor from local cohorts and The Cancer Imaging Archive (TCIA) cohorts with GBM. Edema was mainly enriched for homeostasis whereas necrosis was associated with texture features. The proportional volume size of the edema was about 1.5 times larger than the size of the solid part tumor. The volume size of the solid part was approximately 0.7 times in the necrosis area. Therefore, the multi-parametric MRI-based radiomics model reveals efficiently classified tumor subregions of GBM and suggests that prognostic radiomic features from routine MRI examination may also be significantly associated with key biological processes as a practical imaging biomarker.
... Additionally, the use of glucocorticoids for other extraparenchymal lesions is well established. So, there is scientific consensus regarding the beneficial role of the latter in meningiomas [8][9][10][11], as it helps reduce the volume of the edema due to unknown mechanisms. Furthermore, in chronic subdural hematomas, where there is no apparent damage to the brain parenchyma, glucocorticoids are effective in low doses for a short period [12][13][14]. ...
Background:
The use of glucocorticoids in trauma patients with parenchymal damage is deemed unnecessary and is not advocated. Notwithstanding, acute epidural hematomas (aEH) are extra-parenchymal lesions, so the patients could benefit from the use of glucocorticoids.
Methodology/results:
97 patients with acute epidural hematoma were separated into two groups, whether they received glucocorticoid treatment or not. Depending on the severity of the deficit and their clinical status, some of the patients were operated on and others not. The patients who received glucocorticoids had better neurological status upon discharge, while their hospitalization was shorter.
Conclusions:
The surgical management of the acute epidural hematomas in combination with glucocorticoid treatment had the best outcome in our protocol.
... First, in this study, we have not provided other neurological developments which may occur in the vicinity of tumour, as it grows physically. These neurological developments may include the development of cerebral oedema [48] or general disturbances in blood-brain barrier. This factor would be the next focus in our future studies pertaining to brain tumour. ...
Brain is an actuator for control and coordination. When a pathology arises in cranium, it may leave a degenerative, disfiguring and destabilizing impact on brain physiology. However, the leading consequences of the same may vary from case to case. Tumour, in this context, is a special type of pathology which deforms brain parenchyma permanently. From translational perspective, deformation mechanics and pressures, specifically the intracranial cerebral pressure (ICP) in a tumour-housed brain, have not been addressed holistically in literature. This is an important area to investigate in neuropathy prognosis. To address this, we aim to solve the pressure mystery in a tumour-based brain in this study and present a fairly workable methodology. Using image-based finite-element modelling, we reconstruct a tumour-based brain and probe resulting deformations and pressures (ICP). Tumour is grown by dilating the voxel region by 16 and 30 mm uniformly. Cumulatively three cases are studied including an existing stage of the tumour. Pressures of cerebrospinal fluid due to its flow inside the ventricle region are also provided to make the model anatomically realistic. Comparison of obtained results unequivocally shows that as the tumour region increases its area and size, deformation pattern changes extensively and spreads throughout the brain volume with a greater concentration in tumour vicinity. Second, we conclude that ICP pressures inside the cranium do increase substantially; however, they still remain under the normal values (15 mmHg). In the end, a correlation relationship of ICP mechanics and tumour is addressed. From a diagnostic purpose, this result also explains why generally a tumour in its initial stage does not show symptoms because the required ICP threshold has not been crossed. We finally conclude that even at low ICP values, substantial deformation progression inside the cranium is possible. This may result in plastic deformation, midline shift etc. in the brain.
... Based on the biophysical model, the increase in VF iso may reflect the severity of vasogenic edema. Similarly, the decrease in VF ic (neurite density index) may reflect focal neurologic deficits (neuron injury or axonal loss) and could also refer to the cognitive function decline (Kaal and Vecht, 2004;Parker et al., 2018). The edematous fiber tracts that only existed in DTI-derived tractography (D-only condition) found significant differences in the comparison between patients with and without motor function decline. ...
Diffusion Tensor Imaging (DTI) tractography has been widely used in brain tumor surgery to ensure thorough resection and minimize functional damage. However, due to enhanced anisotropic uncertainty in the area with peritumoral edema, diffusion tractography is generally not practicable leading to high false-negative results in neural tracking. In this study, we evaluated the usefulness of the neurite orientation dispersion and density imaging (NODDI) derived tractography for investigating structural heterogeneity of the brain in patients with brain tumor. A total of 24 patients with brain tumors, characterized by peritumoral edema, and 10 healthy counterparts were recruited from 2014 to 2021. All participants underwent magnetic resonance imaging. Moreover, we used the images obtained from the healthy participants for calibrating the orientation dispersion threshold for NODDI-derived corticospinal tract (CST) reconstruction. Compared to DTI, NODDI-derived tractography has a great potential to improve the reconstruction of fiber tracking through regions of vasogenic edema. The regions with edematous CST in NODDI-derived tractography demonstrated a significant decrease in the intracellular volume fraction (VFic, p < 0.000) and an increase in the isotropic volume fraction (VFiso, p < 0.014). Notably, the percentage of the involved volume of the concealed CST and lesion-to-tract distance could reflect the motor function of the patients. After the tumor resection, four patients with 1–5 years follow-up were showed subsidence of the vasogenic edema and normal CST on DTI tractography. NODDI-derived tractography revealed tracts within the edematous area and could assist neurosurgeons to locate the neural tracts that are otherwise not visualized by conventional DTI tractography.
... Drug repositioning/repurposing is a strategy for identifying new uses for alreadyapproved drugs and is effective in reducing the time and cost associated with the processes of drug development. Dexamethasone is currently used in cancer patients as an antiemetic [12,13], to prevent hypersensitivity [33], and to treat cerebral edema [34] and malignant bowel obstruction [35]. As the safety profile of dexamethasone is well-established in cancer patients, it may also be repurposed and used effectively as a chemo-sensitizing agent. ...
Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.
... Therefore, loss of GPD1 could result in impairment of GSC maintenance pathways in GBM, prolonging patient survival. Furthermore, it is better to shed light on the crosstalk between GPD1 and edema in GBM, as edema occurs in patients suffering from human GBM (103). ...
Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.
... The typical, vasogenic mechanism of BTRE is related to the disruption of the BBB, in particular disturbed TJs expression and functioning, as well as the enhanced endothelial fenestrations [201], which allow leakage of fluids from the blood into the brain parenchyma [202]. In the formation of edema, VEGF-induced dysfunction of TJ proteins may play an important role [203]. ...
Angiogenesis, a complex, multistep process of forming new blood vessels, plays crucial role in normal development, embryogenesis, and wound healing. Malignant tumors characterized by increased proliferation also require new vasculature to provide an adequate supply of oxygen and nutrients for developing tumor. Gliomas are among the most frequent primary tumors of the central nervous system (CNS), characterized by increased new vessel formation. The processes of neoangiogenesis, necessary for glioma development, are mediated by numerous growth factors, cytokines, chemokines and other proteins. In contrast to other solid tumors, some biological conditions, such as the blood–brain barrier and the unique interplay between immune microenvironment and tumor, represent significant challenges in glioma therapy. Therefore, the objective of the study was to present the role of various proangiogenic factors in glioma angiogenesis as well as the differences between normal and tumoral angiogenesis. Another goal was to present novel therapeutic options in oncology approaches. We performed a thorough search via the PubMed database. In this paper we describe various proangiogenic factors in glioma vasculature development. The presented paper also reviews various antiangiogenic factors necessary in maintaining equilibrium between pro- and antiangiogenic processes. Furthermore, we present some novel possibilities of antiangiogenic therapy in this type of tumors.
... Initially, the influence of seeding densities and cell ratios on BBB spheroid sizes and compound diffusivity was evaluated in our work to establish an improved and reliable BBB model. Additionally, the penetration enhancer mannitol, which is applied in, e.g., glioblastoma patients inducing the opening of endothelial tight junctions to allow the passage of chemotherapeutics that normally cannot enter the parenchyma, [74,75] was used to demonstrate spheroid sizedependent paracellular transport kinetics. The results indicated significant differences in larger and smaller spheroids independent of the employed cell ratios during mannitol treatment. ...
Physiological‐relevant in vitro tissue models with their promise of better predictability have the potential to improve drug screening outcomes in preclinical studies. Despite the advances of spheroid models in pharmaceutical screening applications, variations in spheroid size and consequential altered cell responses often lead to nonreproducible and unpredictable results. Here, a microfluidic multisize spheroid array is established and characterized using liver, lung, colon, and skin cells as well as a triple‐culture model of the blood‐brain barrier (BBB) to assess the effects of spheroid size on (a) anticancer drug toxicity and (b) compound penetration across an advanced BBB model. The reproducible on‐chip generation of 360 spheroids of five dimensions on a well‐plate format using an integrated microlens technology is demonstrated. While spheroid size‐related IC50 values vary up to 160% using the anticancer drugs cisplatin (CIS) or doxorubicin (DOX), reduced CIS:DOX drug dose combinations eliminate all lung microtumors independent of their sizes. A further application includes optimizing cell seeding ratios and size‐dependent compound uptake studies in a perfused BBB model. Generally, smaller BBB‐spheroids reveal an 80% higher compound penetration than larger spheroids while verifying the BBB opening effect of mannitol and a spheroid size‐related modulation on paracellular transport properties.
... Corticosteroids, most commonly dexamethasone, are regularly administered to patients with intracranial tumors to combat cerebral edema and provide symptomatic relief [37]. Additionally, corticosteroids are used to treat patients who develop irAEs as a result of immunotherapy. ...
Background
Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.
Methods
Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.
Results
Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.
Conclusions
Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.
... 117,118 This logic would have been acceptable if this phenomenon was a major drawback for FDG as a useful tracer for this purpose. Over the years, the authors and other groups have demonstrated that brain tumors are associated with significant edema in the surrounding white matter, which can be readily visualized by MR. 83,119,120 Such edema frequently is associated with significant suppression of cortical uptake of FDG. Therefore, the validity of the argument by the proponents of non-FDG tracers in examining brain tumors is questionable. ...
The brain is a common site for metastases as well as primary tumors. Although evaluation of these malignancies with contrast-enhanced MR imaging defines current clinical practice, 18F-fluorodeoxyglucose (FDG)-PET has shown considerable utility in this area. In addition, many other tracers targeting various aspects of tumor biology have been developed and tested. This article discusses recent developments in PET imaging and the anticipated role of FDG and other tracers in the assessment of brain tumors.
... The brain constitutes approximately 80% of intracranial volume, and blood and CSF each account for 10% [49][50][51]. The first compensatory mechanism for maintenance of normal ICP involves displacement and reduction of the CSF compartment, reduction of CBF, and lastly, displacement of cerebral parenchyma causing herniation. ...
Intracranial pressure (ICP) can be analyzed for its absolute value, usually in mmHg or cmH2O, its tendency over time and the waveform of its pulse. This chapter will focus on the waveform of the ICP pulse (ICPwf), already observed since 1881, and for a long time not understood. Studies conducted in recent decades show the correlation between the ICPwf and intracranial compliance (ICC), another important clinical parameter added to the practice in the second half of the last century. ICC allows physicians early analyzing patients' neurological conditions related to disorders resulting from variations in cerebrospinal fluid (CSF), blood and intracranial tissue volumes. This chapter is an invitation to dive into the history and development of ICPwf analysis, clinical uses already adopted and others still u nder s t udy.
Introduction
The main mission of the Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG) is to develop and facilitate local access to the world's leading evidence‐based clinical trials for all paediatric cancers, including brain tumours, as soon as practically possible. Diffuse intrinsic pontine gliomas (DIPGs) — a subset of a larger group of tumours now termed diffuse midline glioma, H3K27‐altered (DMG) — are paediatric brain cancers with less than 10% survival at two years. In the absence of any proven curative therapies, significant recent advancements have been made in pre‐clinical and clinical research, leading many to seek integration of novel therapies early into standard practice. Despite these innovative therapeutic approaches, DIPG remains an incurable disease for which novel surgical, imaging, diagnostic, radiation and systemic therapy approaches are needed.
Main recommendations
All patients with DIPG should be discussed in multidisciplinary neuro‐oncology meetings (including pathologists, neuroradiologists, radiation oncologists, neurosurgeons, medical oncologists) at diagnosis and at relapse or progression.
Radiation therapy to the involved field remains the local and international standard of care treatment.
Proton therapy does not yield a superior survival outcome compared with photon therapy and patients should undergo radiation therapy with the available modality (photon or proton) at their treatment centre.
Patients may receive concurrent chemotherapy or radiation‐sensitising agents as part of a clinical trial.
Biopsy should be offered to facilitate consideration of experimental therapies and eligibility for clinical trial participation.
After radiation therapy, each patient should be managed individually with either observation or considered for enrolment on a clinical trial, if eligible, after full discussion with the family.
Re‐irradiation can be considered for progressive disease.
Changes in management as a result of the guideline
Every child diagnosed with DIPG should be offered enrolment on a clinical trial where available. Access to investigational drugs without biological rationale outside the clinical trial setting is not supported. In case of potentially actionable target identification with molecular profiling and absence of a suitable clinical trial, rational targeted therapies can be considered through compassionate access programs.
Neurological and Neurosurgical Emergencies addresses emergencies in all fields of neuroscience, including disciplines like Neurology, Neurosurgery, Neuroanaesthesia, and Neuroradiology. This volume covers neurosurgical emergencies, like hydrocephalus, brain edema, intracranial bleed, intracranial hematoma, infection, and trauma, alongside neurovascular emergencies like acute ischemic stroke, non-traumatic, aneurysmal subarachnoid hemorrhage, carotid cavernous fistula, and arteriovenous malformation.
Patients with neurologic symptoms are frequently seen in the emergency department and require rapid and thorough evaluation. Appropriate assessment with tailored history-taking, localization of the neurological problem, differential diagnosis, focused testing, and urgent treatment when indicated are essential to prevent patient morbidity. Neurological examination and testing of patients are covered in-depth, along with common neurological presentations using a symptom-based approach, such as coma, dizziness and gait disturbance. Specific neurological disorders are also explored, including traumatic brain injury, ischemic stroke and transient ischemic attack and neurotoxicology. Chapters follow a basic outline, including an introduction and a pearls and pitfalls section, providing a succinct overview and key takeaway points for the busy clinician. This well organized handbook will serve as a concise, valued reference for the clinician to use in assisting the evaluation of the most common neurology related emergency department visits.
OBJECTIVE
The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection.
LATEST DEVELOPMENTS
In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non–enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism.
ESSENTIAL POINTS
Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.
Dexamethasone, a long-acting potent glucocorticoid, is one of the most widely used medications in neurosurgery. In this paper, the authors recount the history of dexamethasone’s rise in neurosurgery and discuss its use in brain tumors in the context of emerging neuro-oncological immunotherapies. In 1958, Glen E. Arth synthesized a 16-alpha-methylated analog of cortisone (dexamethasone) for treatment of rheumatoid arthritis. Joseph Galicich, a neurosurgery resident at the time, applied the rheumatological drug to neurosurgery. He gave doses to patients who had undergone craniotomy for tumor removal and saw their paresis improve, midline shift resolve, and mortality rates decrease. He advocated for clinical trials and the drug became a mainstay in neurosurgery. As neuro-oncological treatments evolve to include immunotherapy, the immunosuppressive effects of dexamethasone are becoming an unwanted effect. The question then becomes: how does one treat the patient’s symptoms if the only drug that has been used throughout history may become a detriment to their oncological treatment? Since its discovery, dexamethasone has maintained an impressive staying power in the field, acting as a standard drug for cerebral edema for more than 60 years. However, with the advent of immunotherapy, research is warranted to evaluate ways of treating symptomatic edema in the context of modern neuro-oncological therapies.
Dexamethasone (DEXA) is a potent corticosteroid, commonly used for treating inflammatory, hypersensitive and allergic conditions. It is administered to birds with tumours. Many studies were conducted on its immunosuppressive effects; however none of the similar study is available employing chicken splenocytes culture system. The present study was conducted to assess DEXA induced alterations in inflammatory and oxidative stress biomarkers in chicken splenocytes due to its in vitro exposure. The maximum non-cytotoxic dose (MNCD) was evaluated and was further used for conducting lymphocytes proliferation assay (LPA), antioxidant assays (lipid peroxidation, GSH, superoxide dismutase and nitric oxide assays) and assessment of mRNA levels of various genes (IL-1β, IL-6, IL-10, LITAF, iNOS, NF-κB1, Nrf-2, Caspase-3 and -9) through qPCR. The MNCD was determined to be 30 ng/ml in chicken splenocytes culture system. DEXA caused reduction in B and T lymphocytes proliferation indicating its immunosuppressive effects, however improved the antioxidant status of the exposed splenocytes. The expression levels of IL-1β, IL-6, iNOS, LITAF and NF-κB1 were significantly reduced while IL-10 was enhanced, which signify potent anti-inflammatory potential of DEXA. NF-κB is a major transcription factor that regulates genes responsible for both, innate and adaptive immune responses and elicits inflammation. The nuclear factor erythroid 2-related factor 2 (Nrf-2) level was found to be up-regulated. Nrf-2 plays important role in combating the oxidant stress and its increased expression could be the reason of improved antioxidant status of DEXA exposed cells. Present findings indicated that DEXA exhibited modulation in anti-inflammatory, immunomodulatory and antioxidant mediators in chicken splenocytes.
Mannitol, derived from mannose sugar, is crucial in treating patients with elevated intracranial pressure (ICP). Its dehydrating properties at the cellular and tissue levels increase plasma osmotic pressure, which is studied for its potential to reduce ICP through osmotic diuresis. While clinical guidelines support mannitol use in these cases, the best approach for its application continues to be debated. Important aspects needing further investigation include: 1) bolus administration versus continuous infusion, 2) ICP-based dosing versus scheduled bolus, 3) identifying the optimal infusion rate, 4) determining the appropriate dosage, 5) establishing fluid replacement plans for urinary loss, and 6) selecting monitoring techniques and thresholds to assess effectiveness and ensure safety. Due to the lack of adequate high-quality prospective research data, a comprehensive review of recent studies and clinical trials is crucial. This assessment aims to bridge the knowledge gap, improve understanding of effective mannitol use in elevated ICP patients, and provide insights for future research. In conclusion, this review aspires to contribute to the ongoing discourse on mannitol application. By integrating the latest findings, this review will offer valuable insights into the function of mannitol in decreasing ICP, thereby informing better therapeutic approaches and enhancing patient outcomes.
Background:
Epilepsy is a prevalent comorbidity in patients with brain metastases (BM) and could result in sudden and accidental damage, as well as increased disease burden due to its rapid onset. Foreseeing the potential for the development of epilepsy may permit timely and efficient measures. This study aimed to analyze the influencing factors of epilepsy in advanced lung cancer (ALC) patients with BM and construct a nomogram model to predict the likelihood of developing epilepsy.
Methods:
Socio-demographic and clinical data of ALC patients with BM were retrospectively collected from the First Affiliated Hospital of Zhejiang University School of Medicine between September 2019 and June 2021. Univariate and multivariate logistic regression analyses were applied to determine the influencing factors for epilepsy in ALC patients with BM. Based on the results of the logistic regression analysis, a nomogram was built to represent the contribution of each influencing factor in predicting the probability of epilepsy development in ALC patients with BM. The Hosmer-Lemeshow test and receiver operating characteristic (ROC) curve were utilized to evaluate the goodness of fit and prediction performance of the model.
Results:
The incidence of epilepsy among 138 ALC patients with BM was 29.7%. On the multivariate analysis, having a higher number of supratentorial lesions (odds ratio [OR] = 1.727; p = 0.022), hemorrhagic foci (OR = 4.922; p = .021), and a high-grade of peritumoral edema (OR = 2.524; p < .001) were independent risk factors for developing epilepsy, while undergoing gamma knife radiosurgery (OR = .327; p = .019) was an independent protective factor. The p-value of the Hosmer-Lemeshow test was .535 and the area under the ROC curve (AUC) was .852 (95% CI: .807-.897), suggesting the model had a good fit and exhibited strong predictive accuracy.
Conclusion:
The nomogram was constructed that can predict the probability of epilepsy development for ALC patients with BM, which is helpful for healthcare professionals to identify high-risk groups early and allows for individualized interventions.
Glucocorticoids are commonly used in clinic but are also a double-edged sword. While treating tumors, they are reported to promote tumor growth and metastasis. To explore the role and elucidate the mechanism of dexamethasone in promoting tumor growth and metastasis, we detected the levels of cortisol and adrenocorticotropic hormone (ACTH) in peripheral blood of patients with gastric cancer, and immunohistochemical staining was used to detect the expression of GR and ROR1 in the surgically resected gastric cancer samples. The levels of cortisol and ACTH in peripheral blood of patients with stage III and IV gastric cancer were higher than those of patients with stage I/II gastric cancer. Dexamethasone up-regulated the ROR1 level on gastric cancer cell lines in a concentration-dependent manner. Gastric cancer specimen with high ROR1 had higher rates of relapse and metastasis than gastric adenocarcinomas expressing low levels of ROR1.Gastric cancer patients with high expression of ROR1 had a short survival time. ROR1 was expressed by gastric cancer cell lines, but not on normal gastric epithelial cell line. Suppressing ROR1 in gastric cancer cell lines impaired their invasion, migration, scratch healing and clone formation ability in vitro and slowed down the tumor growth of MKN-45 cells in immunodeficient mice in vivo. Collectively, our study indicated that dexamethasone up-regulated ROR1 levels on gastric cancer cells. ROR1 participated in and mediated the role of dexamethasone in promoting gastric tumor growth, and blocking ROR1 can prevent the tumor growth.
Care for Complications After Catastrophic Brain Injury
Purpose
The extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal.
Methods
A systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients.
Results
A total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B).
Conclusions
A growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity.
Purpose:
To investigate the consistency between preoperative and postoperative dosimetry when 125I brachytherapy for brain tumors is performed with magnetic resonance (MR) guidance and a three-dimensional non co-planar template (3DNPT).
Methods and materials:
Thirty patients with brain tumors (metastatic or gliomas) underwent radioactive 125I seed implantation. A preoperative treatment plan was determined with MR imaging, and the operation was done under 3DNPT assistance and MR guidance. The dosimetry was verified postoperatively based on postoperative CT-MR fusion images. Postoperative dosimetric parameters and implant quality indices were defined and compared with those in the preoperative treatment plan. Furthermore, a comparison of preoperative and postoperative doses to normal brain tissues and organs at risk was also performed.
Results:
All mean postoperative dosimetries were calculated. Target coverage parameters D90, D100, %CTV100, %CTV150, and %CTV200 were 143.6 cGy, 76.6 cGy, 88.2%, 63.1%, and 41.4%, respectively. The values of implant quality indices CI, EI, and HI were 0.75, 0.14, and 0.28, respectively. No significant differences between most preoperative and postoperative dosimetric parameters were found (p > 0.05). The differences were also insignificant for organs at risk. Postoperative %CTV150 and %CTV200 were higher than the preoperative, whereas postoperative HI was significantly lower than in the treatment plan.
Conclusions:
Magnetic resonance guidance combined with 3DNPT allows accurate positioning and direction in 125I brachytherapy for brain tumors. However, seed distribution and dose homogeneity require further improvement.
Patients with central nervous system (CNS) neoplasms are potentially subjected to develop many neurologic complications of their disease or its treatment. The central and peripheral nervous systems can be also significantly affected by systemic malignancies. These neuro-oncologic conditions are common and represent a significant cause of morbidity and hospital admission, not rarely at risk for serious, timely, and life-threatening events. Early diagnosis and timely treatment are required to ensure the best possible outcome, prolonging survival, and improving the quality of life; appropriate management may preserve neurologic function and may be life-saving. Neuroimaging evaluation represents a critical point in management of these patients, being helpful and often essential to define the diagnosis. Noncontrast head computed tomography (CT) is often the preferred imaging modality for the first examination of acute patients, due to speed and availability. Magnetic resonance imaging (MRI) is superior in identifying lesions and related features, characterizing them, and detecting the associated complications in order to obtain a more complete diagnosis. Central nervous system infections still have a great impact in terms of severity, affecting all age groups; they may represent a real medical emergency because of the consequent complications and fatal outcome if not diagnosed and treated promptly. The role of diagnostic imaging is fundamental, because CT and MR imaging have had a great impact on the diagnosis and management of CNS infections together with the physical examination and laboratory investigations, especially in identifying and narrowing the differential diagnosis and monitoring the therapeutic response. The relevant literature concerning all of these topics is summarized in this chapter.
Das Spektrum an lebenslimitierenden Erkrankungen im Kindesalter ist sehr breit gefächert. Es reicht von seltenen genetischen Erkrankungen, angeborenen/erworbenen Anomalien und (Mehrfach-) Behinderungen über neurologische Symptomenkomplexe bis hin zu Krebserkrankungen. Genauso weit sind auch das Altersspektrum pädiatrischer Palliativpatienten und so unterschiedlich sind die Versorgungsorte, an denen uns diese Patienten und ihre Familien begegnen. Das Kapitel beschreibt, wie eine gute palliative Versorgung gelingen kann - ob schon perinatal, in der Neonatologie, auf der pädiatrischen Intensivstation oder beim Übergang in das Erwachsenenleben. Zusätzlich bietet es viel Information zu den wichtigsten Themenkomplexen in der pädiatrischen Palliativversorgung, wie z. B. bei chromosomalen und metabolischen Störungen, neuro-muskulären Erkrankungen, schweren Mehrfachbehinderungen u. v. a. m. Der Fokus in diesem Kapitel liegt vermehrt auf den palliativ-psycho-sozialen Aspekten, detaillierte Angaben zur medikamentös-medizinischen Behandlung finden sich in der gesonderten Ausgabe Pädiatrische Palliativversorgung – Schmerzbehandlung und Symptomkontrolle.
BACKGROUND: In intracranial tumors, glucocorticoids are the main therapy to treat peritumoral edema. Neurologic Assessment in Neuro-Oncology (NANO) score is an instrument that can assess neurological function objectively and practically in patients with intracranial tumors. AIM: This study aims to determine the effect of dexamethasone administration on the NANO score of intracranial tumor patients. METHODS: This study was a pre-experimental study with a pre and post-test design at the H. Adam Malik General Hospital in Medan from March to September 2020. The study population was intracranial tumor patients. The research subject were 37 subjects taken consecutively. Treated with dexamethasone injection, then examined the NANO score before and after receiving dexamethasone injection on days 1, 2, and 3. Statistical analysis with Friedman test. RESULTS: Based on the demographic characteristics of the research subjects, the mean age was 53.29 ± 8.5 years. Most of the research subjects were male (54.1%) while female (45.9%). Most types of intracranial tumors were secondary tumors (59.5%) while primary tumors (40.5%). The significant effect of dexamethasone on NANO score in patients with intracranial tumors (p < 0.001). CONCLUSION: There is an effect of dexamethasone on the NANO score of patients with intracranial tumors.
Cancer can affect the central nervous system in many forms, and most of them are potentially lethal or cause permanent neurological deficits. Early recognition and prompt treatment are crucial steps in the care of neuro-oncological patients, and the attending physician can only offer appropriate care by knowing the mechanisms involved in neuro-oncological emergencies. Herein, we review the direct, indirect, and iatrogenic aspects of central nervous system involvement in cancer patients.
Oxygen is the vital substrate for the maintenance of tissue and cellular homeostasis and brain requests a high demand for oxygen and glucose continuously. Insufficient delivery or reduced cellular utilization of oxygen results in failure of aerobic metabolism and glycolysis. This fact results in the reduction of energy generation and increases the production of by-products like hydrogen ions, carbon dioxide, and lactate, which can lead to cerebral ischemia. Cardiac output and systolic volume are influenced by preload, afterload, and contractility. Adequate assessment of volume status and cardiac output usually assists the rational use of fluids. The aim of treatment should be normotension and euvolemia, to seek for physiological parameters, considering evolutionary parameters and fluid responsiveness. Treatment should aim goal to avoid secondary brain injury and the interruption of the inflammatory cascade, treating early as possible neurosurgical lesions, each with its particularities. Most of the available evidence to date comes from traumatic brain injury studies, but often ends up being extrapolated to other acute brain injuries. Using multimodal monitoring, individualizing neurointensive care to avoid secondary injury and neurological deficit, one can reduce morbidity and mortality in neurocritical patients. Thus, it is important to measure cerebral perfusion pressure and intracranial pressure in acute severe brain injuries, ideally with evaluation of cerebral autoregulation measures. Hemodynamic management may include the use of crystalloids and vasoactive and inotropic drugs. Multimodal monitoring is essential to define the need for the use of this armamentarium in a rational and appropriate manner, without adding morbidity to the neurocritical patient.
Patients having undergone neurosurgical procedures often require close observation of neurologic function in an intensive care unit (ICU) postoperatively. While some ICU stays may be brief, those patients requiring a prolonged course may be best served by an ICU capable of identifying residual effects of the prior anesthetic as well as understanding how radiographic findings and intraoperative events such as blood loss, fluid resuscitation, and ongoing mechanical ventilatory support may complicate the ICU course post-neurosurgical procedure. Further, imperative are the abilities to identify crucial, yet sometimes subtle, acute reversible neurological conditions requiring urgent optimization or emergent intervention. This chapter focuses on common strategies utilized within the neurologic-neurosurgical ICU (NSICU) to improve outcomes after neurosurgical procedures, particularly for those patients at high risk for neurologic impairment.
Meningioma is associated with the development of vasogenic edema defined as disrupted blood brain barrier. Vitamin D3 through its own nuclear receptor can regulate the expression of many effective agents on the integrity of the blood brain barrier. This study aimed to investigate the association between preoperative serum levels of 25(OH)D and peritumoral brain edema in patients with meningioma. One hundred and twelve patients with meningioma completed the study. Serum 25(OH)D levels assessment and magnetic resonance imaging (MRI) were done for all patients at the beginning of the study. The percentage of edema index (EI) was used to estimate the extent of peritumoral brain edema through preoperative MRI. The median serum level of 25(OH)D in the patients with the percentage of EI < 100% was significantly higher than those with > 100% (65.58 vs. 37.33, P < 0.001). The median percentage of EI was 24.9. Preoperative serum levels of 25(OH)D had an inverse and significant correlation with the percentage of EI as by increasing each 1 ng/mL of serum 25(OH)D, EI was decreased approximately 4% (95% CI; −5.984 to −1.952, P < 0.001). Vitamin D may be a protective factor for peritumoral brain edema of meningioma.
Despite their relatively high prevalence of approximately 37.1% of primary CNS tumors, the molecular makeup of meningiomas has not been well understood until now (Ostrom et al. Neuro Oncol 30(suppl_4):iv1–86, 2018). Recent studies have defined the genomic landscape of these tumors, identifying somatic driver mutations in several genes in approximately 80% of sporadic meningiomas, categorizing them into six distinct molecular subgroups with important clinical implications. This chapter offers an extensive review of the current understanding of the genomic landscape of meningiomas and offers insight into the clinical applicability of these findings.
Membrane water transport is critically involved in brain volume homeostasis and in the pathogenesis of brain edema. The cDNA encoding aquaporin-4 (AQP4) water channel protein was recently isolated from rat brain. We used immunocytochemistry and high-resolution immunogold electron microscopy to identify the cells and membrane domains that mediate water flux through AQP4. The AQP4 protein is abundant in glial cells bordering the subarachnoidal space, ventricles, and blood vessels. AQP4 is also abundant in osmosensory areas, including the supraoptic nucleus and subfornical organ. Immunogold analysis demonstrated that AQP4 is restricted to glial membranes and to subpopulations of ependymal cells. AQP4 is particularly strongly expressed in glial membranes that are in direct contact with capillaries and pia. The highly polarized AQP4 expression indicates that these cells are equipped with specific membrane domains that are specialized for water transport, thereby mediating the flow of water between glial cells and the cavities filled with CSF and the intravascular space.
Human corticotropin-releasing factor (hCRF) is an endogenous peptide responsible for the secretion and synthesis of corticosteroids. In animal models of peritumoral brain edema, hCRF has significant anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effect on endothelial cells. We conducted a feasibility and phase I study with hCRF given by continuous infusion to patients with brain metastasis.
Peritumoral brain edema documented by MRI and the use of either no steroids or stable steroid doses for more than a week were required. MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weighted images) of the amount of peritumoral edema were performed. The study was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 microgram/kg/h of hCRF or placebo over 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses.
Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose-limiting toxicity (hypotension) was observed at 4 micrograms/kg/h x 72 hours in two out of four patients, while zero of five patients treated at 2 micrograms/kg/h developed dose-limiting toxicities. Flushing and hot flashes were also observed. Improvement of neurological symptoms and/or exam were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol levels, and changes in cortisol levels were not correlated with changes in peritumoral edema.
hCRF is well tolerated in doses up to 2 micrograms/kg/h by continuous infusion x 72 hours. Hypotension limits administration of higher doses. The observation of clinical benefit in the absence of corticosteroids suggests hCRF may be an alternative to steroids for the treatment of patients with peritumoral brain edema. Further exploration of this agent in efficacy studies is warranted.
Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.
The fms-like tyrosine kinase (Flt) is a transmembrane receptor in the tyrosine kinase family. Expression of flt complementary
DNA in COS cells conferred specific, high-affinity binding of vascular endothelial growth factor, also known as vascular permeability
factor (VEGF-VPF), a factor that induces vascular permeability when injected in the guinea pig skin and stimulates endothelial
cell proliferation. Expression of Flt in Xenopus laevis oocytes caused the oocytes to release calcium in response to VEGF-VPF.
These findings show that flt encodes a receptor for VEGF-VPF.
An understanding of the mechanisms responsible for tumor-associated edema involves the elucidation of the role played by a number of intra-related processes. These include (i) the permeability of new tumor microvessels that are associated with tumor angiogenesis; (ii) alterations in microvascular permeability due to factors secreted by tumor cells; (iii) immunological mechanisms and (iv) increased microvessel permeability associated with inflammation. The rationale for a role for inflammatory processes in tumor-associated edema has been outlined and the role of non-steroidal anti-inflammatory drugs in modulating experimental and human tumor-associated edema has been explored.
Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.
Recently, we found that ZO-1, a tight junction-associated protein, was concentrated in the so called isolated adherens junction fraction from the liver (Itoh, M., A. Nagafuchi, S. Yonemura, T. Kitani-Yasuda, Sa. Tsukita, and Sh. Tsukita. 1993. J. Cell Biol. 121:491-502). Using this fraction derived from chick liver as an antigen, we obtained three monoclonal antibodies specific for a approximately 65-kD protein in rats. This antigen was not extractable from plasma membranes without detergent, suggesting that it is an integral membrane protein. Immunofluorescence and immunoelectron microscopy with these mAbs showed that this approximately 65-kD membrane protein was exclusively localized at tight junctions of both epithelial and endothelial cells: at the electron microscopic level, the labels were detected directly over the points of membrane contact in tight junctions. To further clarify the nature and structure of this membrane protein, we cloned and sequenced its cDNA. We found that the cDNA encoded a 504-amino acid polypeptide with 55.9 kDa. A search of the data base identified no proteins with significant homology to this membrane protein. A most striking feature of its primary structure was revealed by a hydrophilicity plot: four putative membrane-spanning segments were included in the NH2-terminal half. This hydrophilicity plot was very similar to that of connexin, an integral membrane protein in gap junctions. These findings revealed that an integral membrane protein localizing at tight junctions is now identified, which we designated as "occludin."
Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS- and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.
Membrane water transport is critically involved in brain volume homeostasis and in the pathogenesis of brain edema. The cDNA encoding aquaporin-4 (AQP4) water channel protein was recently isolated from rat brain. We used immunocytochemistry and high-resolution immunogold electron microscopy to identify the cells and membrane domains that mediate water flux through AQP4. The AQP4 protein is abundant in glial cells bordering the subarachnoidal space, ventricles, and blood vessels. AQP4 is also abundant in osmosensory areas, including the supraoptic nucleus and subfornical organ. Immunogold analysis demonstrated that AQP4 is restricted to glial membranes and to subpopulations of ependymal cells. AQP4 is particularly strongly expressed in glial membranes that are in direct contact with capillaries and pia. The highly polarized AQP4 expression indicates that these cells are equipped with specific membrane domains that are specialized for water transport, thereby mediating the flow of water between glial cells and the cavities filled with CSF and the intravascular space.
We prospectively evaluated 15 adult cancer patients being treated with adrenocorticosteroids (steroids) to determine the frequency and time course of "steroid myopathy." Nine (60%) developed clinically detectable proximal muscle weakness that, in six, was severe enough to interfere with activities of daily living. Proximal muscle weakness developed within 15 days in eight of nine patients and was significantly related to the cumulative dose of steroid. Eight of nine patients with proximal muscle weakness, and two of six without such weakness, experienced a significant decline in respiratory function, leading to symptomatic dyspnea in four patients of the former group. In three patients who could be followed for more than 3 months off steroids, there was either improvement or resolution of the weakness and, when present, of the respiratory impairment. Steroid myopathy is a common complication among cancer patients receiving steroids. It can often affect respiratory function even when proximal limb muscles remain strong. Clinical recognition is important since steroid myopathy can lead to increased morbidity and may be reversible with reduction or discontinuation of steroids.
Endothelial cells provide a crucial interface between blood and tissue environments. Free diffusion of substances across endothelia is prevented by the endothelial tight junction, the permeability of which varies enormously depending on tissue. Endothelial cells of the blood-brain barrier possess tight junctions of severely limited permeability, whereas those of non-neural tissue are considerably leakier, but the molecular basis for this difference is not clear. Occludin is a major transmembrane protein localizing at the tight junction. In this study, we show, by immunocytochemistry, that occludin is present at high levels and is distributed continuously at cell-cell contacts in brain endothelial cells. In contrast, endothelial cells of non-neural tissue have a much lower expression of occludin, which is distributed in a discontinuous fashion at cell-cell contacts. The apparent differences in occludin expression levels were directly confirmed by immunoblotting. The differences in occludin protein were reflected at the message level, suggesting transcriptional regulation of expression. We also show that occludin expression is developmentally regulated, being low in rat brain endothelial cells at postnatal day 8 but clearly detectable at post-natal day 70. Our data indicate that regulation of occludin expression may be a crucial determinant of the tight junction permeability properties of endothelial cells in different tissues.
Patients with cancers, particularly those affecting the nervous system, frequently suffer from disabling symptoms, some of which are only indirectly related to the cancer (Table 1). Some examples include pain, asthenia, fatigability, loss of appetite, and depression. These symptoms, which are often more distressing to the patient than the tumour itself, often do not respond to treatment directed at the underlying neoplasm and, thus, must be treated independent of treatment of the neoplasm.
Prehospital care providers frequently encounter patients with altered mental status (AMS). One of the more difficult aspects of managing these patients is assessing the extensive differential etiology of the symptoms. AMS can broadly be separated into traumatic and non-traumatic causes, with non-traumatic causes being the focus of this chapter. Prehospital endotracheal intubation has been performed in the United States for over 30 years, but has been the source of considerable debate for the past 10 years. This is primarily due to the large variance of reported success rates in multiple studies of both adult and pediatric patients and the negative outcome associated with the inability to successfully intubate the patient in the field. Hypoglycemia is a common cause of AMS in the prehospital setting, justifying the need for obtaining a blood glucose level on any patient who presents as altered.
A common property of brain tumours is their ability to cause oedema in the surrounding brain. Oedema forms as a result of a leaky blood‘tumour barrier and persists when the brain fails to clear the excess fluid. It is a significant source of morbidity and mortality. The principal anatomical component of the blood‘brain barrier is the endothelial tight junction which opens in glioma microvessels. Multiple tight junction proteins have recently been identified, such as occludin, claudin, ZO-1, ZO-2 and ZO-3. We propose a model to explain tight junction opening in gliomas based on vascular endothelial growth factor secretion and loss of tight junction inducing factor production by tumour cells. The level of expression of the water channel aquaporin-4 in peritumoural astrocytes may determine the rate of oedema fluid clearance. The identification of the molecular mechanisms of brain tumour oedema may allow the design of novel anti-oedema medications.
Pneumocystis carinii has been recognized as
a human pathogen for nearly 50 years. We present a case of P carinii infection that typifies clinical presentation in the era
of the acquired immunodeficiency syndrome epidemic. The high incidence of P carinii pneumonia in persons infected with human immunodeficiency
virus (HIV) has served to focus laboratory and clinical research efforts on
better understanding the biology of the organism and on improving diagnosis,
treatment, and prevention of this disease. Although inability to culture P carinii has hampered research efforts, molecular and
immunologic approaches have led to the recognition that the organism represents
a family of fungi with a very restricted host range and have allowed characterization
of clinically relevant antigens and enzymes. Molecular epidemiologic studies
have identified more than 50 strains of human-derived P
carinii and have suggested that recently acquired infection, as opposed
to reactivation of latent infection, may account for many cases of clinical
disease. Diagnosis has been improved by the development of organism-specific
monoclonal antibodies and, more recently, by polymerase chain reaction using
multicopy gene targets, together with induced sputum or oral wash samples.
Chemotherapeutic prophylaxis is very effective in preventing P carinii pneumonia; the combination of trimethoprim-sulfamethoxazole
remains the first-line agent for both therapy and prophylaxis. Prophylaxis
needs to be administered only during periods of high risk; in HIV-infected
patients responding to effective antiretroviral therapies, prophylaxis no
longer needs to be lifelong. Molecular studies have identified mutations in
the target of sulfa drugs that appear to represent emerging resistance in P carinii. Resistance to atovaquone, a second-line agent,
may also be developing.
Aquaporin-4 (AQP4) is a highly conserved water channel protein. In rats, AQP4 is expressed in astrocyte foot processes and is important in brain water homeostasis. AQP4 expression has not been investigated in non-neoplastic human brain or oedematous brain tumours, where water homeostasis is disrupted. Therefore, immunohistochemistry was used to study AQP4 expression in non-neoplastic and neoplastic human brain and blood-brain barrier permeability was assessed using contrast enhanced computed tomograms. AQP4 was present around microvessels in five specimens of non-neoplastic brain and five low grade (Daumas-Duport I or II) astrocytomas. AQP4 was massively upregulated in four and absent in one high grade (Daumas-Duport III or IV) astrocytoma. Massive upregulation of AQP4 was also found in reactive astrocytes in five metastatic adenocarcinomas. There was significant (p<0.0001) correlation between blood-brain barrier opening and upregulated AQP4 expression. Increased AQP4 expression in high grade astrocytomas and adenocarcinomas may facilitate the flow of oedema fluid.
: With the use of positron emission tomography, regional cerebral blood flow, oxygen utilization, and glucose utilization were measured in the peritumoral low-density areas on x-ray computed tomographic images in 23 patients with supratentorial brain tumors: 7 meningiomas, 11 malignant gliomas, and 5 metastatic brain tumors. Findings on positron emission tomography in these areas revealed characteristic patterns associated with the types of tumor and the degree of mass effect. It is likely that two different types of pathophysiological states exist in "peritumoral edema": 1) primary ischemia caused by mechanical compression by the tumor mass in meningiomas: and 2) primary metabolic suppression (mainly in oxygen metabolism) in malignant brain tumors. (Neurosurgery 26:615-621, 1990)
Copyright (C) by the Congress of Neurological Surgeons
The present studies investigated the expression of the platelet-derived growth factor (PDGF) and PDGF-receptor genes in human meningiomas. Northern blot analysis demon strated that all meningiomas examined expressed both the c-sis/PDGF-2 proto-oncogene and the PDGF-receptor gene. In situ hybridization localized the c-sis mRNA and the PDGF receptor mRNA in the tumor cells of the meningioma tissues. Control pachymeninges derived from adult individuals, with out meningiomas, expressed only PDGF-receptor mRNA but not the c-sis mRNA. Immunocytochemistry studies detected both the c-sis and the PDGF-receptor protein products in me ningioma tissues but only the PDGF-receptor protein prod ucts in control pachymeninges. These findings indicate the presence of an autocrine mechanism in human meningiomas based on the co-expression of the c-sis/PDGF-2 proto-onco gene and PDGF-receptor gene and their protein products. This co-expression of a potent mitogen and its receptor may contribute to the growth and maintenance of human menin giomas.
q Background: Glucocorticoids are frequently prescribed drugs. Nearly half of the patients treated with glucocorticoids over a longer period develop a deranged glucose metabolism. In about 50%, these disturbances persist despite reduction or even withdrawal of the drug.
q Pathophysiology: Glucocorticoids antagonize the insulin-mediated inhibition of hepatic glucose release, decrease glucose utilisation in muscle, and reduce the binding affinity of insulin receptors. Therefore, glucocorticoid-induced diabetes mellitus is equivalent to unmasked type 2 diabetes. New studies presume that an increased endogenous production of glucocorticoids particularly in adipocytes could play a role in type 2 diabetes as well.
q Therapy: Patients with glucocorticoid-induced diabetes bear, comparable to patients with other types of diabetes, a considerable risk of arteriosclerotic and cardiovascular diseases and should therefore receive an intensified treatment. Therapy of glucocorticoid-induced diabetes basically corresponds to that of type 2 diabetes. Applicable are oral antidiabetic drugs, particularly metformin and the glitazones as insulin sensitizers both requiring consideration of contraindications, or treatment with insulin.
We report a series of the in vivo and in vitro studies that evaluate the anti-neoplastic potential of hCRF in W256 rat mammary carcinoma. Using magnetic resonance imaging (MRI) and direct measurements of tumor and peritumoral brain water content we found that hCRF treatment (100 micrograms/kg subcutaneously twice a day for 3 days) caused significant inhibition of growth and vascular permeability of the i.c. W256 tumors. hCRF also exhibited antiproliferative and differentiation-inducing effects in W256 cells in vitro. The calculated IC50 values were 70 nM and 100 nM of hCRF, as measured by digital videomicroscopic quantitation of tumor cell population growth rate and by [3H]-thymidine incorporation assay, respectively. The observed effects in W256 cells were CRF receptor mediated. This was shown in two ways: by the presence of relatively high levels of CRF1 receptor mRNA in W256 cells, and by the fact that the tumor growth inhibitory and differentiation inducing effects of hCRF in vitro were abolished by the CRF receptor antagonist a-helical CRF (9-41). Antiproliferative and differentiation inducing effects of hCRF in W256 cells involve activation of nitric oxide synthase (NOS) and L-arginine-NO pathway. This was shown by using the inhibitor of NOS, the L-nitro-arginine methyl esther (L-NAME), which prevented the antiproliferative and differentiation inducing effects of hCRF in vitro. The cytotoxicity of NO in W256 cells was assessed by the addition of sodium nitroprusside (SNP) to the media. SPN exhibited dose-dependent cytotoxicity in W256 cells with IC50 of 100 muM SNP as measured by [3H]-thymidine incorporation assay. We conclude, that hCRF has substantial anti-neoplastic effects which include inhibition of proliferation and induction of differentiation of the tumor cells in vitro, and a decrease in tumor vascular permeability (and possibly neo-angiogenesis) in vivo.
Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular proliferations. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.
Cerebral edema is a common clinical disorder that results from an abnormal increase in water content within the extracellular (EC) compartment of the brain. It is distinguished from two other types of brain bulk enlargement: (1) vascular swelling, caused by arterial dilatation or venous obstruction; and (2) cellular swelling, caused by cytotoxic injuries or metabolic storage. Under normal conditions, the EC compartment has two fluids, the interstitial fluid (ISF) and the cerebrospinal fluid (CSF), and extends from the blood brain barrier (BBB) through a series of 100 to 150-A-wide intercellular spaces that are anatomically continuous with the CSF spaces. There are four primary types of EC edema: (1) vasogenic edema, which results from an increase in brain capillary permeability, the most common type, in which leakage of plasma constituents into the brain follows the pathways of ISF bulk flow and is governed by the interaction of systemic arterial pressure and tissue resistance; (2) osmotic edema, which results from an unfavorable osmotic gradient between the plasma and ISF across an intact BBB; (3) compressive edema, which results from obstruction of ISF bulk flow pathways; and (4) hydrocephalic edema, which results from obstruction of CSF bulk flow pathways. In this latter type of edema, distension of the collecting channels proximal to the block leads to retrograde flooding of the EC compartment with the formation of periventricular edema. The syndrome of pseudotumor cerebri includes several different types of brain bulk enlargement.
Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a potent polypeptide regulator of blood vessel function. VPF promotes an array of responses in endothelium, including hyperpermeability, endothelial cell growth, angiogenesis, and enhanced glucose transport. VPF regulates the expression of tissue factor and the glucose transporter. All of the endothelial cell responses to VPF are evidently mediated by high affinity cell surface receptors. Thus, endothelial cells have a unique and specific spectrum of responses to VPF. Since each of the responses of endothelial cells to VPF are also elicited by agonists, such as bFGF, TNF, histamine and others, it remains a major challenge to determine how post-receptor signalling pathways maintain both specificity and redundancy in cellular responses to various agonists.
The study of proliferative characteristics and biochemical aspects seem to be of great importance in order to define brain neoplastic behavior.
The purpose of this study is to verify the existence of any possible correlation between Arachidonic Acid (AA) metabolism and proliferative characteristics in 30 meningiomas and 30 neuroepithelial tumors. The most represented metabolite in neuroepithelial tumors is TxB2, while 6-Keto-PGF1α is the lowest represented product. Unimodal DNA distribution was observed in 66% of neuroepithelial tumors and in 87% of meningiomas. Aneuploidy was more frequent in glioblastomas and anaplastic meningiomas as previously reported; AA overall synthesis capacity and profile were similar between unimodal and bimodal cases of neuroepithelial tumors. Total AA metabolite, as well as TxB2 and PGD2, synthesis capacity are significantly higher in cases with S-phase cell percentage ≥ 3% than in cases with S-phase % < 3%.
Total production of AA metabolites via the cyclooxygenase pathway is significantly higher in meningiomas with bimodal DNA distribution than in cases with unimodal DNA content; when considering S-phase cell percentage, similarly to what observed in neuroepithelial tumors, meningiomas with S% > 3% shows a significantly higher overall synthesis capacity for AA. AA metabolism capacity well correlates with proliferative patterns in neuroepithelial tumors: the relationship depends preferentially on TxB2 and PGD2 synthesis capacity. In cases of meningiomas, the amount of AA metabolites seem to be related to DNA content and proliferative activity when anaplastic features are histologically demonstrated.
We used quantitative autoradiography (QAR) to evaluate the effect of systemically administered dexamethasone on capillary permeability in brain tumors and surrounding brain. Rats bearing unilateral right hemispheric C6 gliomas were studied at one and twelve hours after 10 mg/kg of intraperitoneal dexamethasone. Capillary permeability was determined by measuring unidirectional blood-to-brain and blood-to-tumor transport of 14C-alpha aminoisobutyric acid (14C-AIB) over fifteen minutes. 14C-AIB entry into tumor, brain adjacent-to-tumor (BAT), and ipsilateral and contralateral cortices was determined and expressed as a unidirectional transfer constant, K. Nontreated tumor K was more than two-fold greater than K for BAT and ten-fold greater than ipsilateral cortical K, confirming substantial barrier disruption in tumor. In addition, the K for BAT was also significantly greater than K for cortex, indicating that the barrier in the peritumoral region was also disrupted. One hour after dexamethasone treatment, tumor K fell to 63% of its pretreatment value (p less than 0.025). By twelve hours post-treatment, tumor K fell to 25% of the untreated value (p less than 0.001) and to 47% of the one-hour value (p less than 0.005). BAT K fell to 29% of its untreated value (p less than 0.02) and to 46% of its one-hour value (p less than 0.02). By 12 hours, ipsilateral cortical K fell to 67% of the untreated cortical value (p less than 0.05). Compared to untreated values, there was no significant difference between contralateral cortical K at either one or twelve hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Four drugs with potential anti-peritumoral brain edema activity were studied using the VX2 rabbit brain tumor model. Meclofenamate and indomethacin were tested in an attempt to confirm recent reports of anti-edema activity in non steroidal anti-inflammatory drugs (NSAID's). The 'angiostatic' steroids 17 hydroxyprogesterone and epicortisol were tested because of their lack of glucocorticoid and mineralocorticoid effects and their structural similarity to glucocorticoids. The protein and water component of brain edema were indirectly quantitated. None of the test drugs demonstrated significant anti-edema activity. This work does not confirm reports that NSAID's have anti-edema activity and suggests that there may be no correlation between 'angiostatic' and anti-edema activity in certain steroid compounds.
Forty-two patients with supratentorial gliomas not involving the basal ganglia (extraganglionic) were studied pre- and postoperatively with computed tomographic (CT) scans to evaluate the effect of the extent of surgical resection on the immediate postoperative results. Thirty-three patients (79%) had malignant astrocytic gliomas (glioblastoma or anaplastic astrocytoma), 4 patients (10%) had well-differentiated astrocytomas, and 5 (12%) had oligodendrogliomas. The median age was 58 years, and the median Karnofsky rating was 70. There was no operative mortality. Six patients (14%) had surgical complications. A gross total resection was defined as the absence of any abnormal enhancement on the postoperative CT scan. A nearly gross total resection had been accomplished when less than 10% of the preoperatively enhancing mass was still seen. A partial resection was indicated by the presence of more than 10% of the enhancing lesion on the postoperative CT scan. A gross total or nearly gross total resection was accomplished in 36 patients (86%), and an improved or stable postoperative neurological status was present in 35 of these patients (97%). In contrast, the rate of neurological morbidity after a partial resection was 40%. Supratentorial extraganglionic gliomas, regardless of their histological type, generally were well-circumscribed lesions except at the level of the ventricular wall, where glioblastomas and anaplastic astrocytomas blended with the subependymal white matter from which they seemed to arise.
Extensive surgical resection of supratentorial gliomas increases survival. However, some reports suggest that the perioperative morbidity and mortality outweigh the potential benefit of the procedure. We examined prospectively morbidity and mortality in 104 consecutive patients who underwent surgery for supratentorial glioma, as well as other factors that might affect the short-term outcome. To determine if our experience was unusual, we compared these results with those obtained from another academic neurosurgical center by a review of the records of 109 patients also treated surgically for supratentorial glioma. Mortality was 3.3% and the medical plus neurologic morbidity was 31.7%. Functionally significant neurologic worsening occurred in 42 (19.7%) patients. Complications were more frequent in patients with moderate or severe preoperative disabilities than those with mild or no preoperative disability. Patients with complete resection had fewer acute neurologic complications, and no greater risk of being neurologically impaired at 1 week, than patients with biopsy or less extensive procedures. Morbidity and mortality correlated with location: deep-midline lesions had a higher overall rate of perioperative complications (p = 0.032) and mortality (p = 0.019) and bilateral lesions a higher rate of hemorrhage (p = 0.017) and hydrocephalus (p = 0.010). Older patients (greater than 55 years) and those receiving high daily dose of preoperative dexamethasone (greater than or equal to 24 mg) had a significantly higher risk of surgical mortality. Reoperation for recurrent tumor carried no greater risk of mortality, neurologic deterioration, and infection than a first operation.(ABSTRACT TRUNCATED AT 250 WORDS)
Leukotrienes are pharmacologically active compounds that promote vascular permeability. In this study we sought to determine whether tissue leukotriene-like immunoreactivity was increased in intracranial tumors associated with peritumoral edema. In 20 patients undergoing craniotomy tissue specimens were immediately frozen after removal and tissue leukotriene C4 levels were determined by radioimmunoassay. An index of peritumoral edema was estimated from preoperative contrast-enhanced computed tomographic scans. There was a significant correlation between brain edema and tissue leukotriene levels (p less than 0.003). Metastatic tumors (n = 8) had the highest leukotriene C4 level at 13.8 +/- 8.5 pg/mg tissue (mean +/- SE) and the highest index of edema 5.7 +/- 1.8. The mean leukotriene C4 level in the gliomas (n = 5) was 6.2 +/- 2.3 pg/mg tissue and the edema index was 2.1 +/- 0.6. There was no edema and no neoplasm in the temporal lobes removed for seizure (n = 2), and their level of leukotriene C4 was 0.4 +/- 0.1 pg/mg tissue. The formation of leukotriene C4 is stimulated by intracranial tumors. Leukotrienes increase blood-brain barrier permeability and may be important in the formation of vasogenic edema surrounding tumors.
We studied the action of high doses (500 mg/daily for 7 days) of methylprednisolone sodium succinate in 12 patients with supratentorial intracranial tumors. 10 tumors were malignant (5 gliomas and 5 metastases), and 2 benign (meningiomas). Clinical improvement ranged from moderate to marked after 24-48 h of therapy. In the 5 metastases, mean reduction of peritumoral edema was 27%, and in apparent tumor volume was 18%; in the gliomas, corresponding reductions were 31 and 15%. 1 of the meningioma cases showed a decrease in edema volume of 21%. These results indicate that methylprednisolone, at least for a short period of time, produces a definite decrease in apparent tumor size, in addition to the reduction of peritumoral edema.
Clinical features of Cushing's syndrome developed in 22 male patients with pulmonary tuberculosis who received prednisone, 30 mg daily, and zinc corticotropin (ACTH), 40 U every other day, for 3 months in addition to antituberculous chemotherapy. The prednisone was tapered during an additional 3-week period and the zinc ACTH was continued throughout the tapering period for an additional 4 days. Following discontinuation of prednisone-ACTH therapy, the patients developed features of the steroid withdrawal syndrome—anorexia, nausea, lethargy, arthralgia, weakness, desquamation and weight loss. The integrity of the hypothalamic-pituitary-adrenal system was evaluated in 13 patients while steroid withdrawal symptoms were present, and in randomly chosen controls with tuberculosis by measuring the response of plasma and urine steroids to the administration of methopyrapone (Su-4885) and to exogenous ACTH. The base line levels of plasma and urine steroids and response to ACTH were similar in the steroid-ACTH with...
A retrospective study of cerebral edema in 40 patients with intracranial meningiomas seems to demonstrate that the extent of edema is not related to anatomical factors such as location. Histological type is more significant; cerebral edema is usually observed with meningothelial forms. Furthermore, the study of tumor cells by electron microscopic methods indicates that secretory-excretory activity is closely associated with with the production of peritumoral edema. The ultrastructural aspects of this secreted material are described, but further biochemical studies are necessary to determine its exact nature. The possible role of tumoral steroid receptors in the secretory-excretory phenomenon is discussed.
In a prospective study the effect of dexamethasone treatment on tumor volume and contrast enhancement was evaluated by computed tomography (CT) in 15 patients with intracranial lesions. Histological diagnoses were confirmed in 13 patients who had undergone surgical intervention. A CT study of the head, with and without contrast medium, was performed prior to the dexamethasone treatment and at various intervals during the treatment for 8-19 days. The volume, attenuation, and contrast enhancement of the tumor were measured and related to the time after the start of the treatment. In six meningiomas there was no change in the volume and enhancement of the tumors. Out of four gliomas, there was an increase in volume of two tumors, whereas the other two cases showed a decrease in the tumor volume. In one glioma a distinct decrease in enhancement was observed. In three cases of metastasis a decrease in enhancement and tumor volume was noted. An acoustic neurinoma and an unverified lesion, considered radiologically to be a glioma, also showed a decrease in tumor volume and contrast enhancement. In tumors that responded to the treatment, a decrease both in volume of the tumor and peritumoral brain edema as well as a decrease in contrast enhancement of the tumor were observed.
To test the hypothesis that preoperative head computed tomography scans could be used to predict the likelihood that a patient with a supratentorial brain tumor would develop intracranial hypertension during surgery before the cranium was opened, intraoperative intracranial pressure and blood pressure records of 60 patients undergoing craniotomy were compared with the appearance of their preoperative computed tomography scans. The scans were interpreted by a neuroradiologist who was unaware of the clinical events in each case. A positive correlation was found between the amount of preoperative brain edema observed surrounding tumors (on an arbitrary 0 to 3 + scale) and subsequent increases in intracranial pressure greater than base line values. No such correlation could be found with regard to tumor size, shift of midline structures, or effacement of the lateral ventricles. When preoperative brain edema seen on computed tomography scan was taken into consideration, increases in intracranial pressure during craniotomy also correlated with simultaneous increases in blood pressure. It is concluded that patients with large amounts of preoperative brain edema surrounding supratentorial tumors should be considered at risk for developing intraoperative intracranial hypertension and may benefit from preoperative insertion of an intracranial pressure monitor before general anesthesia is induced.
Three independent methods were used to quantify the therapeutic effect on peritumoral brain edema with respect to different forms of treatment (dexamethasone, furosemide, and their combination with different dosages and different periods of treatment). 1. The neurological deficit evaluated by frequency distribution analysis showed an improvement in nearly all cases. In a few cases the initial improvement was followed by a secondary deterioration. The various symptoms showed significant differences in regression with regard to the extent of the reduced deficit as well as the time dependence. 2. With a certain delay (compared to item 1), diminution of brain edema was detected by CT follow-up. The effect of dexamethasone and the combination with furosemide differed depending on the nature of the brain tumor. 3. Compared to the untreated patients, the water content was reduced by nearly 3% following dexamethasone treatment 4 x 4 mg for 4 to 6 days. Following dexamethasone/furosemide therapy for 4 to 6 days, it was reduced by about 4.5%. The result of long-term therapy with dexamethasone alone was similar. The sodium content changed parallel to the water content. Dexamethasone and dexamethasone/furosemide was most effective in patients with glioblastoma, where the water content decreased by nearly 6%. The data presented suggest that preoperative antiedema treatment with dexamethasone is necessary for several days or a few weeks in some cases. The period of treatment can be reduced significantly by dexamethasone/furosemide or extremely high doses of dexamethasone. On the other hand, the results of follow-up scoring of the neurological situation show that the optimal time of pretreatment must be limited with respect to the individual case. The therapeutic results presented allow inferences to be made concerning pathophysiology of the resolution of brain edema.
Cerebral edema and fluid-filled cysts are common accompaniments of brain tumors. They contribute to the mass effect imposed by the primary tumor and are often responsible for a patient's signs and symptoms. Cerebral edema significantly increases the morbidity associated with tumor biopsy, excision, radiation therapy, and chemotherapy. Both edema and cyst formation are thought to result from a deficiency in the blood-brain barrier, with consequent extravasation of water, electrolytes, and plasma proteins from altered tumor microvessels. The resultant expansion of the cerebral interstitial space contributes to the elevated intracranial pressure observed with brain tumors. Departure from the typical blood-brain barrier microvascular architecture may only partially explain the occurrence of edema and tumor cyst formation. Biochemical mediators have also been implicated in vascular extravasation. Vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) is a protein that has recently been isolated from a variety of tumors including human brain tumors. VPFb is an extraordinarily potent inducer of both microvascular extravasation (edemagenesis) and the formation of new blood vessels (angiogenesis). Its role in tumor growth and progression would therefore appear pivotal. Herein, the author presents an updated account of the investigation of VPF. Historical and clinical perspectives of the study and treatment of tumor associated edema are provided. The efficacy of high-dose dexamethasone in the treatment of neoplastic brain edema is discussed. A hypothetical role for VPF in edemagenesis is presented and discussed. It is hoped that an expanded understanding of the mechanisms responsible for the genesis of edema will ultimately facilitate therapeutic intervention.
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Examination of flk-1 receptor tyrosine kinase mRNA expression by in situ hybridization analysis revealed specific association with endothelial cells at all stages of mouse development, including the blood islands in the yolk sac of day 8.5-10.5 embryos, in which the early progenitors of this lineage originate. flk-1 transcripts were abundant in proliferating endothelial cells of vascular sprouts and branching vessels of embryonic and early postnatal brain, but were drastically reduced in adult brain, where proliferation has ceased. Identification of the angiogenic mitogen, vascular endothelial growth factor (VEGF), as the high affinity ligand of Flk-1 and correlation of the temporal and spatial expression pattern of Flk-1 and VEGF suggest a major role of this ligand-receptor signaling system in vasculogenesis and angiogenesis.
This meta-analysis was performed to determine whether corticosteroid therapy induces the development of peptic ulcer and other putative complications of steroid therapy.
A retrospective investigation in which we analysed all the randomized, double-blind, controlled trials (RDBCT) in which steroids had been administered that we were able to identify. The number of episodes of peptic ulcer, dermatological effects, sepsis, diabetes, hypertension, osteoporosis, psychosis and tuberculosis reported in both the placebo and steroid groups were compared.
The international medical literature was analysed for any RDBCT in which any steroid or ACTH had been administered in any dosage for any duration, and any putative complication of steroid therapy was reported.
Of 1857 articles, 93 satisfied our requirements and were analysed by the meta-analytic techniques of Peto, DerSimonian and Laird. A total of 6602 patients were included.
The relative frequencies of each of these eight 'complications' were compared in the placebo and steroid groups using conventional statistics and meta-analysis. The relative frequencies of 'annualized' subgroups of patients who received treatment for 1 to 7 days, 1 week to 1 month, 1 to 3 months and more than 3 months, were similarly analysed.
Nine of 3267 patients in the placebo group (0.3%) and 13 of 3335 patients in the steroid group (0.4%) were reported to develop peptic ulcer (P > 0.05). The dermatological cosmetic effects of steroid therapy were observed more frequently in the steroid group (P < 0.001), as was diabetes (P < 0.001), hypertension (P < 0.01) and psychosis (P < 0.001). Sepsis, osteoporosis and tuberculosis all occurred more frequently in the steroid than in the placebo group, but the differences are not statistically significant.
Peptic ulcer is a rare complication of corticosteroid therapy that should not be considered a contraindication when steroid therapy is indicated.
Many factors have been suggested as possible mechanisms for the development of peritumoural oedema in meningioma. Venous compression by the tumour is thought to be one factor, but reports presenting a direct relationship between venous compression and the formation of oedema are rare. We have recently observed 6 meningioma patients in whom venous stasis contributed to peritumoural oedema. The stasis was due to1)
compression of an adjacent cortical vein by the tumour with stasis at the site of compression and/or its distal portion.
2)
compression of adjacent brain by the tumour with prolonged perfusion and delayed venous return (visualized as pial staining in the capillary and venous phases), and
3)
presence of an early draining vein linked to a nearby cortical vein with stasis at its periphery.
Venous compression and stasis seem to be related not only to the formation of peritumoural oedema but also to the occurrence of haemorrhagic infarction after the resection of meningiomas.
The purpose of this study was to determine whether lower doses of dexamethasone for treatment of brain tumor edema are as effective as the conventional dose of 16 mg/d. We consecutively executed two double-blind randomized trials in patients with CT-proven brain metastasis and Karnofsky scores of 80 or less. In the first series, we compared 8 mg dexamethasone per day versus 16 mg/d; in the second series, 4 mg/d versus 16 mg/d. Standardized evaluation of quality of life and side effects took place at days 0, 7, 28, and 56. We randomized a total of 96 patients and evaluated eighty-nine. The Karnofsky score improved in the 8-mg group, which had improvement of 8.0 +/- 10.1 (mean +/- SD) points at day 7 versus 7.3 +/- 14.2 points in the 16-mg group. In the second series, the 4-mg group had improvement of 6.7 +/- 11.3 points at day 7 and 7.1 +/- 18.2 points at day 28 versus 9.1 +/- 12.4 and 5.6 +/- 18.5 points in the 16-mg group. Toxic effects occurred more frequently in the 16-mg group (p < 0.03). We conclude that administration of 4 mg dexamethasone per day for treatment of brain tumor edema results in the same degree of improvement as does administration of 16 mg/d after 1 week of treatment in patients who have no signs of impending herniation. Toxic effects are dose-dependent and, during a 4-week period, occurred more frequently in patients using 16 mg/d.(ABSTRACT TRUNCATED AT 250 WORDS)
We examined 111 consecutive patients with primary or metastatic brain tumors identified by CT or MRI to characterize brain tumor headache. The median age was 44 years; 34% had primary and 66% metastatic tumors. Headaches were present in 48%, equally for primary and metastatic brain tumors. Headaches were similar to tension-type in 77%, migraine-type in 9%, and other types in 14%. The typical headache was bifrontal but worse ipsilaterally, and was the worst symptom in only 45% of patients. Unlike true tension-type headaches, brain tumor headaches were worse with bending over in 32%, and nausea or vomiting was present in 40% of patients. The "classic" early morning brain tumor headache is uncommon. Nausea, vomiting, an abnormal neurologic examination, or a significant, change in prior headache pattern suggest that the headache may be caused by a tumor.
Angiogenesis, the development of new capillaries, is tightly controlled by the balance of positive and negative regulatory pathways. A newly described angiogenic factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), binds exclusively to endothelial cells and promotes their proliferation. Here we have studied the role of p53, a tumor suppressor, and v-Src, an oncogene on VEGF regulation. Wild-type p53 down-regulated endogenous VEGF mRNA level, as well as VEGF promoter activity, in a dose-dependent manner, whereas mutant forms of p53 had no effect. Overexpression of v-Src, known to up-regulate VEGF expression, activated a VEGF promoter-luciferase construct in a dose-dependent manner. Moreover, v-Src, in the presence of wt-p53, was unable to activate transcription of the VEGF promoter. Collectively, these data suggest that wild-type p53 may play a role in suppressing angiogenesis.
Marked neovascularization is a hallmark of many neoplasms in the nervous system. Recent reports indicate that the endothelial mitogen vascular endothelial growth factor (VEGF) may play a critical role in the regulation of vascular endothelial proliferation in malignant gliomas. Using novel monoclonal antibodies to the VEGF polypeptide we have determined the expression and cellular distribution of VEGF protein in a representative series of 171 human central nervous system (CNS) tumors by immunohistochemistry and immunoblotting. In agreement with previous in situ hybridization data, 19 out of 20 glioblastomas (95%) showed immunoreactivity for VEGF, whereas both the percentage of immunoreactive tumors and the extent of immunoreactivity for VEGF were significantly lower in astrocytomas. Of the pilocytic astrocytomas (WHO grade I) 44% were immunoreactive for VEGF, but we observed several cases with pronounced vascular proliferates in the absence of VEGF. In ependymomas, meningiomas, hemangioblastomas, and primitive neuroectodermal tumors, there was no correlation between VEGF expression, vascular endothelial proliferation and the grade of malignancy. Oligodendrogliomas and the oligodendroglial component of mixed gliomas lacked immunoreactive VEGF, indicating that endothelial growth factors other than VEGF may regulate tumor angiogenesis in these neoplasms. Western blot analysis showed a predominant VEGF protein species of 23 kDa and confirmed the immunohistochemical data in all cases. Our findings demonstrate that VEGF is expressed in a wide spectrum of brain tumors in which it may induce neovascularization. However, other angiogenic factors also appear to contribute to the vascularization of CNS neoplasms.
We have reported previously that topical administration of vascular endothelial growth factor165 (VEGF) to a microvascular bed supplied with a continuous endothelium can rapidly induce the formation of endothelial fenestrations (W. G. Roberts and G. E. Palade, J. Cell Sci., 108: 2369-2379, 1995). From these results, we hypothesized that tumor vasculature, in general, may also be fenestrated because it has been reported that tumor secretion of VEGF causes the surrounding host vasculature to invade and feed the growing tumor. Using electron microscopy to characterize the endothelial cell morphology in tumor vessels from either the periphery or the core of the tumor and immunoblotting to detect secreted VEGF, we analyzed the vasculature of human and murine neoplastic tumors grown s.c. in male nude mice. To clarify the role of VEGF165 two models were used: (a) Chinese hamster ovary (CHO) cells stably transfected with hu VEGF165 and injected into mice (VEGF:CHO tumors); and (b) slow-release pellets containing purified VEGF or basic fibroblast growth factor implanted on the rat cremaster muscle. All tumors had vessels with fenestrated endothelium, open interendothelial junctions, and clustered fused caveolae. From all of the peripheral tumor vessels observed, fenestrated endothelium was observed in 41% from EMT, 35% from M1S, 37% from U87, and 56% from VEGF:CHO tumors, whereas surrounding skin and muscle, from which tumor vessels were derived, had fenestrated endothelium in 2 and 0% of all vessels, respectively. Additionally, further analysis revealed a substantial decrease in the anionic glycocalyx on the luminal face of the fenestral diaphragms in endothelium from tumors (especially VEGF:CHO) when compared to intestine or pancreas. Because the host tissue microvascular endothelium which supplies the tumor is not fenestrated, tumors can transform nonproliferating, nonfenestrated vessels into proliferating vessels, many of which have fenestrated endothelium. These data provide evidence that chronic VEGF exposure can induce fenestrations in nonfenestrated endothelium similar to the fenestrated endothelium found in tumor vessels.
Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, is important in the angiogenesis of glioblastoma. A major difference between pilocytic astrocytoma, a grade I tumor, and the grade II fibrillary astrocytoma is the vascular proliferation, highly vascularized stroma, and great propensity for cyst formation in the former. In order to explore factors regulating such angiogenesis and cyst formation in pilocytic astrocytoma, we examined expression of VEGF and its receptors (KDR and Flt-1) using in situ hybridization. In all 14 cases a high level of VEGF transcripts could be demonstrated. These were found in specific regions, namely, in the tumor cyst wall, in areas of hyaline cystic degeneration, in stellate reticulated astrocytes around microcysts in the biphasic compact and loose areas, and in tumor cells with degenerative pleomorphic multicoated nuclei. KDR and Flt-1 were expressed in the tumor vasculature, with particularly high levels seen in coiled young proliferating vessels, especially those in the cyst wall. Given the known angiogenic and vascular permeability activities of VEGF, we propose that VEGF plays an important role in molding the characteristic morphologic features of this tumor, namely, the formation of cysts, microcystic pattern, hyaline cystic degeneration, hyaline vessels, and vascular proliferation. Mechanisms that block the VEGF pathway could constitute a potential therapeutic strategy for the treatment of this tumor.