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Home , Cerebral edema, Osmotherapy

The management of in brain tumors Evert C.A. Kaal and Charles J. Vecht

This review focuses on , clinical signs, and Introduction imaging of brain edema associated with intracranial tumors Brain edema is a prominent feature of brain cancer and and its treatment. Brain edema in brain tumors is the result of often contributes to neurologic dysfunction and impaired leakage of plasma into the parenchyma through dysfunctional quality of life. This review focuses on treatment of brain cerebral . The latter type of edema (ie, vasogenic edema in brain tumors. Clinical features of patients with edema) and the role of other types in brain tumors is brain tumors are discussed, followed by pathologic and discussed. Vascular endothelial growth factor-induced pathophysiologic aspects of brain edema, and methods dysfunction of tight junction proteins probably plays an for diagnosing its presence. The practice of corticoste- important role in the formation of edema. are roid administration, dependency, and the mainstay of treatment of brain edema. When possible, withdrawal effects are discussed, together with a number corticosteroids should be used in a low dose (eg, 4mg of new agents that can influence the development of daily) to avoid serious side effects such as brain edema. myopathy or diabetes. Higher doses of dexamethasone (16 mg/day or more), sometimes together with Clinical presentation (, glycerol) or surgery, may be used in emergency Papilledema, occipital worsening in the morn- situations. On tapering, one should be aware of the possible ing, nausea and vomiting, abnormal eye movements, and development of corticosteroid dependency or withdrawal impaired consciousness are the classic signs of raised in- effects. tracranial pressure. Headache can be a prominent feature Novel therapies include vascular endothelial growth factor of patients with brain edema and is probably caused by receptor inhibitors and corticotropin releasing factor, which traction or pressure on pain-sensitive structures such as should undergo further clinical testing before they can be dural coverings and blood vessels. In one large series, recommended in practice. 60% of patients with brain tumors reported headache. The pain seems dependent on size and location of the Keywords tumor (infra- vs supratentorial), presence of midline shift, , edema, corticosteroids, toxicity, blood–brain a prior history of , and the amount of edema barrier, imaging surrounding the tumor [1,2]. Headache in patients with cancer is an ominous sign: Intracranial metastases were Curr Opin Oncol 16:593–600. © 2004 Lippincott Williams & Wilkins. found in more than 30% of cancer patients with head- ache as the presenting symptom. Headache duration of 10 weeks or less, emesis, and pain not of a tension type are significant clinical predictors for the presence of brain metastases in cancer patients [3]. Department of Neurology, Medical Centre Haaglanden, The Hague, Netherlands

Correspondence to Charles J. Vecht, MD, PhD, Department of Neurology, Medical Centre Haaglanden, PO Box 432, 2501 CK The Hague, The Netherlands An important, although less frequently found, feature is Tel: 31 70 330 2067; fax: 31 70 330 3113; e-mail: [email protected] papilledema. However, its absence would not exclude a Current Opinion in Oncology 2004, 16:593–600 brain tumor: Papilledema was absent in more than two

Abbreviations thirds of patients with cerebellar metastases and head- CRF corticotropin-releasing factor ache. In older patients with atrophic , the occur- VEGF vascular endothelial growth factor rence of brain edema would often not result in increased VEGFR vascular endothelial growth factor receptor , probably because of a surplus of © 2004 Lippincott Williams & Wilkins intracranial space, and this may explain the more con- 1040-8746 spicuous absence of papilledema in the elderly. Vomit- ing is more common in children than in adults, and is more often associated with infratentorial lesions.

Hemiparesis, dysphasia, cognitive decline, and other fo- cal neurologic signs may either be the result of brain edema or of tumor growth. Thirty to 40% of patients with 593 594 Brain and brain tumors present with focal neurologic deficits, and a the ventricles and the brain parenchyma. Brain similar percentage develops [4,5]. capillaries are not affected, and restitution of the normal flow will therefore lead Infratentorial lesions need special attention given the to clearance of hydrocephalic edema. vulnerability of the brainstem. Under these conditions, a Osmotic edema is the result of an altered osmotic small amount of edema may result in severe symptoms of gradient between the plasma and the interstitial increased intracranial pressure such as impaired con- fluid. Severe osmotic edema can be seen after wa- sciousness, and emergency treatment is often necessary. ter intoxication, acute , or too rapid reduction of hyperosmolarity [7]. Pathology and pathophysiology Stasis, induced by tumor in venous drainage areas (eg, During the last decade, pathophysiologic mechanisms of compression of an adjacent cortical vein by the tu- brain edema have been extensively studied. Brain mor), with stasis at the site of the compression, edema can be defined as an expansion of brain volume results in peritumoral edema [8]. resulting from an increase in water and content. An excretory–secretory mechanism in in Two major types of edema can be characterized: intra- which tumor-produced substances appear in the and extracellular edema. peritumoral tissue was postulated in the 1980s. Based on electron microscopic studies, a close cor- Intracellular edema relation was found between secretory activity and Increased intracellular water content results in cellular production of edema [9]. swelling. This type of edema is often the result of cyto- Hydrodynamic processes, in which fluids originate toxic injury such as cerebral or trauma and is from the tumor itself, may contribute to the forma- therefore called “cytotoxic edema.” In this type of tion of edema. It was recently shown that contrast edema, the primary targets are the ATP-dependent so- agent effusion from the extracellular space of me- dium pumps: Energy depletion-induced dysfunction of ningiomas into the interstitium of the peritumoral these pumps results in increased intracellular sodium tissue was detectable 3 to 6hours after contrast levels and, as a consequence, results in the accumulation administration [10•]. of intracellular water. Cytotoxic edema is probably not an important component of brain tumor edema, although it Morphologic and molecular alterations in may play a role in situations when (micro)circulation is the blood–brain barrier impeded (eg, after ). The blood–brain barrier is a highly selective interface Extracellular edema separating the brain from the blood. Its most important In the extracellular compartment, water can either be component is the endothelial cell. In contrast to part of the cerebrospinal fluid or of the interstitial fluid. extracerebral capillaries, cerebral endothelial cells are The production of interstitial fluid is probably driven by nonfenestrated, lack intracellular clefts, contain low a pressure and osmotic gradient, is often called “bulk numbers of pinocytotic vesicles, have a high mitochon- flow,” and it may have a role in transporting nutrients drial content, and are enclosed by astrocytic foot pro- and metabolites. An increase in extracellular water leads cesses. These endothelial cells are connected by tight to brain edema. This type of edema is mostly located in junctions, which have both a high electric impedance the . Its properties, consisting of axons run- and a low permeability to polar solutes, and they con- ning parallel to one other and surrounded by an extra- tribute to the selective barrier in this way. Opening of cellular space with a low cell density, would contribute to tight junctions probably plays a key role in the formation a concentration of the edema within the white matter of vasogenic brain edema. and may also serve as a conduit for transporting fluid [6••]. Edema accumulates around brain tumors at a rate of 14 to 78 mL/day [11]. Absorptive mechanisms help to main- The various types of extracellular edema are as follows. tain equilibrium between edema formation and edema absorption. Edema is absorbed by transependymal flow Vasogenic edema is the most common type in brain into the ventricles and by absorption into microvessels. tumors. As a result of increased brain capillary per- The resulting excess of extracellular protein is removed meability and a pressure gradient from vascular to by phagocytosis by and microglia. extracellular compartments, plasma leaks into the brain parenchyma and follows the pathways of bulk The proteins occludin, claudins, and the junctional ad- flow. This type of edema is described in more de- hesion molecule are all part of the molecular composition tail in the next section. of tight junctions in the normal brain [12–15,16•,17•]. Hydrocephalic edema is the result of the obstruction These transmembrane proteins bind intracellular pro- of cerebrospinal fluid flow. Edema is formed be- teins such as ZO-1 and ZO-2, and this binding results in cause of a hydrostatic pressure gradient between the coupling of tight junctions to the cytoskeleton of Brain edema Kaal and Vecht 595 endothelial cells. One has suggested that a decreased of the aquaporin family. In the brain, aquaporin-4 is ex- expression or function of these tight junction proteins pressed in endothelial astrocytic foot processes. Aquapo- leads to opening of the tight junction and to the forma- rin-4 is highly upregulated in high-grade [27,28]. tion of edema. Several studies support this hypothesis. Whether this upregulation results in increased edema For example, microvessels in multiforme formation or in enhanced clearance of edema is still un- express only low levels of claudin-1, and high-grade glio- clear. mas (grades III and IV) do not express functional occlu- din [18,19]. A key mediator in these mechanisms is vas- Meningiomas cular endothelial growth factor (VEGF). Meningiomas are extraaxial tumors comprising approxi- mately 20% of all primary intracranial tumors. Meningi- Vascular endothelial growth factor omas are separated from the brain by the arachnoid, the VEGF was originally described as vascular permeability subarachnoid space, and the pia mater. In contrast to factor and it functions as a regulator of angiogenesis and intraaxial tumors such as gliomas, the relation between vascular permeability [20]. VEGF binds to endothelial VEGF expression and grade of malignancy is unclear. cells via interaction with the high-affinity tyrosine kinase Therefore, the presence of edema does not automatically receptors flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR2). imply a high grade of malignancy. For example, secretory These receptors are expressed predominantly on endo- meningiomas are benign meningiomas (World Health thelial cells [21,22]. VEGF has a very strong vascular Organization grade I) and display extensive edema sur- permeability activity and is a thousand times more po- rounding the tumor [29–31]. These tumors do not dis- tent than histamine [23,24], and probably has direct ef- play severe , and other VEGF-regulating factors fects on the endothelial tight junction (which is de- may be involved. Upregulation of VEGF is probably scribed later). Besides, VEGF induces edema formation regulated by platelet-derived growth factor, epidermal via the synthesis and release of nitric oxide, an activator growth factor, and estrogens in these tumors [32,33,34•]. of cyclic GMP-dependent pathways [25]. VEGF may im- pair the function of occludin: VEGF phosphorylates oc- Gliomas cludin, with the opening of tight junctions as a conse- VEGF expression in gliomas is largely dependent on the quence [18]. Others report that VEGF induces grade of malignancy. Low-grade gliomas express low lev- fenestration of the and enhances capillary els of VEGF, and progression of low-grade gliomas into permeability in this way [26]. The role and expression of malignant gliomas is associated with an up to 50-fold VEGF in meningiomas and gliomas is discussed in the increase in VEGF mRNA [35]. The expression of VEGF next section. VEGF-mediated vasogenic edema is pre- is largely restricted to the perinecrotic cells, suggesting sented in Figure 1. that hypoxia regulates its expression in high-grade glio- mas [36]. An exception to this rule seems to be pilocytic Alternative hypotheses on the formation and regulation astrocytoma. This World Health Organization grade I of brain edema have been generated after the discovery tumor has a good prognosis and displays high levels

Figure 1. Mechanism of VEGF-mediated vasogenic edema formation 596 Brain and nervous system

VEGF mRNA without necrosis [37]. In these tumors, patients may benefit from simple general or pharmaco- VEGF expression may be the result of other factors, such logic measures as well. Overhydration may lead to an as a loss of function of the P53 tumor suppresser gene increase in interstitial fluid accumulation, especially [38]. when the osmotic gradient is disturbed (eg, in hypona- tremia). The observation that the diuretic Other mediators of edema has beneficial effects in combination with corticosteroids Apart from VEGF, other vasoactive substances released supports the importance of adequate hydration [48]. Fur- by the tumor itself or by the injured peritumoral tissue thermore, prevention of severe may be im- may contribute to the formation of brain edema. Arachi- portant: Hypertension leads to increased hydrostatic donic acid metabolites may be important in this respect: pressure and may lead to an increased generation rate of Elevated levels of leukotriene C4 (produced via the li- edema. However, reduction should be poxygenase pathway) are found in glioblastoma multi- done with care to prevent cerebral hypoperfusion and forme, as well as in the surrounding edematous tissue. ischemia. Symptomatic epilepsy should be treated: Sei- More important, the concentration of leukotriene C4 cor- zures create an increased metabolic need and blood flow, relates significantly with the amount of peritumoral potentially leading to edema [49]. edema [39,40]. Another interesting aspect is the obser- vation that the degree of peritumoral macrophage infil- Surgery tration is associated with the amount of edema. This has Surgery, for the purpose of edema treatment, should be prompted the suggestion that secretory products of mac- considered only when life is in immediate danger. Es- rophages would contribute to the formation of edema. pecially, edema-induced obstructive can The list of other potential vasogenic substances that may be treated with shunting. Furthermore, surgery may be promote the development of brain edema is long, includ- necessary in patients with extensive brain edema and ing serotonin, thromboxanes, and platelet-activating fac- impaired consciousness. However, surgery in patients tor [41–43]. with extensive brain edema may be associated with in- creased morbidity: It has been shown that intraoperative Imaging increases in intracranial pressure mostly occur in patients Brain edema can be identified with CT and MRI. On with large amounts of edema. Patients with extensive CT and T1-weighted MRI, brain edema can be visual- preoperative edema may also be at higher risk for post- ized as a hypodense or hypointense lesion. Brain edema operative edema and even brain herniation [50–52]. In and other structures with a high water (proton) content practice, pharmacologic treatment with corticosteroids such as cerebrospinal fluid are hyperintense on T2- (which is described later) results in therapeutic effects weighted MRI. Fluid-attenuated inversion-recovery MR within 24 to 48 hours and would help to avoid emergency images provide additive information, because brain surgery. edema is clearly visualized as a hyperintense lesion against an iso- or hypointense background. Fluid- Osmotherapy attenuated inversion recovery MRI has been compared Osmotherapy with mannitol, glycerol, or hypertonic sa- with T2-weighted MRI in patients with meningiomas line is often used in patients with severe brain edema and is superior to T2-weighted images with respect to after or neurotrauma. A typical dose of, for ex- tumor delineation, contrast of tumor to cerebrospinal ample, mannitol is 1 g/kg (250 mL of a 20% solution in fluid, and contrast of tumor to brain parenchyma [44]. an average adult), resulting in a reduction in intracranial Various methods can be used to display alterations in pressure of 30 to 60% for 2 to 4 hours [53]. Osmotherapy biochemistry in peritumoral brain edema. Changes in results in massive osmotic , so fluid and electro- have recently been studied with dynamic per- lyte balance should be monitored carefully. fusion-weighted MRI. Relative regional cerebral blood volume and flow were almost 50% lower in peritumoral Evidence from randomized studies for a role of osmo- brain edema than in the contralateral white matter in therapy in brain tumor edema is lacking (the same holds patients with meningiomas [45]. Others found significant true for stroke and trauma). Osmotherapy may have reductions in blood flow, oxygen, and glucose in peritu- negative effects in brain cancer as well. As a result of a moral edema using positron emission tomography [46]. disrupted blood–brain barrier, the osmotic agent may Intraoperative studies have shown that peritumoral tis- leak into the brain parenchyma, with further disturbance sue oxygen levels increases up to threefold after decom- of the osmotic gradient as a result. An alternative to man- pression by opening the dura [47]. nitol is glycerol. The “rebound phenomenon” after ad- ministration of an oral glycerol solution (40 mL 85% glyc- Treatment erol) may be less prominent, because this drug is Specific therapies such as surgery, osmotherapy, and cor- metabolized intracellularly [54]. Interestingly, osmo- ticosteroids contribute to the treatment of brain edema therapy may even enhance disturbance of the blood– and are described in the next sections. However, many brain barrier: Mannitol-induced shrinkage of cerebral Brain edema Kaal and Vecht 597 capillaries results in the opening of endothelial tight thors prefer prednisone instead of dexamethasone [54]. junctions and is used (in experimental conditions) to al- A comparison of dexamethasone with other corticoste- low passage of, for example, chemotherapeutics that nor- roids is presented in Table 1. mally cannot enter the brain parenchyma [55]. Regarding all the possible caveats of osmotherapy, we would not Randomized trial routinely recommend osmotherapy in patients with brain One randomized study has addressed the therapeutic ef- tumor edema. fects and side effects of corticosteroids. Ninety-six pa- tients with brain metastases were randomized between Other methods such as hyperventilation, elevation of the 4, 8, and 16mg/day dexamethasone. Administration of 4 head of the bed and fluid restriction may be applied, mg/day or 16mg/day dexamethasone resulted in the although true evidence is not available. same improvement in neurologic function. However, the increase in side effects was dose dependent. Treatment Corticosteroids with 16mg/day dexamethasone resulted in a an approxi- Corticosteroids have been in use since the 1960s, and mate 25% increase in the percentage of patients with although they are associated with substantial side effects, proximal muscle weakness 4 weeks after the start of ste- they play a decisive role in the management of brain roid treatment. Muscle weakness did not increase after 4 edema associated with primary or secondary brain tumors mg/day [64•]. The percentage of cushingoid faces in- [56]. The introduction of corticosteroid therapy in the creased significantly (32% vs 65%, 4 mg/day vs 16 early 1960s coincided with a remarkable decline in peri- mg/day; P = 0.03). These data indicate that many pa- operative mortality rates and indicates the importance of tients can be treated with 4 mg dexamethasone/day, re- these drugs [57]. Several mechanisms for corticosteroid- sulting in significantly less side effects. In patients with induced edema reduction have been proposed: inhibi- impaired consciousness or signs of increased intracranial tion of phospholipase A2, an enzyme of the arachidonic pressure, we would recommend 10 mg intravenously, fol- acid cascade, stabilization of lysosomal membranes, and lowed by 4 × 4 mg/day orally. improvement of peritumoral microcirculation [58]. Side effects Mechanisms of action Apart from steroid myopathy, which may be the result of Corticosteroid treatment results in a decreased edema catabolic effects of corticosteroids, and cushingoid faces formation rate without a noticeable effect on absorption. (resulting from the characteristic redistribution of fat Recent studies have shown that corticosteroids reduce from peripheral to central parts of the body), other seri- the expression of the edema-producing factor VEGF ous side effects are prominent after (high-dose) steroid [59,60]. The edema-reducing effect of corticosteroids is treatment [65]. rapid: Reductions in capillary permeability were ob- served already 1 hour after a single dose of a corticoste- Almost 50% of patients treated with corticosteroids over roid [61]. Apart from an edema-reducing effect, a reduc- a longer period develop a disturbed glucose , tion in tumor size of 15% after corticosteroid treatment and in nearly half of these patients, disturbances persist has been observed, although this effect could not be despite reduction or even withdrawal of the drug [66]. confirmed by others [62,63]. Meta-analyses of the magnitude of the risk corticoste- Dexamethasone is the most commonly used corticoste- roid-induced peptic ulcers provide conflicting results roid. It is approximately six times as potent as prednisone [67,68]. Treatment with H2 blockers or proton pump (20 mg dexamethasone is equivalent to 130 mg predni- inhibitors is recommended in patients receiving drugs sone) and reaches full effect within 24 to 72 hours. Dos- with potential gastrointestinal side effects, such as non- ages of dexamethasone vary between 4 to 100 mg/day. steroidal antiinflammatory drugs, , and Dexamethasone has lower mineralocorticoid (salt- high doses of dexamethasone. Also, in the elderly, peri- retaining) effects than other corticosteroids. The latter operative conditions or in patients with a prior history of effect may lead to increased risk of hyponatremia, which peptic ulcer may benefit from peptic ulcer prophylactics enhances the generation of edema. Therefore, some au- [69•].

Table 1. Dexamethasone compared with other corticosteroids

Antiinflammatory Mineralocorticoid Dose equivalent to Biological activity activity Variable 20 mg cortisol, mg half-life, h (cortisol = 1) (cortisol = 1)

Dexamethasone 0.75 36–54 25–30 <0.2 Hydrocortisone or cortisol 20 8–12 1 1 Prednisone 5 12–36 3.5 0.8 Methylprednisolone 4 12–36 5 0.5 598 Brain and nervous system

Psychiatric complications in patients receiving cortico- Novel treatments steroids seem to be dose dependent as well. A total of Corticotropin-releasing factor (CRF) is an endogenous 676 patients free of psychiatric disease were investigated peptide responsible for the secretion and synthesis of before corticosteroid treatment in the early 1970s. Severe corticosteroids, and has been studied in animal models psychiatric illness (ie, psychosis, mania, or depression) and in patients. was uncommon (1.3%) after receiving less than 40 mg/day prednisone (equivalent to 3 mg/day dexametha- Rats with intracerebral gliomas were treated systemically sone), but increased to 18.5% at doses more than 80 with human CRF or dexamethasone. Both agents effec- mg/day prednisone (equivalent to 12 mg/day dexameth- tively decreased blood–brain barrier permeability mea- asone; as reviewed by Brown and Chandler [70]). sured with MRI. Increased levels of adrenal corticoste- roids were not observed, and it has been concluded that human CRF has a direct action on tumor microvascula- Patients with brain tumors receiving steroids are also at ture, resulting in restoration of blood–brain barrier integ- risk for Pneumocystis carinii pneumonia. In one study of rity [74]. brain tumors, the reported incidence was almost 2% [71]. Prophylactic treatment with trimethoprim–sulfameth- Intravenously administered human CRF resulted in re- oxazole may prevent this potentially life-threaten- covery of neurologic function in 10 of 17 patients with ing pneumonia and is mainly applied to patients who brain metastases. Improvement in symptoms did not cor- have additional reasons for being immune compromised. relate with changes in cortisol levels. Only a small change in brain edema was detected with MRI after CRF treat- Withdrawal of corticosteroids ment. Dose-limiting toxicity () was observed After successful treatment (eg, gross tumor resection), at a dose of 4 µg/kg/hour. Flushing and hot flashes were corticosteroids can be tapered. Corticosteroids should be also observed. Lower doses did not result in severe tox- tapered within 2 to 3 weeks. Decreasing the dose by 50% icity [75]. Although long-term side effects have not been every 4 days is a reasonable approach in patients with a investigated, the data indicate that further studies are good clinical condition. However, patients with poorly necessary. controlled tumors or extensive brain edema may dete- riorate after rapid tapering. Corticosteroids should be ta- Selectively inhibiting VEGF may be effective, and data pered by 25% every 8 days in the latter group. Eventu- from experimental studies are promising: SU5416, a ally, chronic treatment with a low dose of corticosteroids small, lipophilic synthetic molecule that selectively in- (eg, 1 to 2 mg/day) may be needed to have an acceptable hibits the tyrosine kinase activity of the VEGF receptor quality of life. However, the risk of long-term side ef- Flk-1/KDR, was administrated systemically in rats with fects is increased in these patients. intracerebral gliosarcoma. SU5416prolonged survival without any significant systemic adverse effect. Histo- logic analysis of the treated tumors showed an increase in Withdrawal of corticosteroids is associated with morbid- necrosis and reduced vascularity after treatment with ity as well. The so-called “steroid withdrawal syndrome” SU5416[76].SU5416is currently being tested in various was described in the 1960s and is characterized by ar- phase II studies and has shown biologic activity in pa- thralgias, myalgias, and more general symptoms such as tients with hematologic malignancies [77,78]. headache, lethargy, and sometimes low-grade [72]. Especially, leg and joint pain can be severe and may The cyclooxygenase-2 inhibitor SC-236has been inves- result in an inability to walk. The steroid withdrawal tigated recently. Rats with intracerebral gliosarcomas re- syndrome usually follows rapid tapering of corticoste- ceived SC-236, dexamethasone, or no treatment. Median roids (particularly after prolonged periods of high-dose survival increased almost 50% after SC-236or dexameth- use), although it may occur on slow tapering (2 mg asone treatment [79]. In another study, rats with intra- dexamethasone/week) [73]. cerebral gliosarcomas were treated with rofecoxib, an- other selective cyclooxygenase-2 inhibitor. Rofecoxib Another side effect of corticosteroid withdrawal is adre- was as effective as dexamethasone in decreasing the dif- nal insufficiency. Administration of corticosteroids in- fusion of contrast material into the brain parenchyma, duces a negative feedback on the hypothalamic– suggesting a reduction in blood–tumor barrier permeabil- pituitary–adrenal axis. Tapering that occurs too fast may ity. The data from the aforementioned studies indicate lead to secondary adrenal insufficiency with weakness, that selective cyclooxygenase-2 inhibitors appear to be as pigmentation of skin, and weight loss as the most promi- effective as dexamethasone in preventing brain edema nent symptoms. Acute adrenal insufficiency is a feared and that survival is enhanced in these animal models. In but probably rare complication and may lead to hypoten- the past, other nonsteroidal antiinflammatory drugs have sion that is refractory to fluids and requires vasopressors shown variable results in animal models [80]. In a small and admission. series, the classic cyclooxygenase-2 inhibitor ibuprofen Brain edema Kaal and Vecht 599 improved the Karnofsky performance score in 40% of 13 Furuse M, Fujita K, Hiiragi T, et al.: Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J patients [81]. Novel cyclooxygenase-2 inhibitors need Cell Biol 1998, 141:1539–1550. further testing in humans with tumor-induced brain 14 Hirase T, Staddon JM, Saitou M, et al.: Occludin as a possible determinant of edema. tight junction permeability in endothelial cells. 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