Radiation-induced Brain Edema Research Articles

Short-term topiramate treatment prevents radiation-induced cytotoxic edema in preclinical models of breast-cancer brain metastasis.

Brain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema, and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in preclinical models of breast-cancer brain metastases (BCBM). Using in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER), and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM. Radiation-induced astrocytic swelling and transient upregulation of AQP4 occurred within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling and loss of TEER in astrocytes in vitro, and acute short-term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple preclinical models of BCBM. AQP4 was expressed in clinical BM and breast-cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation. Patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function.

Hypo-fractionated Gamma Knife Radiosurgery for Intra-cranial Pathologies: A Single-Center Prospective Analysis of Feasibility, Safety, Efficacy, and Complication Profile.

Single-session stereotactic radiosurgery (SRS) is a proven and effective treatment modality for various benign, malignant, and functional intra-cranial pathologies. In certain situations, single-fraction SRS is limited because of lesion size and location. Hypo-fractionated gamma knife radiosurgery (hfGKRS) is an alternative approach for such unconventional indications. To evaluate the feasibility, efficacy, safety, and complication profile of hfGKRS with evaluation of different fractionation schemes and dosing patterns. The authors prospectively evaluated 202 patients treated with frame-based hfGKRS over a 9-year period. GKRS was administered fractionated because of either a large volume (>14 cc) or an inability to spare neighboring organs at risk from permissible radiation in single-session GKRS. The inter-fraction interval was kept at 24 hours, and the dose calculation was performed with linear quadratic equations. Patients with more than 3 years of clinical and radiological follow-up were included in prospective analysis. At pre-decided follow-up criteria, treatment effects and side effects were documented on objective scales. A total of 169/202 patients met inclusion criteria. 41% patients received treatment in three fractions, whereas 59% received two-fraction GKRS. Two patients of giant cavernous sinus hemangiomas were treated with 5 Gy in the five-fraction regimen. In patients with more than 3 years of follow-up, the obliteration rate was 88% for complex arteriovenous malformations (AVMs) treated with hfGKRS because of eloquent locations, whereas it was 62% for Spetzler-Martin grade 4-5 AVMs. For non-AVM pathologies (meningiomas, schwannomas, pituitary adenomas, paragangliomas, hypothalamic hamartomas, etc.), the 5-year progression free survival was 95%. Tumor failure was noted in 0.05% patient population. Radiation necrosis developed in 8.1% patients, and radiation-induced brain edema developed in 12% patients. It was resistant to treatment in 4% patients. No patient developed radiation-induced malignancy. Hypo-fractionation did not provide any hearing improvement in giant vestibular schwannomas. hfGKRS is a valuable standalone treatment option for candidates unsuitable for single-session GKRS. The dosing parameters need to be tailored as per the pathology and neighboring structures. It provides comparable results to single-session GKRS with an acceptable safety and complication profile.

BSCI-17 TOPIRAMATE DECREASES RADIATION-INDUCED CYTOTOXIC EDEMA IN HER2+ BRAIN METASTASES VIA AQUAPORIN 4 INHIBITION

Abstract Brain metastasis (BM) occurs in 30-40 % of breast cancer patients with Her2+ tumors, and radiation is part of the standard treatment for BM. About 10% of BM patients treated with radiation develop brain edema. We have shown that combination of Ado-trastuzumab Emtansine (T-DM1)-the main targeted therapy for metastatic Her2+ Breast Cancer- and radiation increases the risk of developing radionecrosis by 13.5-fold (Stump et al., 2019). We also showed that T-DM1 enhances radiation-induced astrocytic toxicity and cytotoxic edema through upregulation of aquaporin-4 water-transporter (AQP4). Here, we determined whether blockage of AQP4 would prevent astrocytic swelling –cytotoxic edema- in vitro and in vivo models of Her2+ BM. Results: Electron microscopy of brain cortex from mice treated with 35 Gy (single dose), showed acute astrocytic end-feet swelling and a significant increase in AQP4 expression compared with non-irradiated mice. Consistent with prior findings in murine astrocytes, primary human astrocytes (huAST) also upregulated AQP4 levels 24 h post-radiation (8 Gy), and T-DM1 treatment exacerbated this effect. AQP4 upregulation was concomitant with 4.8 fold increase in the astrocytic area (indicative of cytotoxic edema). The FDA-approved anti-epileptic and migraine prevention drug, Topiramate (TPM), which works as an AQP4 inhibitor, blocked radiation-induced astrocytic swelling in huAST in vitro. Thus, we tested whether pre-treatment with TPM could prevent radiation-induced edema in a mouse model of HER2+BMs. Mice were injected intracardially JmT1BR3 brain metastatic cells and ten days later randomized based on the total head flux to (1) Radiation + vehicle, (2) Radiation + TPM (2 days prior to irradiation), (3) Non-Radiation + vehicle, and (4) Non-radiation + TPM. TPM decreased brain-water content (a marker of brain edema) in irradiated mice as compared with vehicle-treated mice, without alteration of metastatic burden 21 days post-injection. These results suggest TPM could be repurposed as a preventive agent of radiation-induced brain edema.

Analyzing the association between dose-volume parameters and radiation-induced brain edema in patients with brain tumor receiving stereotactic radiosurgery

In this paper, three-dimensional images were used to analyze the association between dose-volume parameters and radiation-induced brain edema in patients with a brain tumor after receiving stereotactic radiosurgery (SRS). The computed tomography (CT), magnetic resonance images (MRI) and treatment parameters were transferred through the treatment planning system (Multiplan, version 5.1.3). The correlation between the dose of radiation therapy and brain edema was evaluated by image processing methods, such as image normalization, registration, filtering, segmentation, and feature extraction. The association was evaluated by volume index and intersection index. The study results suggest that the volume receiving radiation dose above 30% of the prescribed dose is highly associated with the brain edema in brain tumor patients after SRS. The small number of patients limits the study. Further investigation with larger populations and long-term epidemiological studies are required.

Effect of X-rays on transcript expression of rat brain microvascular endothelial cells: role of calcium signaling in X-ray-induced endothelium damage.

Radiation-induced brain edema is a serious adverse effect of radiotherapy. Although there are many causes of radiation-induced brain edema, the pathogenesis is not clear and clinical treatment is not ideal. Therefore, knowing the differential expression of the brain microvascular endothelial cell (BMEC) transcriptome after brain radiotherapy may shed light on the pathogenesis of radiation-induced brain edema. The present study used RNA-Seq technique to identify 383 BMEC transcripts differentially expressed (many 2-fold or higher; P < 0.05) between control and X-ray–treated primary cultured rat BMECs. Compared with controls, X-ray–treated BMECs had 183 significantly up-regulated transcripts and 200 significantly down-regulated transcripts. The differentially expressed genes were associated with the biological processes of the cell cycle, apoptosis, vascular permeability, and extracellular junctions. The functional changes identified in the X-ray–treated BMECs included Ca2+ signaling, phosphoinositide 3-kinase–Akt signaling, and methionine degradation. These results indicated that transcript expression was substantially affected by radiation exposure and the proteins encoded by these differentially expressed genes may play a significant role in radiotherapy-induced brain edema. Our findings provide additional insight into the molecular mechanisms of radiation-induced brain edema and may be helpful in the development of clinical treatment of this adverse reaction to radiotherapy.

Abstract P5-14-20: Mechanisms of radiation-induced brain edema alone and in combination with T-DM1 in Her2+ brain metastases

Abstract Introduction: Brain metastases (BM) occurs in ~40% of breast cancer patients with Her2+ tumors, which are typically treated with the Her-2 targeting drugs ado-trastuzumab emtansine (T-DM1) and trastuzumab. Radiotherapy (RTx), including stereotactic radiosurgery (SRS), is often utilized to treat BM. A subset of BM patients treated with SRS develops brain edema and radionecrosis (ERN), causing neurological deterioration, functional loss, and rarely death. We have reported an increased rate of ERN in patients treated with T-DM1 and SRS (39.1%), compared to those receiving SRS alone (4.5%). Thus, defining the mechanisms underlying ERN alone or in combination with T-DM1, is critical to reduce life-threatening side effects. While brain edema associated with BM and RTx is often attributed to blood-brain-barrier (BBB) disruption (vasogenic edema), recent studies now identify cytotoxic edema (osmotic cell expansion) as the initial andreversible step in a sequence of changes that leads to ionic edema, vasogenic edema, and ultimately brain swelling and necrosis. Here, we test the hypothesis that RTx alone and in combination with T-DM1 induces cytotoxic edema in astrocytes via upregulation of the water channel Aquaporin 4 (AQP4) and that blockage of cytotoxic edema will decrease ERN. Results: A cohort of BM from Her2+ patients treated with T-DM1/SRS showed enlarged reactive astrocytes expressing high levels of AQP4. To assess the role of astrocytic swelling in ERN, human astrocytes (THV) were treated with increasing doses of RTx and astrocytic cell size was measured 24 h later. A single 8 Gy RTx-dose increased cell size by 4.5 times compared to non-treated astrocytes (1248 ± 760.8 µm2 vs 5685 ± 4475 µm2, P&amp;lt;0.0001). Consistent with a role for AQP4 in mediating astrocytic swelling, western blot (WB) showed increased AQP4 levels in RTx treated cells. To assess whether Her2-targeting (or directed) therapies impacted AQP4 expression and astrocytic survival/swelling, astrocytes were treated with increasing doses of RTx alone (0, 2, 4, 8 Gy), with trastuzumab or T-DM1 (1 μg/mL). WBs showed that only T-DM1 further exacerbated RTx-induced AQP4 upregulation and increased PARP cleavage. The combination of 4 Gy-RTx and T-DM1 showed a synergistic effect in reducing astrocytic confluence (32.1%), compared with astrocytes treated with 4 Gy-RTx alone (32.8 ± 3 vs 64.9 ± 13.3% respectively, P=0.0001, at 5 days). Moreover, T-DM1/RTx increased astrocytic size (P = 0.004) to a greater extent than equivalent RTx dose in combination with trastuzumab (P = 0.005). Other chemotherapeutic agents (paclitaxel and cisplatin) did not affect AQP4 protein levels, astrocytic survival or astrocytic swelling. TGN-020, a novel AQP4 inhibitor, and topiramate (TPM), an FDA-approved anticonvulsant/antiepileptic able to inhibit AQP4 activity, were evaluated for their potential role in reducing astrocytic swelling. Pretreatment with 100 µM TPM reduced RTx-induced astrocytic swelling by 36 % (7153 ± 4522 µm2 vs 4627 ± 3999 µm2, P&amp;lt;0.0001). TPM pretreatment did not prevent 8 Gy-RTx-induced cell death (24.96 ± 5.7 % vs 23.47 ± 4.7 %) nor prevent DNA double stranded breaks measured by IF of p-γH2AX (89.17 ± 13.89 % vs 97.32 ± 2.94 %). Ongoing studies are assessing the effect of TPM on blocking astrocytic swelling and decreasing brain edema in vivo. Conclusions: These results suggest that astrocytic swelling (cytotoxic edema) is involved in the pathophysiology of ERN during BM treatment. In vitro, AQP4-inhibitors decreased astrocytic swelling without affecting astrocyte survival, suggesting that blockage of AQP4 could reduce brain edema without rescuing lethally-damaged astrocytes. Thus, a combination of drugs preventing vasogenic dysfunction (i.e bevacizumab) and AQP4-inhibitors (i.e TPM) could diminish ERN by targeting both, vasogenic and cytotoxic edema. Citation Format: María J Contreras-Zárate, Steven Lai, Priscilla Stumpf, Christine Fisher, Ryan Ormond, Sana D Karam, Peter Kabos, Diana M Cittelly. Mechanisms of radiation-induced brain edema alone and in combination with T-DM1 in Her2+ brain metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-20.

The Safety and Efficacy of Bevacizumab for Radiosurgery - Induced Steroid - Resistant Brain Edema; Not the Last Part in the Ship of Theseus.

Radiation-induced brain edema (RIBE) is a serious complication of radiation therapy. It may result in dramatic clinico-radiological deterioration. At present, there are no definite guidelines for management of the complication. Corticosteroids are the usual first line of treatment, which frequently fails to provide long-term efficacy in view of its adverse complication profile. Bevacizumab has been reported to show improvement in cases of steroid-resistant radiation injury. The objective of this study is to evaluate the role of Bevacizumab in post-radiosurgery RIBE. Since 2012, 189 out of 1241 patients who underwent radiosurgery at our institution developed post-radiosurgery RIBE, 17 of which did not respond to high-dose corticosteroids. We systematically reviewed these 17 patients of various intracranial pathologies with clinic-radiological evidence of RIBE following gamma knife radiosurgery (GKRS). All patients received protocol-based Bevacizumab therapy. The peer-reviewed literature was evaluated. 82 percent of the patients showed improvement after starting Bevacizumab. The majority began to improve after the third cycle started improvement after the third cycle of Bevacizumab. Clinical improvement preceded radiological improvement by an average of eight weeks. The first dose was 5 mg/kg followed by 7.5-10 mg/kg at with two-week intervals. Bevacizumab needs to be administered for an average of seven cycles (range 5-27, median 7) for best response. Steroid therapy could be tapered in most patients by the first follow-up. One patient did not respond to Bevacizumab and needed surgical decompression for palliative care. One noncompliant patient died due to radiation injury. Bevacizumab is a effective and safe for treatment of RIBE after GKRS. A protocol-based dose schedule in addition to frequent clinical and radiological evaluations are required. Bevacizumab should be considered as an early treatment option for RIBE.

Apatinib in refractory radiation-induced brain Edema: A case report: Erratum.

Apatinib in refractory radiation-induced brain Edema: A case report: Erratum.

Relationship between therapy of radioactive cerebral edema with methylprednisolone and dexamethasone and transcription level of epidermal growth factor receptor 1

Objective To study the effect of methylprednisolone (MP) and dexamethasone (DXM) on radioactive cerebral edema and the transcription level of epidermal growth factor receptor 1 (erb-B1). Methods One hundred male Wistar rats were divided into 5 groups randomly (n=20). Group A was irradiated in combination with 30 mg/kg MP, group B was irradiated in combination with 10 mg/kg MP, group C was irradiated in combination with 5 mg/kg DXM, group D was irradiated without glucocorticoid (GC), and group E served as normal control. Glioma cells were planted into brains of rats in groups A, B, C, D and E, and the animals in groups A, B, C, and D were given irradiateion of 60Co after 15 days. All groups were give GC or normal saline 3 days before and 6 days after irradiation. The water content of the brains and the transcription level of erb-B1 were measured 6 days after irradiation. Results The water content of the rats brain: A: 0.758 8±0.015 9, B: 0.766 9±0.017 4, C: 0.796 5±0.019 7, D: 0.828 3±0.021 6, E: 0.727 0±0.011 3. There was significant difference between group D, E and group A, B, C (P 0.05). The level of erb-B1 mRNA: A: 0.739 1±0.041 5, B: 0.741 0±0.034 4, C: 0.775 4±0.054 6, D: 0.802 1±0.055 8, E: 0.715 6±0.059 2. There were significant difference between group D, E and group A, B, C (P 0.05). Conclusion MP and DXM can both protect the radiation-induced injury and brain edema changes by inhibiting the transcription level of erb-B1 mRNA in rats, and the MP is more efficient than DXM. Key words: Radioactive cerebral edema; Glioma; Methylprednisolone; Dexamethasone; erb-B1

Efficacy analysis of Gamma knife for the treatment of different types of acoustic neuroma

Objective To analyze the efficacy of Gamma knife for the treatment of different types of acoustic neuroma. Methods From April 1997 to June 2013, 123 patients with acoustic neuroma (<3 cm) treated with Gamma knife in Xiangya Hospital, Central South University were enrolled retrospectively. Hasegawa classification: type A 5 cases, type B 38 cases, type C 47 cases, and typed D 33 cases. Different types of tumor growth and complications after treatment were analyzed and the related factors of influencing the effective tumor control rate were investigated. Results The follow-up time of 123 patients ranged from 6 to 135 months (median, 41 months). The 5-year effective tumor control rate was 92.1%. The tumor control rate of type D was lower than A+ B+ C types (74.1% and 96.1% respectively; P<0.01). Multivariate Cox model analysis showed that the tumor type was an independent factor for affecting tumor control rate (RR, 12.172, 95% CI 2.584-57.348; P=0.002). In the 123 patients, the incidence of radiation-induced brain edema was 12.2% (n=15), and the type A, B, C, and D were 0%, 2.6% (n=1), 10.6% (n=5), and 27.3% (n=9), respectively. The incidences of type C and D were higher than those of type A and B (P=0.014). The incidence of hydrocephalus was 2.4% (n=3, all type D). Of the patients with complete assessment data, the incidence of facial palsy was 10.8% (n=8), and the type A, B, C, and D were 1/4 (n=1), 8.0% (2/25), 4.2% (1/24), and 19.0% (4/21), respectively. The incidence of rigeminal nerve dysfunction was 29.7% (n=22), and type A, B, C, and D were 0%, 4% (1/25), 37.5% (9/24), and 57.1% (12/21), respectively. The incidences of type C and D were higher than those of type A and B (P=0.001). Conclusions The effective control rate of Gamma knife for the treatment of <3 mm acoustic neuroma and the neurological retention rate were closely associated with the tumor typing. The prognoses of type A and B were better, and those of type C and D were poor. Key words: Neuroma, acoustic; Gamma knife; Tumors categories; Complications

Positive correlation between occlusion rate and nidus size of proton beam treated brain arteriovenous malformations (AVMs)

Background. Proton beam radiotherapy of arteriovenous malformations (AVM) in the brain has been performed in Uppsala since 1991. An earlier study based on the first 26 patients concluded that proton beam can be used for treating large and medium sized AVMs that were considered difficult to treat with photons due to the risk of side effects. In the present study we analyzed the result from treating the subsequent 65 patients.Material and methods. A retrospective review of the patients’ medical records, treatment protocols and radiological results was done. Information about gender, age, presenting symptoms, clinical course, the size of AVM nidus and rate of occlusion was collected. Outcome parameters were the occlusion of the AVM, clinical outcome and side effects.Results. The rate of total occlusion was overall 68%. For target volume 0–2cm3 it was 77%, for 3–10 cm3 80%, for 11–15 cm3 50% and for 16–51 cm3 20%. Those with total regress of the AVM had significantly smaller target volumes (p < 0.009) higher fraction dose (p < 0.001) as well as total dose (p < 0.004) compared to the rest. The target volume was an independent predictor of total occlusion (p = 0.03). There was no difference between those with and without total occlusion regarding mean age, gender distribution or symptoms at diagnosis. Forty-one patients developed a mild radiation-induced brain edema and this was more common in those that had total occlusion of the AVM. Two patients had brain hemorrhages after treatment. One of these had no effect and the other only partial occlusion from proton beams. Two thirds of those presenting with seizures reported an improved seizure situation after treatment.Conclusion. Our observations agree with earlier results and show that proton beam irradiation is a treatment alternative for brain AVMs since it has a high occlusion rate even in larger AVMs.

The efficiency of adjusted-da-chai-ling-tang in radiation-induced brain edema in patients with brain tumors

Background: Brain edema induced by radiotherapy is a common complication in patients with brain tumors, for which medical treatment is the treatment of choice. Adjusted-Da-Chai-Ling-Tang, a Chinese herbal formulation, has been confirmed to be protective against the radiation-induced edema. In this study, we investigated the efficiency of adjusted-Da-Chai-Ling-Tang in radiation-induced brain edema in patients with brain tumors. Materials and Methods: A total of 46 patients with brain tumors treated with radiotherapy alone or combined with surgery were enrolled. These patients were divided into two groups: The experimental group with adjusted-Da-Chai-Ling-Tang and the control group with conventional medical treatment. Clinical data including symptoms and serologic results were collected pretreatment and on the 4^th, 7^th and 10^th day posttreatment. Magnetic resonance imaging of the brain was performed to investigate changes in brain edema. Results: Clinical symptoms including headache, dizziness, nausea/vomiting and fatigue significantly improved in the experimental group (P＜0.05). No difference in serological results was observed. Brain edema was significantly reduced in the experimental group in magnetic resonance imaging (P＜0.05). Conclusion: Adjusted-Da-Chai-Ling-Tang is effective in the treatment of radiation-induced brain edema in patients with brain tumors. No obvious side effects were observed.

Early Draining Vein Occlusion After Gamma Knife Surgery for Arteriovenous Malformations

Increased signals on T2-weighted magnetic resonance imaging usually interpreted as radiation-induced changes or brain edema is a common short- to mid-term complication after Gamma Knife surgery (GKS) for intracranial arteriovenous malformations (AVMs), although its nature remains to be clarified. Early draining vein occlusion with resultant brain edema or hemorrhage, although well established in surgical series, was not described in radiosurgical literature until recently. To outline the incidence, clinical manifestations, and outcomes of this unusual complication in our series of 1256 AVM patients treated with GKS. From 1989 to 2008, 1400 patients underwent GKS for cerebral AVMs or dural arteriovenous fistulae at the University of Virginia. In 1256 patients, magnetic resonance imaging after GKS was available for analysis of radiation-induced changes and early draining vein occlusion. After GKS, 456 patients (36%) developed radiation-induced changes surrounding the treated nidi. Among these patients, 12 had early thrombosis of the draining vein accompanied by radiation-induced changes. Venous thrombosis occurred 6 to 25 months (median 11.6 months) after GKS. Three patients were asymptomatic on the image findings of venous occlusion and brain edema, 3 experienced headache, 1 had seizure and headache, and neurological deficits developed in 5. Patients with neurological deficits were treated with corticosteroids; 2 of the patients recovered completely, 1 still had slight hemiparesis, 1 had short-term memory deficits, and 1 died of massive intracerebral hemorrhage. Although venous structures are considered more radioresistant, endothelial damage accompanied by venous flow stasis might cause early venous thrombosis and premature venous occlusion after radiosurgery for AVMs. In our series, all patients had a favorable outcome except 1 with a fatal hemorrhage.

The Relationship Between the Therapy of Radioactive Cerebral Edema With Methylprednisolone and Dexamethasone and the Transcription Level of erb-B1: A Research Study

Objective To study the effect of methylprednisolone and dexamethasone to radioactive cerebral edema and the transcription level of erb-B1. Methods One hundred male Wistar rats were divided into 5 groups at random (n=20). Group A was irradiated and treated with 30 mg/kg methylprednisolone, group B was irradiated and treated with 10 mg/kg methylprednisolone, group C was irradiated and treated with 5 mg/kg dexamethasone, group D was irradiated without glucocorticoid, and group E was normal control. Implanted glioma cells in brains of rats of groups A, B, C, D, and E were irradiated with Co60 15 days after implantation. All groups were given daily intravenous glucocorticoid or normal saline, beginning 3 days before irradiation and ending 6 days after irradiation. The water content of the brains of the rats and the transcription level of erb-B1 were measured 7 days after irradiation. Results Regarding the water content of the rat brains and the transcription level of erb-B1 mRNA, there is significant difference (P<0.05) between group D and groups A, B, and C and also group E and groups A, B, and C. There is significant difference (P<0.05) between group D and group E and between group C and group A and also group C and group B, but there is no significant difference between group A and group B. Conclusions Methylprednisolone and dexamethasone can protect both the radiation-induced injury and brain edema changes by inhibiting the transcription level of erb-B2 mRNA in rats. Methylprednisolone is more efficient than dexamethasone.

Meclomen Potentiates Dermatologic Effects of Steroids

To the Editor. —In an earlier letter, we reported on the potentiating effect of meclofenamate sodium (Meclomen) on the clinical brain edema—reducing effect of cortical steroids. 1 This study was based on experiments in monkeys and mice in which meclofenamate reduced radiation-induced brain edema and mucositis. It also reduced ultraviolet radiation—induced dermal pathology, including carcinogenesis in hairless mice. Meclomen appears to block both the cyclooxygenase pathway leading to the synthesis of prostaglandins and thromboxanes and also lipooxygenase leading to the production of leukotrienes. In addition, it blocks prostaglandin E 2 receptors. All of these factors appear to be involved in inflammatory reactions and edema, including radiation-induced reactions of normal tissues. This may explain therapeutic effects of meclofenamate in the above system. 2-5 Several investigators reported activity of anti-prostaglandins in animal models of allergic dermatitis 6 and, possibly, in human inflammatory skin disorders. 7 A 62-year-old man had extensive dermatitis