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48646ournal ofNeurology, Neurosurgery, and Psychiatry 1992;55:486-490

Mifepristone (RU 486) treatment of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from meningiomas

S W J Lamberts, H L J Tanghe, C J J Avezaat, R Braakman, R Wijngaarde, J W Koper, F H de Jong

Abstract grow during ,2 while an association Meningiomas are common brain tumours between breast cancer and meningiomas has which are generally benign, well circum- been reported.3 These observations suggest a scribed and slow growing. In a minority of biological role of female sex in the patients complete surgical removal is not regulation of the growth of meningiomas. possible and re-growth of tumour tissue is Indeed, , but not oestradiol recep- a major clinical problem. Most meningio- tors have been found in virtually all meningio- mas contain progesterone receptors. The mas, both from female and male patients.4-9 anti-progestational drug mifepristone The first clinically available progesterone (RU 486) binds to these receptors. Ten antagonist mifepristone (RU 486) has patients were treated with 12 recurrent or been shown to bind to the progesterone primary "inoperable" meningiomas, all receptors in meningiomas.9 Both studies with of whom had shown recent neuroradio- cultured meningioma cells or explants and logical and/or ophthalmological evidence with nude mice carrying meningioma tissue of tumour growth. They received 200 mg suggest that hormonal manipulation can influ- mifepristone daily for 12 months. Most ence growth in part of the tumours.'"'7 Our patients initially had complaints of nau- own culture studies indicate that progesterone sea, and/or tiredness. In four increases the sensitivity of cultured meningio- patients (7.5 mglday) was giv- ma cells to mitogenic stimuli, while mifepris- en after which these side-effects subsided. tone counteracts these stimulating effects.18 CT scan analysis of tumour size, showed Preliminary studies of treatment of meningio- progression of growth of five meningio- ma patients with ace- mas in four patients, stable disease in tate, tamoxifen, and LHRH analogs suggest three patients with three tumours and that the growth of meningiomas in a minority regression of four tumours in three of patients can be controlled.' 9-22 patients. A decrease in the complaints of In this study we investigated the effect of headache and an improved general well therapy with mifepristone (200 mg/day) for 12 being was observed in five patients. Two months on 10 meningiomas patients who patients died during the treatment period showed neuroradiological and/or ophthalmo- from unrelated causes. Mifepristone logical evidence of recent progressive tumour

treatment resulted in control of tumour growth. http://jnnp.bmj.com/ growth (= stable disease) in six of 10 patients who had shown recent evidence of tumour growth. In three of these six Patients and methods patients consistent tumour shrinkage was Patients and experimental protocol observed. In this study 10 patients with single or multiple Erasmus University, meningiomas were investigated (table). Apart Rotterdam, The Netherlands Meningiomas occur more frequently in women from patient 10, all females were menopausal. men.' Previous clinical and In all patients there was neuroradiological on September 30, 2021 by guest. Protected copyright. Department of than in epidemio- Medicine logical studies suggest that these tumours often evidence (nine patients) and/or ophthalmo- S W J Lamberts J W Koper F H de Jong Table Patient data Department of MIF Age Localisation meningioma, size at start (cm3), previous therapy, recent growth Radiology therapy H L J Tanghe 1 F 71 - Tuberculum sellae (right): 8-3 cm3; continuous growth since 2 years, blindness right eye Department of 2 F 53 - Inner ridge (left) and tentorium (left) of 10-2 and 5-3 cm3; slow, persistent growth since 1-5 Neurosurgery yr; visual loss left eye C J J Avezaat 3 M 63 + Inner/middle ridge (left): 67-4 cm3; previous operations 1972, 1982, 1986; rapid R Braakman progressive growth, visual loss left eye 4 F 72 + Frontal: 66-5 cm': previous operations 1965, 1981; continuous growth since 6 years; slow Department of affect; epilepsy Ophthalmology 5 F 48 - Suprasellar: 28 cm3: previous operation 1978; tumour size unchanged since 8 years; RWijngaarde blindness right eye, progressive visual loss left eye Correspondence to: 6 M 54 + Parasagittal (right): 68-7 cm3; previous operation 1974; continuous growth since 2 years Professor Lamberts, 7 M 68 + Sphenoid (right) with infratemporal and intraorbital extension: 164 cm3; previous Department of Medicine, operations 1973, 1986; blindness right eye and continuous growth since 2 years; proptosis University Hospital Dijkzigt, right eye 40 Dr Molewaterplein, 3015 8 F 64 - Parasellar (left) at apex left opticus (9-6 cm3); continuous growth since 3 years, progressive GD Rotterdam, The visual loss left eye, proptosis left eye Netherlands. 9 F 53 - Sphenoid (left) with para-sellar, sellar and infratemporal extension: 89-5 cm'; previous operations 1983 and 1987; rapid growth since 2 years; tumour palpable in upper jaw, Received 19 March 1991 hypopituitarism, treated with (30 mg/day) and in revised form 10 F 32 + Falx (left) and cerebellar/tentorium (right) tumours of 25-3 and 21-5 cm3; bilateral 19 March 1991. acousticus neurinomas, bilateral opticus tumours, previous operation in 1987 Accepted 8 August 1991 Mifepristone (RU 486) treatment of meningiomas 487

logical evidence of recent progressive tumour side effects in six patients: and anorexia J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from growth (patients 1, 2, 3 and 5). In seven occurred for a period ofa few days to up to two patients this was tumour progression or recur- weeks in three patients, while three patients rence after previous operation(s), while three took the drug without side effects. The other patients had not had a previous operation. All four patients (2, 3, 4 and 6), however, experi- patients had been selected by at least two enced more severe complaints of nausea (4) independent neurosurgeons of the staff of the and recurrent attacks of vomiting (3) starting department of neurosurgery of the University during the first week of therapy. In addition Hospital Rotterdam because: a) Reoperation these four patients felt exhausted and anor- was not expected to completely remove the ectic. In patient 4 prolonged vomiting stopped tumour; b) The localisation of the tumour on the third day of mifepristone therapy, caused a high risk of severe complications shortly after the start of the simultaneous during/after surgery; c) The general condition administration of 7-5 mg prednisone daily. In of the patient was so poor, that surgery seemed patients 2, 3 and 6 these complaints persisted contraindicated (patients 3 and 4). Exclusion and concomitant prednisone therapy (7 5 mg) criteria were pregnancy, the use of oral contra- was started after three weeks. Thereafter these ceptives, patients with a very poor performance complaints subsided, but prednisone therapy status, signs or symptoms of an elevated was continued in all four patients throughout intracranial pressure, coexistent psychiatric the study. No changes in blood pressure diseases, other cancer, renal and insuffi- (supine and/or standing) were noted during ciency. mifepristone treatment for up to one year. Also The experimental protocol had been ECG and routine clinical chemical investiga- approved by the ethical committee of the tions did not show changes. These included the University Hospital Rotterdam. All patients measurements of fasting glucose, potassium, signed an form in which the chloride and sodium concentration in serum, seriousness of their disease and the unknown renal and liver functions, as well as haemoglo- effects of mifepristone therapy were bin, haematocrit, white blood cell and throm- explained. bocyte counts. Body weights did not change According to the experimental protocol the significantly in these 10 patients during mife- patients were treated for 12 months with 200 pristone treatment. mg mifepristone daily. If side effects or signs of (relative) adrenocortical insufficiency devel- 2) Changes in tumour size and tumour related oped, a daily dose of 7-5 mg prednisone would complaints during treatment be added to mifepristone therapy. Clinical Mifepristone resulted in a general improve- evaluation was done every two to three weeks ment of well being in four patients (1, 7, 8 and during the first three months and every two 9). Especially complaints of headaches and/or months during the second part of the study. If tension in the jaw, skull or eye improved or visual abnormalities existed, the patients were disappeared in five patients. In patient 2 the also followed on a regular basis by an ophthal- visual acuity of the left eye improved slightly, mologist. Side effects were carefully noted and while in patient 8 the palpable part of the soft ECGs, measurement of blood pressure and tissue mass in the upper jaw shrank con-

routine clinical chemical determinations were siderably. The proptosis of one eye in patients 7 http://jnnp.bmj.com/ carried out at least four times during the and 8 did not change during mifepristone investigation period. treatment. In patient 5, however, the already very bad visual acuity of the remaining eye CT scanning and analysis of tumour size further deteriorated during therapy. The size of the meningiomas was measured Changes in tumour volume were measured repeatedly with the same Philips Tomoscan in these 10 patients by CT scanning at regular 310 apparatus. Tumour volume was calculated intervals during and after mifepristone therapy on September 30, 2021 by guest. Protected copyright. by CT planimetry independently by the same (figure). In four patients clear growth of five neuroradiologist (HT) and neurosurgeon (RB) meningiomas was observed during therapy. under the same conditions. The thickness of Two of these patients died during this period. the slices was kept constant at 3 mm. Measure- Fourteen months before the start of therapy ment of the planar surface of the tumour in patient 3 had undergone a coronary bypass each slice was calculated by computer after operation because of longstanding angina. In circling the outer border. All calculated sur- parallel he developed progressive visual loss of faces were added to calculate the volume of the the left eye, aphasia, headaches, paresis of the tumour. Ifhyperostotic bone was present at the right arm, while he could no longer walk surface of the tumour, this was added in a because of loss of equilibrium. These symp- constant manner as part of the tumour. This toms were attributed to a rapidly growing also applied to the cavernosus sinus in the few meningioma in the inner and middle ridge with cases were no sharp margin with the tumour intra-orbital expansion on the left side. The could be determined. Repeated measurement initiation of mifepristone therapy resulted in by a given neuroradiologist ofthe same tumour side effects (see above), which were well on the same CT scan had an error rate of controlled by prednisone (7-5 mg/day). There < 5%. were no complaints of headaches. Precordial pains were controlled with beta-blocking agents. No signs or symptoms of congestive Results heart failure were observed. After 4*5 months 1) Tolerancelside effects of mifepristone therapy he developed pulmo- Mifepristone caused no or minimal transient nary oedema and a period of ventricular 488 Lamberts, Tanghe, Avezaat, Braakman, Wijngaarde, Koper, de long

Figure The course of treatment (the fig. lower section). The right J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from tumour size before, during Mifepristone 200 mg/day and after mifepristone (200 parasagittal meningioma of patient 6 only mg/day) treatment of 10 300 transiently decreased in size after two months patients with inoperable ,(10~~~~~1) of treatment, while the huge sphenoid menin- primary or recurrent 250 meningiomas. Top: five gioma with considerable extension in the tumours in four patients infratemporal fossa and into the pituitary fossa which showed growth; (4)8~~~4)1 of patient 9 also transiently decreased in size. middle: three tumours in ( 1 0 three patients which )~~~~~~~~(0 This was accompanied by an impressive clin- - this patient throughout remained stable and I - I0 ical improvement in bottom: four tumours in -8 -6-4-2 o 2 4 6 8 10 12+2+4+~6+;810 the 12 month treatment period with dis- three patients which showed (transient) decrease in size. appearance of pain and swelling of the jaw. In (The numbers correspond patient 2 both a parasellar and a tentorium to the patient numbers in meningioma decreased in size, while the visual the table, on the x-axis acuity of the left eye improved. time is expressed in months, before (-) and after (+) therapy). Discussion Meningiomas are common tumours of the arachnoidea, which account for about 20% of intracranial tumours.2' They are generally benign, well circumscribed, and slow growing. They can, however, be accompanied by inva- sion of the bone and/or encasement of major blood vessels, or they may grow to massive proportions, compromising the likelihood of total surgical removal. In addition multiple fibrillation was treated by defibrillation. No meningiomas occur in 5-10% of patients. The evidence of an acute myocardial infarction was primary and central role of surgery in the found. After four months of treatment the size treatment of meningiomas is well-established of the meningioma had further increased from and the operative and long-term mortality 67-4 to 77X4 cm3 (+ 15%). This patient died rates have considerably declined over the past after 5.5 months of mifepristone treatment decades.24 However, the likelihood of complete from sudden asystole. resection ofmeningiomas is determined in part Patient 4 had a frontal meningioma and by the tumour site.25 For example, convexity severe flattened affect. Her skull was open with meningiomas can be removed easily in most local uncontrollable inflammation after the instances and have a low recurrence rate (3% removal of a large piece of osteomyelitic bone after five years25), while the operative results of at a previous operation. She often experienced parasellar and sphenoid ridge meningiomas are small epileptic fits despite therapy with pheny- less impressive and show a much higher toin. These attacks did not change after the incidence of recurrence (19% and 34%, start of mifepristone therapy. The tumour respectively25). Medical treatment which

progressively increased in size from 66-5 to might slow or inhibit tumour growth would be http://jnnp.bmj.com/ 80-8 after three months and to 90 cm3 after of benefit especially in these last categories of nine months of treatment. After 12 months of patients. therapy this patient died at home from a severe The discovery that a majority of human epileptic attack. In patient 1 an inner ridge meningiomas contain high numbers of high meningioma on the right side had nearly affinity progesterone binding sites was the basis doubled in size in the eight months before the for new thoughts and hypotheses concerning a start ofmifepristone treatment (from 4.4 to, 8-3 medical therapy of meningiomas.4 10 Subse- on September 30, 2021 by guest. Protected copyright. cm3). Thereafter, a further progressive rise in quently, it was shown that the anti-progestin tumour size to maximally 12-2 cm3 (at 12 mifepristone has the same affinity for the months) was observed. Patient 10 was excep- of meningiomas, as tional in that she has neurofibromatosis type 2. does, for example R5020, a known progester- Apart from bilateral acoustic neurinomas and one analog and binder of the progesterone bilateral opticus tumours she had multiple receptor.926 Preliminary studies on cultured meningioma-type tumours along the falx cer- meningioma cells indicated a certain degree of ebri and the tentorium. One tentorium menin- hormonal dependency of these tumour cells, gioma on the right side and a falx meningioma although this was not uniformly found. Stim- on the left side showed progressive further ulation of the growth of meningioma cells in growth during mifepristone therapy. the presence ofphysiologically relevant proges- The meningiomas of patients 5, 7 and 8 terone concentrations was observed in some showed evidence for a stabilisation of tumour but not all tumour cell cultures. "'8 Inter- growth during and also in the period after estingly, mifepristone caused inhibition of cell stopping mifepristone treatment (figure, mid- growth and of thymidine incorporation in dle section). All three tumours initially still several tumours. Our own studies indicate increased in size during the first months of that progesterone causes only minimal effects therapy, but thereafter shrinkage and/or stabil- on the growth of cultured meningioma tissue isation of size was seen. (cells or explants), but that progesterone mod- In patients 2, 6 and 9 (transient) decrease in ulates the stimulatory response of cultured tumour size was observed during mifepristone human meningioma cells to epidermal growth Mifepristone (RU 486) treatment of meningiomas 489

factor and other growth factors, while mife- in six of 10 patients (seven of 12 meningiomas) J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from pristone blocks this enhancing effect ofproges- during mifepristone therapy was in our opinion terone.'8 This suggests that the presence of of special value (except in patient 5 who progesterone in the culture medium increases showed visual loss), because all patients had the sensitivity of meningioma cells to mito- been selected because of recent evidence of genic stimuli, whereas mifepristone counter- tumour growth. acts these stimulating effects of progesterone. Our study suffers from methodological In vivo studies with nude mice carrying shortcomings which makes it only an observa- transplanted human meningiomas tissue indi- tional one. Apart from the low number of cated a growth inhibitory effect of mifepris- patients studied, the size, location and dura- tone. 7 Such a tumour growth inhibitory effect tion of existence of the tumours varied con- of the drug was also observed in several other siderably. Most importantly, there was no hormone-dependent tumour models,27-30 placebo or control arm, which makes definite while (transient) tumour growth inhibition was conclusions on the beneficial effects attributed reported in a minority of breast cancer to mifepristone doubtful at present. patients.3' 32 A further shortcoming of this study is that Medical therapy of meningioma patients we do not have data on the presence and the with the progesterone /antagonist affinity of progesterone receptors on these medroxyprogesterone, with tamoxifen or with tumours. This might be of importance, an LHRH analog resulted in varying, but in because in a preliminary study involving a some cases encouraging results.'9-22 group of 24 meningioma patients36 we showed The results of therapy with mifepristone in that there is an inverse relationship between the present 10 meningioma patients were not the number of progesterone receptors and CT dramatic. All patients had been selected on the scan characteristics of these tumours which basis of recent (mostly neuroradiological) evi- indicate regressive behaviour (for example, the dence of growth of the tumours. The previous presence of necrosis, cyst formation and/or histories of these patients showed that they intratumoural haemorrhage). This might mean represented a group of aggressively growing that medical treatment ofmeningioma patients meningiomas. In four patients we observed a with progesterone receptor blocking drugs is further growth of the meningioma during beneficial and effective especially in those mifepristone therapy, without evidence of patients harbouring meningiomas with a rela- inhibition of growth by the drug. Two of these tively "low degree of aggression", which might patients died during mifepristone treatment: mean those tumours which do not grow very one from a pre-existing cardiovascular compli- fast. cation and one from pre-existing epilepsy. We In conclusion, preliminary evidence has do not know whether these intercurrent deaths been presented that therapy with the proges- were directly tumour-related, but we also do terone receptor blocking drug mifepristone not have evidence that they were treatment- (RU 486) results in control of tumour growth related. The initial complaints ofnausea, tired- in some meningioma patients. Mifepristone ness and vomiting which occurred in some of caused considerable side effects, however, and the patients during the first period of mifepris- new more specific anti-progestins (with less tone therapy was interpreted as relative adrenal -receptor blocking activity) http://jnnp.bmj.com/ insufficiency which was caused by the might be better tolerated and therefore more receptor blocking activity of the drug. Exten- attractive compounds to use in follow up sive endocrine studies in these patients during studies (phase 2). Also future studies should be mifepristone therapy have been published in a placebo-controlled and include patients in separately.33 The two meningiomas of patient whom the progesterone receptor content of the 10 showed a rapid growth both before and meningiomas is known. during mifepristone treatment. This

patient on September 30, 2021 by guest. Protected copyright. had the rare syndrome of neurofibromatosis type 2, consisting of bilateral acoustic neu- 1 Quest DO. Meningiomas: an update. Neurosurg 1978;3: rinomas, bilateral optic tumours and multiple 219-25. 2 BickerstaffER, Small JM, Guest IA. The relapsing course of meningiomas, which is related to a genetic certain meningiomas in relation to pregnancy and men- abnormality, involving chromosome 22.34 35 In struation. j Neurol Neurosurg Psychiatry 1958;21:89-91. the other 3 Schoenberg BS, Christine BW, Whisnant JP. Nervous six patients a total of seven meningio- system neoplasms and primary malignancies of other mas showed stabilisation or slight regression of sites. The unique association between meningiomas and tumour breast cancer. Neurology 1975;25:705-23. growth during mifepristone treatment. 4 Poisson M, Pertuiset BF, Hauw JJ, et al. hormone In patient 5 this therapy can be considered as a receptors in human meningiomas, gliomas and brain metastases. J Neuro-Oncol 1983;1:179-89. failure because the already very low visual 5 Schnegg, JF, Gomez F, Lemarchand-Beraud T, de Tribolet acuity of her remaining eye further deteri- N. Presence of sex receptors in menin- orated, gioma tissue. Surg Neurol 1981;15:415-8. although no change in tumour size was 6 Magdelenat H, Pertuiset BF, Poisson M, et al. Progestin and observed during therapy. In three patients a oestrogen receptors i meningiomas. Biochemical charac- terization, clinical and pathological correlations in 42 (transient) decrease in tumour size was cases. Acta Neurochir 1982;64: 199-213. observed. Medical therapy was accompanied 7 Yu ZY, Wrange 0, Haglund B, et al. Estrogen and progestin receptors in intracranial meningiomas. j Steroid Biochem by a decrease in headaches in five patients, an 1982;16:451-6. increase in the feeling of general well being in 8 Blankenstein MA, Blaauw G, Lamberts SWJ, et al. Presence of progesterone receptors and absence of oestrogen four, a slight improvement in visual acuity of receptors in human intracranial meningioma cytosols. one eye in one (patient 2), and a decrease in Eur J Cancer Oncol 1983;19:365-70. 9 Blankenstein MA, Blaauw G, Lamberts SWJ. Progestin and palpable tumour size in one patient (patient 9). estrogen receptors in human meningioma. Clin Neuro- Stable disease and/or slight tumour shrinkage pharmacol 1984;7:363-7. 490 Lamberts, Tanghe, Avezaat, Braakman, Wijngaarde, Koper, de long

10 Olsen Beck DW, JJ, Schlechte J, Loh PM. Hormonal agement of meningiomas. In: Schmidek HR, Sweet WH, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from manipulation of meningiomas in vitro. J Neurosurg eds. Operative neurosurgical techniques. Indications, methods 1986;65:99-107. and results, Vol 1. New York: Grune and Stratton, 11 Zava DT, Markwalder TM, Markwalder RV. Biological 1982;481-9. expression of steroid hormone receptors in primary 25 Mirimanoff RO, Dosoretz DE, Longgood RM, et al. meningioma cells in monolayer culture. Clin Neuro- Meningioma: analysis of recurrence and progression pharmacol 1984:7:382-8. following neurosurgical resection. J7 Neurosurg 12 Jay JR, MacLaughlin DT, Riley RR, et al. Modulation of 1985;62: 18-24. meningioma cell growth by sex steroid hormones in vitro. 26 Blaauw G, Blankenstein MA, Lamberts SWJ. Sex steroid J Neurosurg 1985;62:757-62. receptors in human meningiomas. Acta Neurochir 13 Weisman AS, Villemure JG, Kelly PA. Regulation of DNA 1986;79:42-7. synthesis and growth of cells derived from primary 27 Lamberts SWJ, Uitterlinden P, Bons EG, Verleun T. human meningiomas. Cancer Res 1986;46:2545-50. Comparison of the actions of RU 38486 and 14 Markwalder TM, Gerber HA, Waelti E, et al. Hormono- acetate in the model of a transplantable adrenocortico- therapy of meningiomas with medroxyprogesterone acet- tropin- and prolactin-secreting rat pituitary tumor. Cancer ate: immunohistochemical demonstration of the effect of Res 1985;45:1015-9. MPA on growth fractions of meningioma cells using the 28 Lamberts SWJ, van Koetsveld P, Verleun T. Prolactin monoclonal antibody Ki-67. Surg Neurol 1988;30: release-inhibitory effects of progesterone, megestrol ace- 97-101. tate, and mifepristone (RU 38486) by cultured rat 15 Markwalder TM, Waelti E, Koenig MP. Endocrine manip- pituitary tumor cells. Cancer Res 1987;47:3667-7 1. ulation of meningiomas with medroxyprogesterone acet- 29 Bakker GH, Setyono-Han B, Henkelman MS, et al. ate. Effect of MPA on receptor status of meningioma Comparison of the actions of the antiprogestin mifepris- cytosols. Surg Neurol 1987;28:3-9. tone (RU 486), the progestin , the 16 Waelti ER, Markwalder TM. Endocrine manipulation of LHRH analog buserelin, and ovariectomy in treatment of meningiomas with medroxyprogesterone acetate. Surg rat mammary tumors. Cancer Treat Rep 1987;71:1021-7. Neurol 1989;31:96-100. 30 Bardon S, Vignon F, Chalbos D, Rochefort H. RU 486, a 17 Olsen JJ, Beck DW, Schleckte JA, Loh PM. Effect of the progestin and glucocorticoid antagonist, inhibits the antiprogesterone RU-38486 on meningioma implanted growth of breast cancer cells via the progesterone into nude mice. J Neurosurg 1987;66:584-7. recepter. J Clin Endocrinol Metab 1985;50:692-7. 18 Koper JW, Foekens JA, Braakman R, Lamberts SWJ. 31 Klijn JGM, de Jong FH, Bakker GH, et at. Antiprogestins, a Effects of progesterone on the response to epidermal new form of endocrine therapy for human breast cancer. growth factor and other growth factors in cultured human Cancer Res 1989;49:2851-6. meningioma cells. Cancer Res 1990;50:2604-7. 32 Romieu G, Maudelonde T, Uhlmann A, et al. The anti- 19 Jaaskelainen J, Laasonen E, Kirkkainen H, et al. Hormone progestin RU 486 in advanced breast cancer: preliminary treatment of meningiomas: lack of response to medroxy- . Bull Cancer 1987;74:455-61. progesterone acetate (MPA). Acta Neurochir 1986;80: 33 Lamberts SWJ, Koper JW, de Jong FH. The endocrine 35-41. effects of long-term treatment with mifepristone (RU 20 Markwalder TM, Seiler RW, Zava DT. Endocrine manip- 486). J Clin Endocr Metab 1991;73:187-91. ulation ofinoperable and recurrent meningiomas-a pilot 34 Seizinger BR, Martuza RL, Gusella JE. Loss of genes on study. Proc 13th International Congress of Chemotherapy. chromosome 22 in tumorigenesis of human acoustic Vienna: Verlag H Egerman, 1983. neuroma. Nature 1986;322:644-7. 21 Blankenstein MA, van 't Verlast JW, Croughs RJM. Hor- 35 Seizinger BR, de la Monte S, Atkins L, et al. Molecular mone dependency of meningiomas. Lancet 1 989;i: 1381. genetic approach to human meningioma: loss of genes on 22 Markwalder TM, Waelti E, Koenig MP. Endocrine manip- chromosome 22. Proc Natl Acad Sci USA 1987;84: ulation of meningiomas with medroxyprogesterone ace- 5419-23. tate. Effect of MPA in receptor status of meningioma 36 Huisman TWA, Tanghe HLJ, Koper JW, et al. The relation- cytosols. Surg Neurol 1987;28:3-9. ship between the presence of progesterone, , 23 Hoessly GF, Olivecrona H. Report on 280 cases of verified somatostatin and epidermal growth factor receptors of parasagital meningioma. J Neurosurg 1955;12:614-26. human meningiomas and their CT characteristics. Eur_J 24 Maxwell RE, Chou SN. Preoperative evaluation and man- Cancer 1991;27:1453-7. http://jnnp.bmj.com/ on September 30, 2021 by guest. Protected copyright.