Tratamento endócrino dos meningiomas: uma revisão

Motta, Luiz Augusto Casulari Roxo Da; Motta, Lucilia Domingues Casulari Da

doi:10.1590/S0004-282X1995000200027

Resumos

Os meningiomas são tumores benignos do sitema nervoso central. Apresentam altas taxas de recidiva e muitas vezes são considerados inoperáveis, como quando se localizam em local de difícil acesso cirúrgico ou quando englobam estruturas nobres do cérebro. Existem evidências clínicas, epidemiológicas, bioquímicas e de experimentos "in vitro" de que seu crescimento sofre influência do meio hormonal esteróideo. Vários ensaios terapêuticos têm explorado estas características do meningioma através do uso de substâncias que interferem na ação destes esteróides: RU486 (antiprogestínico e antiglicocorticóide), acetato de medroxiprogesterona (antiprogestínico), gestrinona (antiestrogênico e antiprogestínico), tamoxifen (antiestrogênico) e buserelin (superagonista do LHRH), além do octreotide (análogo da somatostatina) e a bromocriptina (agonista dopaminérgico). Outros medicamentos possuem potencial para o tratamento dos meningiomas: aminoglutetimina, suramin e trapidil. Nesta revisão, analizamos a literatura sobre esses aspectos.

meningioma; tratamento; fator de crescimento; RU486; receptores esteróides

Meningiomas are begnin tumors of central nervous system. They have high rates of relapse and sometimes are not amenable to total removal mainly when involve vital structures. Clinical, epidemiological, biochemical and "in vitro" experiment show evidence that meningioma growth is influencied by steroid hormonal medium. Several clinical trials have explored these meningioma characteristics with the use of substances interfering with steroid actions: RU486 (antiprogestinic and antiglucocorticoid), medroxiprogesterone acetate (antiprogestinic), gestrinone (antiestrogenic e antiprogestinic), tamoxifen (antiestrogenic) and buserelin (LHRH superagonist), beyond of octreotide (somatostatin analog) and bromocriptine (dopaminergic agonist). Other substances have potential for the meningiomas treatment: aminogluthetimide, suramin and trapidil. In this review, we analyzed the literature about these aspects.

meningioma; treatment; growth factor; RU486; steroid receptors

Tratamento endócrino dos meningiomas: uma revisão

Endocrine treatment of meningiomas: a review

Luiz Augusto Casulari Roxo Da Motta^I; Lucilia Domingues Casulari Da Motta^II

^IUnidade de Neurocirurgia, Hospital de Base do Distrito Federal (Serviço Dr. Kunio Suzuki) e Serviço Médico do MEC (Chefe Dr. Jair Teixeira Campos)

^IIDepartamento de Ginecologia e Obstetrícia, Faculdade de Ciências da Saúde, Universidade de Brasília (Serviço Prof. A. A. de Cantuária)

RESUMO

Os meningiomas são tumores benignos do sitema nervoso central. Apresentam altas taxas de recidiva e muitas vezes são considerados inoperáveis, como quando se localizam em local de difícil acesso cirúrgico ou quando englobam estruturas nobres do cérebro. Existem evidências clínicas, epidemiológicas, bioquímicas e de experimentos "in vitro" de que seu crescimento sofre influência do meio hormonal esteróideo. Vários ensaios terapêuticos têm explorado estas características do meningioma através do uso de substâncias que interferem na ação destes esteróides: RU486 (antiprogestínico e antiglicocorticóide), acetato de medroxiprogesterona (antiprogestínico), gestrinona (antiestrogênico e antiprogestínico), tamoxifen (antiestrogênico) e buserelin (superagonista do LHRH), além do octreotide (análogo da somatostatina) e a bromocriptina (agonista dopaminérgico). Outros medicamentos possuem potencial para o tratamento dos meningiomas: aminoglutetimina, suramin e trapidil. Nesta revisão, analizamos a literatura sobre esses aspectos.

Palavras-chave: meningioma, tratamento, fator de crescimento, RU486, receptores esteróides.

SUMMARY

Meningiomas are begnin tumors of central nervous system. They have high rates of relapse and sometimes are not amenable to total removal mainly when involve vital structures. Clinical, epidemiological, biochemical and "in vitro" experiment show evidence that meningioma growth is influencied by steroid hormonal medium. Several clinical trials have explored these meningioma characteristics with the use of substances interfering with steroid actions: RU486 (antiprogestinic and antiglucocorticoid), medroxiprogesterone acetate (antiprogestinic), gestrinone (antiestrogenic e antiprogestinic), tamoxifen (antiestrogenic) and buserelin (LHRH superagonist), beyond of octreotide (somatostatin analog) and bromocriptine (dopaminergic agonist). Other substances have potential for the meningiomas treatment: aminogluthetimide, suramin and trapidil. In this review, we analyzed the literature about these aspects.

Key words:meningioma, treatment, growth factor, RU486, steroid receptors.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Aceite: 25-outubro-1994.

Dr. Luiz Augusto CR. da Motta - Unidade de Neurocirurgia, Hospital de Base do Distrito Federal - SMHS Q 101- 70335-900 Brasília DF - Brasil.

1. Adams EF, Todo T, Schrell UMH, Thierauf P, White MC, Fahlbusch R. Autocrine control of human meningioma proliferation: secretion of platelet-derived growth factor-like molecules. Int J Cancer 49:398-402,1991.
2. Adams RD, Victor M. Principles of Neurology. Ed 4. New York: McGraw-Hill, 1989, p 516 (Intracranial neoplasms).
3. Antonakis N, Markogiannakis E, Theodoropoulou M, Georgoulias V, Stournaras C, Gravanis A. The antiglucocorticoid RU486 downregulates the expression of interleukin-2 receptors in normal human lymphocytes. J Steroid Biochem Molec Biol, 1991, 39:929-935.
4. Baulieu E-E: The steroid hormone antagonist RU486: mechanism at the cellular level and clinical applications. Endoc Metab Clin N Am 1991, 20:873-891.
5. Blankstein MA, Van't Verlaat JW, Croughs RJM: Hormone dependency of meningiomas [Letter]. Lancet, 1989, 1:1381.
6. Brentani MM, Lopes MTP, Martins VR. Steroid receptors in intracranial tumors. Clin Neuropharmacol 1984, 7:347-350.
7. Cahill DW, Bashirelahi N, Solomon LW, Dalton T, Saloman M, Ducker TB. Estrogen and progesterone receptors in meningiomas. J Neurosurg 1984, 60:985-993.
8. Carpenter G. Vanadate, epidermal growht factor and the stimulation of DNA synthesis. Biochem Biophys Res Commun 1981, 102:1115-1121.
9. Casulari LA, Pimpinelli F, Piva F, Maggi R. The glucocorticoid/progesterone antagonist RU486 exerts cytostatic action on cultured human neuroblastoma cells (SK-N-SH). J Endocrinol Invest 1994, 17 (Suppl 1):102 (Abstr).
10. Davis C. Meningiomas: hormone therapy is an alternative to surgery. J Neurol Neurosurg Psychiatry 1992, 55:515 (Abstr).
11. Donnel MS, Meyer GA, Donegan WL. Estrogen-receptor protein in intracranial meningiomas. J Neurosurg 1979, 50:499-502.
12. Grunberg S, Weiss M, Spitz I, Ahmadi J, Sadun A, Russel CA, Lucci L, Stevenson LL. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 1991, 74:861-866.
13. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ, Ozarks CCOP, Springfield MO. A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. J Neurooncol 1993, 15:75-77.
14. Haak HR, De Keizer RJ, Hagenouw-Taal JC, Van Seters AP, Vielvoye GJ, Van Dulken H. Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 1990, 1:124.
15. Healy DL, Chrousos GP, Schulte HM, Gold PW, Hodgen GD. Increased adrenocorticotropin, Cortisol and arginine vasopressin secretion in primates after the antiglucocorticoid steroid RU486. J Clinical Endocrinol Metab 1985, 60:1-4.
16. Jääskelainen J, Laasonen E, Kärkkäinen J, Haltia M, Troupp H. Hormone treatment of meningiomas: lack of response to medroxyprogesterone acetate (MPA): a pilot study of five cases. Acta Neurochir 1986, 80:35-40.
17. Jay JR, Mac Laughlin DT, Riley KR, Martuza RL. Modulation of meningioma cell growth by sex steroid hormones in vitro. J Neurosurg 1985, 62:757-762.
18. Klijn JGM, de Jong FH, Bakker GH, Rodenburg CJ, Alexieva-Figusch J. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res 1989, 49:2851-2856.
19. Koper JW, Foekens JA, Braakman R, Lamberts SWJ. Effects of progesterone on the response to epidermal growth factor and other growth factors in cultured human meningioma cells. Cancer Res 1990, 50:2604-2607.
20. Lamberts SWJ, Tanghe HLJ, Avezaat CJJ, Braakman, Wijngaarde R, Koper JW, de Jong FH. Mifepristone (RU486) treatment of meningiomas. J Neurol Neurosurg Psychiatry 1992, 55:486-490.
21. Lamberts SWJ, Koper JW, de Jong FH. Long-term treatment with RU486 and glucocorticoid receptor resistance: theoretical and therapeutic implications. TEM 1992, 3:199-204.
22. Lesch KP, Schott W, Engl HG. Gonadal steroid receptors in meningiomas. J Neurol 1987, 234:328-333.
23. Maggi R, Casulari LA, Martini L, Piva F. Effects of sex steroids and steroidal compounds on the binding characteristics of brain u-opioid receptors. In Mornex R, Jaffiol C, Leclčre J (eds). Progress in Endocrinology. Canforth Lanes. Pathernon, 1993, Section II p 160-164.
24. Maggi R, Pereira A Neto, Piva F, Motta LACR. Efeito citostático do RU486 no neuroblastoma humano. Anais do XX Congresso Nacional de Neurocirurgia. Belo Horizonte MG, 3 a 8 setembro 1994; resumo 247, p 152.
25. Markwalder T-M, Waelti E, Konig MP. Endocrine manipulation of meningiomas with medroxyprogesterone acetate: effect of MPA on receptor status of meningioma cytosols. Surg Neurol 1987, 28:3-9.
26. Markwalder T-M, Zava DT, Goldhigsch A, Markwalder RV. Estrogen and progesterone receptors in meningiomas in realtion to clinical and pathologic features. Surg Neurol 1983, 20:42-47.
27. Matsuda Y, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T. Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo. J Neurosurg 1994, 80:527-534.
28. Mirimanoff RO, Dosoretz DE, Longgood RM, Ojeman RG, Martuza RL. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 1985, 62:18-24.
29. Motta LDC, Motta LACR, Gagliardi ART, Ferraz EM. Tratamento de pólipos endometriais com agonista do hormônio liberador das gonadotrofinas (Goserelin): apresentaçăo de um caso. J Bras Ginec 1990, 100:433-436.
30. Olson JJ, Beck DW, Schlechte J, Loh P-M. Hormonal manipulation of meningiomas in vitro. J Neurosurg 1986, 65:99-107.
31. Poisson M, Pertuiset BF, Hauw JJ. Steroid hormone receptors in human meningiomas, gliomas and brain metastases. J Neurooncol 1983, 1:179-189.
32. Romieu G, Maudelonde T, Ulmann A, Pujol H, Grenier J, Cavalié G, Khalaf S, Rochefort H. The antiprogestin RU486 in advanced breast cancer: preliminary clinical trial. Bull Cancer (Paris) 1987, 74:455-461.
33. Rubinstein AB, Shalit MN, Cohen ML, Zandbank U, Reichenthal E. Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 1984, 61:966-971.
34. Rünzi MW, Jaspers C, Windeck R, Benker G, Mehdorn HM, Reinhart V, Reinwein D. Successful treatment of meningioma with octreotide. Lancet 1989, 1:1074.
35. Sallum J. Tumores intracranianos, intra-raquidianos e dos nervos periféricos. In Bogliolo L (ed). Patologia. Rio de Janeiro. Guanabara Koogan, 1976, p 819-841.
36. Santen RJ, Manni A, Harvey H, Redmond C. Endocrine treatment of breast cancer women. Endocr Rev 1990, 11:221-265.
37. Schell UMH, Adams EF, Fahlbusch R.: Hormone dependency of meningiomas. Lancet 1989, 1:1381.
38. Schell UMH, Bickel A, Kiesewetter F, Gauer S, Fahlbusch R, Nomikos P, Hren J. Suramin inhibits proliferation of human cerebral meningioma cells: effects on cell growth, cell cycles phases, extracellular growth factors and autocrine growth loops. J Endocrinol Invest 1993, 16 (Suppl 1):205 (Abstr).
39. Schwartz MR, Randolph RL, Cech DA, Rose JE, Panko WB. Steroid hormone binding macromoleculares in gliomas and meningiomas: failure to meet criteria of specific receptors. Cancer 1984, 53:922-927.
40. Van Seters AP, van Dulken H, DeKeizer RJW, Vielvoye GJ. Symptomatic relief of meningioma by buserelin maintenance therapy. Lancet 1989, 1:564-565.
41. Todo T, Adams EF, Fahlbusch R. Inhibitory effect of trapidil on human meningioma cell proliferation via interruption of autocrine growth stimulation. J Neurosurg 1993, 78:463-469.
42. Waelti ER, Markwalder T-M. Endocrine manipulation of meningiomas with medroxiprogesterone acetate: effect of MPA on growth of primary meningioma cells in monolayer tissue culture. Surg Neurol 1989, 31:96-100.
43. Weisman AS, Villemure J-G, Kelly PA. Regulation of DNA synthesis and growth of cells derived from primary human meningiomas. Cancer Res 1986, 46:2545-2550.
44. Yu ZY, Wrange O, Haglund B. Estrogen and progestin receptors in intracranial meningiomas. J Steroid Biochem 1982, 16:451-456.
45. Zava DT, Markwalder TM, Marwalder RV. Biological expression of steroid hormone receptors in primary meningioma cells in monolayer culture. Clin Neuropharmacol 1984, 7:382-388.

Datas de Publicação

Publicação nesta coleção
20 Jan 2011
Data do Fascículo
Jun 1995

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Adams EF, Todo T, Schrell UMH, Thierauf P, White MC, Fahlbusch R. Autocrine control of human meningioma proliferation: secretion of platelet-derived growth factor-like molecules. Int J Cancer 49:398-402,1991.

[2] 2. Adams RD, Victor M. Principles of Neurology. Ed 4. New York: McGraw-Hill, 1989, p 516 (Intracranial neoplasms).

[3] 3. Antonakis N, Markogiannakis E, Theodoropoulou M, Georgoulias V, Stournaras C, Gravanis A. The antiglucocorticoid RU486 downregulates the expression of interleukin-2 receptors in normal human lymphocytes. J Steroid Biochem Molec Biol, 1991, 39:929-935.

[4] 4. Baulieu E-E: The steroid hormone antagonist RU486: mechanism at the cellular level and clinical applications. Endoc Metab Clin N Am 1991, 20:873-891.

[5] 5. Blankstein MA, Van't Verlaat JW, Croughs RJM: Hormone dependency of meningiomas [Letter]. Lancet, 1989, 1:1381.

[6] 6. Brentani MM, Lopes MTP, Martins VR. Steroid receptors in intracranial tumors. Clin Neuropharmacol 1984, 7:347-350.

[7] 7. Cahill DW, Bashirelahi N, Solomon LW, Dalton T, Saloman M, Ducker TB. Estrogen and progesterone receptors in meningiomas. J Neurosurg 1984, 60:985-993.

[8] 8. Carpenter G. Vanadate, epidermal growht factor and the stimulation of DNA synthesis. Biochem Biophys Res Commun 1981, 102:1115-1121.

[9] 9. Casulari LA, Pimpinelli F, Piva F, Maggi R. The glucocorticoid/progesterone antagonist RU486 exerts cytostatic action on cultured human neuroblastoma cells (SK-N-SH). J Endocrinol Invest 1994, 17 (Suppl 1):102 (Abstr).

[10] 10. Davis C. Meningiomas: hormone therapy is an alternative to surgery. J Neurol Neurosurg Psychiatry 1992, 55:515 (Abstr).

[11] 11. Donnel MS, Meyer GA, Donegan WL. Estrogen-receptor protein in intracranial meningiomas. J Neurosurg 1979, 50:499-502.

[12] 12. Grunberg S, Weiss M, Spitz I, Ahmadi J, Sadun A, Russel CA, Lucci L, Stevenson LL. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 1991, 74:861-866.

[13] 13. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ, Ozarks CCOP, Springfield MO. A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. J Neurooncol 1993, 15:75-77.

[14] 14. Haak HR, De Keizer RJ, Hagenouw-Taal JC, Van Seters AP, Vielvoye GJ, Van Dulken H. Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 1990, 1:124.

[15] 15. Healy DL, Chrousos GP, Schulte HM, Gold PW, Hodgen GD. Increased adrenocorticotropin, Cortisol and arginine vasopressin secretion in primates after the antiglucocorticoid steroid RU486. J Clinical Endocrinol Metab 1985, 60:1-4.

[16] 16. Jääskelainen J, Laasonen E, Kärkkäinen J, Haltia M, Troupp H. Hormone treatment of meningiomas: lack of response to medroxyprogesterone acetate (MPA): a pilot study of five cases. Acta Neurochir 1986, 80:35-40.

[17] 17. Jay JR, Mac Laughlin DT, Riley KR, Martuza RL. Modulation of meningioma cell growth by sex steroid hormones in vitro. J Neurosurg 1985, 62:757-762.

[18] 18. Klijn JGM, de Jong FH, Bakker GH, Rodenburg CJ, Alexieva-Figusch J. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res 1989, 49:2851-2856.

[19] 19. Koper JW, Foekens JA, Braakman R, Lamberts SWJ. Effects of progesterone on the response to epidermal growth factor and other growth factors in cultured human meningioma cells. Cancer Res 1990, 50:2604-2607.

[20] 20. Lamberts SWJ, Tanghe HLJ, Avezaat CJJ, Braakman, Wijngaarde R, Koper JW, de Jong FH. Mifepristone (RU486) treatment of meningiomas. J Neurol Neurosurg Psychiatry 1992, 55:486-490.

[21] 21. Lamberts SWJ, Koper JW, de Jong FH. Long-term treatment with RU486 and glucocorticoid receptor resistance: theoretical and therapeutic implications. TEM 1992, 3:199-204.

[22] 22. Lesch KP, Schott W, Engl HG. Gonadal steroid receptors in meningiomas. J Neurol 1987, 234:328-333.

[23] 23. Maggi R, Casulari LA, Martini L, Piva F. Effects of sex steroids and steroidal compounds on the binding characteristics of brain u-opioid receptors. In Mornex R, Jaffiol C, Leclčre J (eds). Progress in Endocrinology. Canforth Lanes. Pathernon, 1993, Section II p 160-164.

[24] 24. Maggi R, Pereira A Neto, Piva F, Motta LACR. Efeito citostático do RU486 no neuroblastoma humano. Anais do XX Congresso Nacional de Neurocirurgia. Belo Horizonte MG, 3 a 8 setembro 1994; resumo 247, p 152.

[25] 25. Markwalder T-M, Waelti E, Konig MP. Endocrine manipulation of meningiomas with medroxyprogesterone acetate: effect of MPA on receptor status of meningioma cytosols. Surg Neurol 1987, 28:3-9.

[26] 26. Markwalder T-M, Zava DT, Goldhigsch A, Markwalder RV. Estrogen and progesterone receptors in meningiomas in realtion to clinical and pathologic features. Surg Neurol 1983, 20:42-47.

[27] 27. Matsuda Y, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T. Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo. J Neurosurg 1994, 80:527-534.

[28] 28. Mirimanoff RO, Dosoretz DE, Longgood RM, Ojeman RG, Martuza RL. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 1985, 62:18-24.

[29] 29. Motta LDC, Motta LACR, Gagliardi ART, Ferraz EM. Tratamento de pólipos endometriais com agonista do hormônio liberador das gonadotrofinas (Goserelin): apresentaçăo de um caso. J Bras Ginec 1990, 100:433-436.

[30] 30. Olson JJ, Beck DW, Schlechte J, Loh P-M. Hormonal manipulation of meningiomas in vitro. J Neurosurg 1986, 65:99-107.

[31] 31. Poisson M, Pertuiset BF, Hauw JJ. Steroid hormone receptors in human meningiomas, gliomas and brain metastases. J Neurooncol 1983, 1:179-189.

[32] 32. Romieu G, Maudelonde T, Ulmann A, Pujol H, Grenier J, Cavalié G, Khalaf S, Rochefort H. The antiprogestin RU486 in advanced breast cancer: preliminary clinical trial. Bull Cancer (Paris) 1987, 74:455-461.

[33] 33. Rubinstein AB, Shalit MN, Cohen ML, Zandbank U, Reichenthal E. Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 1984, 61:966-971.

[34] 34. Rünzi MW, Jaspers C, Windeck R, Benker G, Mehdorn HM, Reinhart V, Reinwein D. Successful treatment of meningioma with octreotide. Lancet 1989, 1:1074.

[35] 35. Sallum J. Tumores intracranianos, intra-raquidianos e dos nervos periféricos. In Bogliolo L (ed). Patologia. Rio de Janeiro. Guanabara Koogan, 1976, p 819-841.

[36] 36. Santen RJ, Manni A, Harvey H, Redmond C. Endocrine treatment of breast cancer women. Endocr Rev 1990, 11:221-265.

[37] 37. Schell UMH, Adams EF, Fahlbusch R.: Hormone dependency of meningiomas. Lancet 1989, 1:1381.

[38] 38. Schell UMH, Bickel A, Kiesewetter F, Gauer S, Fahlbusch R, Nomikos P, Hren J. Suramin inhibits proliferation of human cerebral meningioma cells: effects on cell growth, cell cycles phases, extracellular growth factors and autocrine growth loops. J Endocrinol Invest 1993, 16 (Suppl 1):205 (Abstr).

[39] 39. Schwartz MR, Randolph RL, Cech DA, Rose JE, Panko WB. Steroid hormone binding macromoleculares in gliomas and meningiomas: failure to meet criteria of specific receptors. Cancer 1984, 53:922-927.

[40] 40. Van Seters AP, van Dulken H, DeKeizer RJW, Vielvoye GJ. Symptomatic relief of meningioma by buserelin maintenance therapy. Lancet 1989, 1:564-565.

[41] 41. Todo T, Adams EF, Fahlbusch R. Inhibitory effect of trapidil on human meningioma cell proliferation via interruption of autocrine growth stimulation. J Neurosurg 1993, 78:463-469.

[42] 42. Waelti ER, Markwalder T-M. Endocrine manipulation of meningiomas with medroxiprogesterone acetate: effect of MPA on growth of primary meningioma cells in monolayer tissue culture. Surg Neurol 1989, 31:96-100.

[43] 43. Weisman AS, Villemure J-G, Kelly PA. Regulation of DNA synthesis and growth of cells derived from primary human meningiomas. Cancer Res 1986, 46:2545-2550.

[44] 44. Yu ZY, Wrange O, Haglund B. Estrogen and progestin receptors in intracranial meningiomas. J Steroid Biochem 1982, 16:451-456.

[45] 45. Zava DT, Markwalder TM, Marwalder RV. Biological expression of steroid hormone receptors in primary meningioma cells in monolayer culture. Clin Neuropharmacol 1984, 7:382-388.