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Studies on the Role of Oral Contraceptive Use in the Etiology of Benign and Malignant Liver Tumors
1044
ONCOLOGY AND CHEMOTHERAPY
Urine collected from 10 patients with transitional cell carcinomas before their excision showed 42 ± 6 per cent of increase in migration. Postoperatively, the same patients showed only 9 ± 2 per cent of increase. Patients with a history of transitional cell cancer had 15 ± 2 per cent, prostate cancer-7 ± 2 per cent, prostatitis-11 ± 3 per cent, urologic infection-7 ± 3 per cent, Crohn's disease-8 ± 3 per cent and the control-16 ± 2 per cent of increased migratory activity. This study demonstrated that urine from patients with transitional cell carcinoma of the bladder was able to stimulate capillary endothelial cell migration in vitro. The agent responsible for the capillary endothelial cell migration stimulating activity in the urine of patients with transitional cell tumors has not been identified and presently is under investigation in the authors' laboratory. This agent probably is related to the angiogenic activity of the tumor. The study indicates a correlation between urinary levels of endothelial cell migration stimulating activity and the presence or absence of a transitional cell tumor. C. E. M. 3 figures, 2 tables, 12 references
In the present study the authors investigated the effect of the chronic administration of megestrol acetate on the growth of the estrogen-induced transplantable prolactin and adrenocorticotropin-secreting rat pituitary tumor 7315a in the rat. Additionally, the effect of megestrol acetate on the ability of the pituitary gland of tumor-bearing rats to secrete prolactin, adrenocorticotropin, luteinizing hormone and follicle-stimulating hormone in vitro and on the total pituitary content of these hormones was compared to that in control rats with or without tumors. A possible direct effect of megestrol acetate on prolactin, adrenocorticotropin, luteinizing hormone and follicle-stimulating hormone release by the rat pituitary gland in vitro also was investigated. G. P. M. 2 figures, 4 tables, 30 references
Bleomycin Inhibits Hepatic Mixed Function Oxidation R. MONTGOMERY, J. FURRY AND s. FERNANDEZ, Research Service, Veterans Administration Hospital and Departments of Pharmacy and Comprehensive Medicine, University of South Florida Medical Center, Tampa, Florida
M.
Familial Carcinoma of Penis
Res. Comm. Chem. Path. Pharm., 34: 287-293 (Nov.) 1981
A.
The pulmonary toxicity of the chemotherapeutic agent bleomycin is well known. The authors investigated the effects of bleomycin on hepatic microsomal mixed function oxidation. Charles River CD rats and BALB/c nu/nu mice were given bleomycin sulfate intraperitoneally or subcutaneously in doses of 50 mg./kg. Animals receiving a single dose of bleomycin were killed 4 days after administration. Other animals received 3 doses of the drug 4 days apart and were killed 4 weeks after the first injection. Hepatic microsomal fractions were assayed for ethylmorphine N-demethylase activity and cytochrome P450 concentration. A single dose of bleomycin resulted in significant decreases in ethylmorphine N-demethylase activity in both species but did nothing to change cytochrome P450 concentrations. These findings were true regardless of the route of administration. The nude mice that received multiple doses of intraperitoneal bleomycin experienced no alteration in the hepatic microsomal enzymatic activity or cytochrome P450 concentration. However, the decrease in enzymatic activity and P450 concentration was dramatic in those mice that received the bleomycin subcutaneously. In the rat a decrease in enzymatic activity and P450 concentration after 3 doses of bleomycin was apparent, regardless of the route of administration. The authors conclude that bleomycin inhibits hepatic enzyme function in 2 species. Hepatic dysfunction was less apparent when the bleomycin was administered many times by the intraperitoneal route in nude mice. G. F. S. 1 figure, 2 tables, 9 references
K. K. JHAVERI, Urology Service, Veterans Administration Center and Thomas Jefferson University Hospital, Philadelphia, Pennsylvania M. RANEY AND
N. Y. State J. Med., 81: 1786-1787 (Nov.) 1981 The authors report on a 59-year-old man with an epidermoid carcinoma of the penis within a phimosis that was treated successfully by partial penile amputation and his 65-year-old brother with a distal penile ulcer demonstrating erythroplasia of Queyrat that was treated successfully by circumcision. The authors raise the possibility of familial origin but present no discussion for or against this concept. H. M. S. 2 figures, 4 references
Effects of Megestrol Acetate on Growth and Secretion of a Pituitary Tumor 8. W.
E. N. W. JANSSENS, E. G. BONS, J.M. P. UITTERLINDEN AND F. H. DE JONG, Department of Medicine III, Erasmus University Rotterdam, University Hospital Dijkzigt, Rotterdam, The Netherlands J. LAMBERTS,
ZuIDERWIJK,
Eur. J. Cancer, 17: 925-931 (Aug.) 1981 Administration of high dosages of megestrol acetate (17aacetoxy-6-methylpregna-4,6-diene-3,20-dione) or medroxyprogesterone acetate (6a-methyl-17a-acetoxy progesterone) has been shown to induce objective remission with improved survival in 25 to 33 per cent of postmenopausal women with metastatic breast cancer who are resistant to cytotoxic drugs and endocrine therapy, including treatment with tamoxifen. Therefore, it has been suggested that these progestational agents are useful compounds in the treatment of end stage cases of advanced mammary carcinoma. The 6-methylated progestins possess high progestational properties and, in addition, demonstrate antiestrogenic, antigonadotropic and antiandrogenic activity, while some degree of adrenal atrophy was observed during long-term use of high dosages of the compounds. They also have been used successfully in the treatment of cancer of the endometrium, kidney and prostate. At present, it is unknown how these progestational drugs accomplish tumor regression in the different types of carcinomas.
Studies on the Role of Oral Contraceptive Use in the Etiology of Benign and Malignant Liver Tumors C.
METTLIN AND N. NATARAJAN, Department of Cancer Control and Epidemiology, Roswell Park Memorial Institute, Buffalo, New York
J. Surg. Oncol., 18: 73-85, 1981 The authors present an extensive review of articles linking oral contraceptive use with the incidence of liver tumors. There appears to be a marked increase in the relative risk of hepatocellular adenomas and focal nodular hyperplasia in women who use oral contraceptives. The duration of exposure may be
-
but in 10 per cent of the cases expos'Jxe was
Abstracter's comment. The reports concerning experimental study with laboratory animals were particularly interesting to me. There appeared to be no effect of oral contraceptives on liver tumor incidence in mice of either sex, whereas there was an increase of benign liver tumors in male but not female rats. F.E. C.
Steroid Metabolism and Oestrogen Receptors in Human Breast Carcinomas W. R. MILLER, R. A. HAWKINS AND A. P. M. FORREST, Department of Clinical Surgery, University of Edinburgh, Edinburgh, United Kingdom Eur. J. Cancer, 17: 913-917 (Aug.) 1981
i
Human breast cancer transforms Cl9 steroid precursors into active androgens and estrogens. Thus, dehydroepiandrosterone and its sulfate are metabolized in vitro to testosterone, estrone and est:rndiol-17,B, the bA androstenedione is converted totestosterone, estrone and estradiol-17,B, and testosterone is metabolized to 5a-dihydrotestosterone, 5a-androstanediol and estradiol-17,B. Synthesis of estradiol from androgen precursors of adrenal origin by breast cancers may be important in response of tumors to endocrine treatments, particularly in postmenopausal patients. In these women, in whom circulating estrogen levels are low, tumor metabolism may provide a supply of estrogen required for tumor growth. Currently, the estrogen receptor activity of a tumor is the best index of its likely hormone sensitivity. A recent review and the present study of 54 tumors were undertaken to determine whether estrogen receptor and tumor steroid metabolism were related. All tumors converted testosterone to t.4 androstenedione, 5adihydrotestosterone, and 5a-dihydrotestosterone and 5a-andrnstanediol but unequivocal evidence for the of estradiol was obtained in 29 of the tumors. There were 37 tumors classified as estrogen rPrPnt.,·w-.nr,s11;1ve. in excess of 5 fmol./mg. versions to D.4 androstenedione, androstanediol were all higher in tumors, compared to the ,m m~tr,~_,,..,,.,,,,,t,uo group, the differences did not reach statistical significance" However, there was a significant trend for estradiol synthesis to be associated with estrogen receptor-positive tumors (p <0.025). All tumors with high level of receptors converted testosterone to estradiol. 0
G.P.M. 2 figures, 3 tables, 21 references
Sacral Chordoma: A Case Study and Review
J.
S. SPRATT, A. E. MARTIN AND J. McKEOWN, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky
J. Surg. Oncol., 18: 101-103, 1981
.''"
-_'
--
-
The authors p~~es":;nt brief re'!-ie~r" of the literature and report ,;vornan vvho had a sacral chord.oma. In addition mr,n~~+;;"~ and x-ray the patient was treated ,.vith various chemotherapy agents (the first time that this has been reThe patient did have some :.,a=,a,,,m, from the chemotherapeutic agents but the time of survival was not increased. It is suggested that chemotherapy be tried as initial treatment. F. E. C. 8 references
Rhabdomyosarcoma of the Female Urogenital Tract D. M. HAYS, R. B. RANEY, JR., W. GEHAN, E. H. SOULE, M. TEFFT
LAWRENCE, JR., AND
H. M.
E. A.
MAURER,
Intergroup Rhabdomyosarcoma Committee, B, Children's Cancer Cancer and Acute Leukemia Study Group and Southwest Oncology Group, and Children's Hospital of Los Angeles, Los Angeles, California J. Ped. Surg., 16: 828-834 (Dec.) 1981
The authors report the results of an Intergroup Rhabdomyosarcoma Study on 27 female patients with rhabdomyosarcoma of the urogenital tract (14 bladder cases, 9 vagina, 2 vulva and 2 cervix uterus). These patients were grouped according to Intergroup Rhabdomyosarcoma Study grouping I to IV, group I being localized tumor and group IV metastatic disease. Group I patients received regimen A consisting of vincristine, dactinomycin and cyclophosphamide, and regimen B including these chemotherapeutic agents and radiation. II patients were randomized to regimen C therapy, consisting of radiotherapy, vincristine, dactinomycin and cyclophosphamide or regimen D, including regimen C doxorubicin. Followup has been for 3 to 7 years. The numbers in these 6 regimens (A, B, C, D, E and F) for the 4 groups are limited. Nevertheless, this is a landmark study with future prospects that will establish firm guidelines as to the optimal of this group of patients, thereby elimina.ting the uncertainties of the previous retrospective studies. The authors found that the results of chemotherapy-radiotherapy trials in these patients are similar to the results in the total grnup of patients as Intergroup Rhab· domyosarcoma Study 1. To summarize, indicate that there was no difference between survival u n u r - « , .., receiving regimen A or B therapy in group I and C or D in group H. This also vvas true for regimens E and F in group III or IV r.,,t,,,n,,~ In state that coma. Since the
have an excellent it is reasonable to avoid such as exenteration. A more con-· servative Qnn..-,~ is partial removal of the involved organ with preservation of the function (organ-sparing followed chemotherapy. The Intergroup Rhabdomyosarcoma group currently is studying primary chemotherapy and radiation therapy and considering surgery as adjuvant therapy. N. J. 2 figures, 4 tables, 17 references 0 ,
Editorial comment. The Intergroup Rhabdomyosarcoma Study has done for childhood rhabdomyosarcoma what the National Wilms Tumor Study has done for that disease. The effectiveness of chemotherapy has been demonstrated quickly and unequivocally. Although a high proportion of patients with metastatic rhabdomyosarcoma at the time of presentation still
ONCOLOGY AND CHEMOTHERAPY
Urine collected from 10 patients with transitional cell carcinomas before their excision showed 42 ± 6 per cent of increase in migration. Postoperatively, the same patients showed only 9 ± 2 per cent of increase. Patients with a history of transitional cell cancer had 15 ± 2 per cent, prostate cancer-7 ± 2 per cent, prostatitis-11 ± 3 per cent, urologic infection-7 ± 3 per cent, Crohn's disease-8 ± 3 per cent and the control-16 ± 2 per cent of increased migratory activity. This study demonstrated that urine from patients with transitional cell carcinoma of the bladder was able to stimulate capillary endothelial cell migration in vitro. The agent responsible for the capillary endothelial cell migration stimulating activity in the urine of patients with transitional cell tumors has not been identified and presently is under investigation in the authors' laboratory. This agent probably is related to the angiogenic activity of the tumor. The study indicates a correlation between urinary levels of endothelial cell migration stimulating activity and the presence or absence of a transitional cell tumor. C. E. M. 3 figures, 2 tables, 12 references
In the present study the authors investigated the effect of the chronic administration of megestrol acetate on the growth of the estrogen-induced transplantable prolactin and adrenocorticotropin-secreting rat pituitary tumor 7315a in the rat. Additionally, the effect of megestrol acetate on the ability of the pituitary gland of tumor-bearing rats to secrete prolactin, adrenocorticotropin, luteinizing hormone and follicle-stimulating hormone in vitro and on the total pituitary content of these hormones was compared to that in control rats with or without tumors. A possible direct effect of megestrol acetate on prolactin, adrenocorticotropin, luteinizing hormone and follicle-stimulating hormone release by the rat pituitary gland in vitro also was investigated. G. P. M. 2 figures, 4 tables, 30 references
Bleomycin Inhibits Hepatic Mixed Function Oxidation R. MONTGOMERY, J. FURRY AND s. FERNANDEZ, Research Service, Veterans Administration Hospital and Departments of Pharmacy and Comprehensive Medicine, University of South Florida Medical Center, Tampa, Florida
M.
Familial Carcinoma of Penis
Res. Comm. Chem. Path. Pharm., 34: 287-293 (Nov.) 1981
A.
The pulmonary toxicity of the chemotherapeutic agent bleomycin is well known. The authors investigated the effects of bleomycin on hepatic microsomal mixed function oxidation. Charles River CD rats and BALB/c nu/nu mice were given bleomycin sulfate intraperitoneally or subcutaneously in doses of 50 mg./kg. Animals receiving a single dose of bleomycin were killed 4 days after administration. Other animals received 3 doses of the drug 4 days apart and were killed 4 weeks after the first injection. Hepatic microsomal fractions were assayed for ethylmorphine N-demethylase activity and cytochrome P450 concentration. A single dose of bleomycin resulted in significant decreases in ethylmorphine N-demethylase activity in both species but did nothing to change cytochrome P450 concentrations. These findings were true regardless of the route of administration. The nude mice that received multiple doses of intraperitoneal bleomycin experienced no alteration in the hepatic microsomal enzymatic activity or cytochrome P450 concentration. However, the decrease in enzymatic activity and P450 concentration was dramatic in those mice that received the bleomycin subcutaneously. In the rat a decrease in enzymatic activity and P450 concentration after 3 doses of bleomycin was apparent, regardless of the route of administration. The authors conclude that bleomycin inhibits hepatic enzyme function in 2 species. Hepatic dysfunction was less apparent when the bleomycin was administered many times by the intraperitoneal route in nude mice. G. F. S. 1 figure, 2 tables, 9 references
K. K. JHAVERI, Urology Service, Veterans Administration Center and Thomas Jefferson University Hospital, Philadelphia, Pennsylvania M. RANEY AND
N. Y. State J. Med., 81: 1786-1787 (Nov.) 1981 The authors report on a 59-year-old man with an epidermoid carcinoma of the penis within a phimosis that was treated successfully by partial penile amputation and his 65-year-old brother with a distal penile ulcer demonstrating erythroplasia of Queyrat that was treated successfully by circumcision. The authors raise the possibility of familial origin but present no discussion for or against this concept. H. M. S. 2 figures, 4 references
Effects of Megestrol Acetate on Growth and Secretion of a Pituitary Tumor 8. W.
E. N. W. JANSSENS, E. G. BONS, J.M. P. UITTERLINDEN AND F. H. DE JONG, Department of Medicine III, Erasmus University Rotterdam, University Hospital Dijkzigt, Rotterdam, The Netherlands J. LAMBERTS,
ZuIDERWIJK,
Eur. J. Cancer, 17: 925-931 (Aug.) 1981 Administration of high dosages of megestrol acetate (17aacetoxy-6-methylpregna-4,6-diene-3,20-dione) or medroxyprogesterone acetate (6a-methyl-17a-acetoxy progesterone) has been shown to induce objective remission with improved survival in 25 to 33 per cent of postmenopausal women with metastatic breast cancer who are resistant to cytotoxic drugs and endocrine therapy, including treatment with tamoxifen. Therefore, it has been suggested that these progestational agents are useful compounds in the treatment of end stage cases of advanced mammary carcinoma. The 6-methylated progestins possess high progestational properties and, in addition, demonstrate antiestrogenic, antigonadotropic and antiandrogenic activity, while some degree of adrenal atrophy was observed during long-term use of high dosages of the compounds. They also have been used successfully in the treatment of cancer of the endometrium, kidney and prostate. At present, it is unknown how these progestational drugs accomplish tumor regression in the different types of carcinomas.
Studies on the Role of Oral Contraceptive Use in the Etiology of Benign and Malignant Liver Tumors C.
METTLIN AND N. NATARAJAN, Department of Cancer Control and Epidemiology, Roswell Park Memorial Institute, Buffalo, New York
J. Surg. Oncol., 18: 73-85, 1981 The authors present an extensive review of articles linking oral contraceptive use with the incidence of liver tumors. There appears to be a marked increase in the relative risk of hepatocellular adenomas and focal nodular hyperplasia in women who use oral contraceptives. The duration of exposure may be
-
but in 10 per cent of the cases expos'Jxe was
Abstracter's comment. The reports concerning experimental study with laboratory animals were particularly interesting to me. There appeared to be no effect of oral contraceptives on liver tumor incidence in mice of either sex, whereas there was an increase of benign liver tumors in male but not female rats. F.E. C.
Steroid Metabolism and Oestrogen Receptors in Human Breast Carcinomas W. R. MILLER, R. A. HAWKINS AND A. P. M. FORREST, Department of Clinical Surgery, University of Edinburgh, Edinburgh, United Kingdom Eur. J. Cancer, 17: 913-917 (Aug.) 1981
i
Human breast cancer transforms Cl9 steroid precursors into active androgens and estrogens. Thus, dehydroepiandrosterone and its sulfate are metabolized in vitro to testosterone, estrone and est:rndiol-17,B, the bA androstenedione is converted totestosterone, estrone and estradiol-17,B, and testosterone is metabolized to 5a-dihydrotestosterone, 5a-androstanediol and estradiol-17,B. Synthesis of estradiol from androgen precursors of adrenal origin by breast cancers may be important in response of tumors to endocrine treatments, particularly in postmenopausal patients. In these women, in whom circulating estrogen levels are low, tumor metabolism may provide a supply of estrogen required for tumor growth. Currently, the estrogen receptor activity of a tumor is the best index of its likely hormone sensitivity. A recent review and the present study of 54 tumors were undertaken to determine whether estrogen receptor and tumor steroid metabolism were related. All tumors converted testosterone to t.4 androstenedione, 5adihydrotestosterone, and 5a-dihydrotestosterone and 5a-andrnstanediol but unequivocal evidence for the of estradiol was obtained in 29 of the tumors. There were 37 tumors classified as estrogen rPrPnt.,·w-.nr,s11;1ve. in excess of 5 fmol./mg. versions to D.4 androstenedione, androstanediol were all higher in tumors, compared to the ,m m~tr,~_,,..,,.,,,,,t,uo group, the differences did not reach statistical significance" However, there was a significant trend for estradiol synthesis to be associated with estrogen receptor-positive tumors (p <0.025). All tumors with high level of receptors converted testosterone to estradiol. 0
G.P.M. 2 figures, 3 tables, 21 references
Sacral Chordoma: A Case Study and Review
J.
S. SPRATT, A. E. MARTIN AND J. McKEOWN, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky
J. Surg. Oncol., 18: 101-103, 1981
.''"
-_'
--
-
The authors p~~es":;nt brief re'!-ie~r" of the literature and report ,;vornan vvho had a sacral chord.oma. In addition mr,n~~+;;"~ and x-ray the patient was treated ,.vith various chemotherapy agents (the first time that this has been reThe patient did have some :.,a=,a,,,m, from the chemotherapeutic agents but the time of survival was not increased. It is suggested that chemotherapy be tried as initial treatment. F. E. C. 8 references
Rhabdomyosarcoma of the Female Urogenital Tract D. M. HAYS, R. B. RANEY, JR., W. GEHAN, E. H. SOULE, M. TEFFT
LAWRENCE, JR., AND
H. M.
E. A.
MAURER,
Intergroup Rhabdomyosarcoma Committee, B, Children's Cancer Cancer and Acute Leukemia Study Group and Southwest Oncology Group, and Children's Hospital of Los Angeles, Los Angeles, California J. Ped. Surg., 16: 828-834 (Dec.) 1981
The authors report the results of an Intergroup Rhabdomyosarcoma Study on 27 female patients with rhabdomyosarcoma of the urogenital tract (14 bladder cases, 9 vagina, 2 vulva and 2 cervix uterus). These patients were grouped according to Intergroup Rhabdomyosarcoma Study grouping I to IV, group I being localized tumor and group IV metastatic disease. Group I patients received regimen A consisting of vincristine, dactinomycin and cyclophosphamide, and regimen B including these chemotherapeutic agents and radiation. II patients were randomized to regimen C therapy, consisting of radiotherapy, vincristine, dactinomycin and cyclophosphamide or regimen D, including regimen C doxorubicin. Followup has been for 3 to 7 years. The numbers in these 6 regimens (A, B, C, D, E and F) for the 4 groups are limited. Nevertheless, this is a landmark study with future prospects that will establish firm guidelines as to the optimal of this group of patients, thereby elimina.ting the uncertainties of the previous retrospective studies. The authors found that the results of chemotherapy-radiotherapy trials in these patients are similar to the results in the total grnup of patients as Intergroup Rhab· domyosarcoma Study 1. To summarize, indicate that there was no difference between survival u n u r - « , .., receiving regimen A or B therapy in group I and C or D in group H. This also vvas true for regimens E and F in group III or IV r.,,t,,,n,,~ In state that coma. Since the
have an excellent it is reasonable to avoid such as exenteration. A more con-· servative Qnn..-,~ is partial removal of the involved organ with preservation of the function (organ-sparing followed chemotherapy. The Intergroup Rhabdomyosarcoma group currently is studying primary chemotherapy and radiation therapy and considering surgery as adjuvant therapy. N. J. 2 figures, 4 tables, 17 references 0 ,
Editorial comment. The Intergroup Rhabdomyosarcoma Study has done for childhood rhabdomyosarcoma what the National Wilms Tumor Study has done for that disease. The effectiveness of chemotherapy has been demonstrated quickly and unequivocally. Although a high proportion of patients with metastatic rhabdomyosarcoma at the time of presentation still