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Response of childhood rhabdomyosarcoma to combination chemotherapy
Volume 74 Number 5
Brief clinical and laboratory observations
Response of childhood rhabdomyosarcoma to combination chemotherapy Charles B. Pratt, M.D. MEMPHIS,
TENN.
R I - t A B D O M Y O S A R C O M A ~ one of the more common malignant solid tumors of children, remains largely a fatal disease in spite of surgery, radiotherapy, or chemotherapy? Early spread of the tumor occurs both by infiltration and through blood and lymphatic vessels9 Aggressive surgical attacks on these tumors h a v e failed to produce a significant increase of cures? These tumors of children are rather sensitive to radiotherapy, with predictable tumor control following treatment with a tumor dose of about 6,000 r in 6 weeks, z' 3 Dactinomycin, cyclophosphamide, and vincristine have been used in the treatment of rhabdomyosarcoma in recent years. 4 Dactinomycin alone produced tumor regressions in 10 of 38 patients with rhabdomyosarcoma. More frequent and extensive responses were obtained when dactinomycin was administered concurrently with radiotherapy, but the contribution of dactinomycin to these results could not be ascertained because rhabdomyosarcomas are responsive to radiotherapy?, z, 4 Cyclophosphamide effected tumor regression in 21 of 37 patients with rhabdomyosarcoma,~' ~ while vincristine had beneficial effects in 10 of 20 patients with this tumor. 4, 6 In the past, James and associates reported objective responses in 6 patients receiving vincristine and dactinomycin concurrently. Four of 5 paFrom the St. Jude Children's Research Hospital and University of Tennessee Medical Units. Supported by United States Public Health Service Research Grants Nos. CA 07594 and CA 08480, and by American Lebanese Syrian Associated Charities (ALSAC). Address: St. ]ude Children's Research Hospital, P. O. Box 318, Memphis, Tenn. 38101.
79 1
tients treated by Sitarz and associates s had responses following administration of combination chemotherapy consisting of dactinomycin, chlorambucil, and methotrexate. A chemotherapy plan employing a combination of these agents was chosen with the hope of producing tumor regression in a greater number of patients with rhabdomyosarcomas. It was anticipated that there would be greater destruction of tumor than could be expected with a single agent and that triple interference with tumor cell metabolism might prevent emergence of drug-resistant neoplasm. M A T E R I A L S AND M E T H O D S Seven children with advanced rhabdomyosarcoma, aged 2 to 16 years, previously untreated with chemotherapeutic agents, were treated with vincristine, dactinomycin, and cyclophosphamide in a designed plan used as part of the total management of their basic disease. Following biopsy or more definitive surgery, dactinomycin, 0.6 mg. per square meter, was administered intravenously twice weekly for 4 doses concurrently with vincristine, 1.5 mg. per square meter, intravenously once weekly for 6 weeks. After the 6 weekly injections of vincristine, this agent was alternated at weekly intervals with cyclophosphamide, 300 mg. per square meter, intravenously. Radio-
Table I. Clinical staging of childhood rhabdomyosarcoma Stage
I
Description
I
Localized disease, completely resectable
II
Regional disease A. Completely resectable B. Nonresectable or partially resectable, e.g., pelvic lymph node involvement from sarcoma botryoides, infiltration of base of skull from nasopharyngeal primary
III
Generalized disease A. Distant metastases with normal bone marrow (pulmonary metastases or disease above and below the diaphragm) B. Distant metastases with positive bone marrow (pulmonary metastases may or may not be present)
79 2
Brie[ clinical and laboratory observations
The Journal of Pediatrics May 1969
Table II. Effects of vincristine, dactinomycin, and cyclophosphamide in patients with rhabdornyo Patient No. 1
Age (years) 69/52
Sex F
Primary site Pharynx
Extension or metastases Skull, antrum, bone marrow
Clinical stage of disease III B
2
15"~2
F
Orbit
Sinuses, lung, bone marrow
III B
3~
2~2
M
Mastoid-nasopharynx
Skull, brain
4
93A2
F
Face
Skull, brain, orbit, bone marrow
III B
5
4
M
Gluteal area
Lungs
III A
Lymph nodes, orbit, skull, brain, lung
IIIA
6
12~z
F
Neck
7
161A2
F
Interosseous muscle of Bone marrow, lymph hand nodes, breasts
IIB
III B
RT= radiotherapy. ~This patient received vlncristine and dactinomycinand measurable regression which followedby radiotherapy. He did not return therapy was administered concurrently with chemotherapy, as was necessary for best clinical management. D r u g therapy was modified or temporarily withheld in the presence of hematopoietic depression or severe neurotoxicity. Serious hematopoietic toxicity was defined as reduction of the circulating leukocyte count to levels below 2,000 per cubic millimeter or platelet count to below 100,000 per cubic millimeter. Accordingly, the dosage of dactinomycin or cyclophosphamide was halved or withheld. Administration of vincristine was temporarily interrupted when there was complete loss of deep tendon reflexes, extensor weakness, paralysis of peripheral nerves, or troublesome paresthesias. Complete history, physical examination, radiographic survey including films of the bony skeleton, skull, and chest, and excretory urogram were performed on each patient. Verification of pathologic diagnosis was obtained when necessary by electron microscopy and histochemical techniques. Hemogram, bone m a r r o w aspiration, liver and kidney function studies, and appropriate bacteriologic studies were routinely performed before initiation of therapy.
Each patient was evaluated as to the primary t u m o r site, extent of disease at time of diagnosis, metastatic lesions, bone m a r r o w involvement, and radiographic evidence of disease. Clinical staging of the disease was then defined as in Table I. Response to therapy was re~orded for each area of measurable tumor and was quantitated in relation to the clinical staging of disease and the extent and duration of response. Grading of response was as defined previously. 4 RESULTS
AND DISCUSSION
Pertinent data concerning the patients, clinical staging of disease, treatment, and response are summarized in Table II. Each of the 7 patients with rhabdomyosarcoma could be evaluated for the effects of the chemotherapeutic agents. Complete or partial responses were obtained in each of these patients. O n e patient with bone marrow involvement achieved a complete response which lasted for 7.5 months. Another patient (Patient No. 7) h a d complete clearing of rhabdomyoblasts from the bone marrow, but other metastatic lesions were only partially reduced in size. Median duration of
Volume 74 Number 5
Brie[ clinical and laboratory observations
793
sarcoma Previous treatment
Concomitant therapy RT to pharynx, 5,600 r
Response Partial
Duration o[ response months 3.5
Survival [rom diagnosis (months) 5.5
RT to orbit bones for pain, 2,700 r
Partial
1.5
5.5
RT to skull, 4,400 r
Partial
4.5
17.0
RT to cheek, 1,800 r
Complete
7.5
17.0
RT to pelvis, 3,500 r
Partial
18.0
29.0
Mastoidectomy
Partial excision neck, 4,400 r
RT to left lung metastasis, 3,460 r
Partial
6.0
40.0
Mid-forearm amputation
RT to breasts, 3.400 r
Partial
3.0
22.0
for follow-up until he had evidence of progressive disease. At that time he received cyelophosphamide.
response for the g r o u p was 4.5 months. T h e m e d i a n d u r a t i o n of survival from diagnosis was 17 months, which equals the m e d i a n survival time of all children with r h a b d o m y o s a r c o m a seen at this institution. Neurologic toxicity associated with the a d m i n i s t r a t i o n of vincristine o c c u r r e d in each of these 7 patients. E a c h of the patients experienced nausea following a d m i n i s t r a t i o n of dactinomycin. O n l y 2 patients h a d modification of d r u g t h e r a p y , one because of absence of deep t e n d o n reflexes, one because of leukopenia. T h r o m b o c y t o p e n i a , w h i c h occ u r r e d in one patient, was n o t life t h r e a t e n ing in severity. Fibrosis of t h e u r i n a r y b l a d d e r was f o u n d at p o s t m o r t e m e x a m i n a t i o n in one p a t i e n t 2 H e h a d e x p e r i e n c e d no urin a r y t r a c t symptoms d u r i n g the p e r i o d of t r e a t m e n t with cyclophosphamide. T h e response of these patients with far a d v a n c e d disease indicates the consistent antineoplastic effect of this c o m b i n a t i o n of c h e m o t h e r a p e u t i c agents on r h a b d o m y o s a r coma. F o r this reason, c o m b i n a t i o n chemot h e r a p y with these t h r e e agents m i g h t be a useful a d j u n c t to surgery a n d / o r r a d i o t h e r a p y in the t r e a t m e n t of localized o r resectable regional disease.
SUMMARY
Seven patients with far a d v a n c e d r h a b d o m y o s a r c o m a were t r e a t e d with c o m b i n a t i o n c h e m o t h e r a p y consisting of vincristine, dactinomycin, a n d c y c l o p h o s p h a m i d e . O n e patient with bone m a r r o w involvement h a d a complete response lasting 7.5 months. Partial responses were o b t a i n e d in 6 patients. T h e responses of these patients indicate that this c o m b i n a t i o n of agents m a y be a valuable a d j u n c t to surgery a n d / o r r a d i o t h e r a p y in t r e a t i n g localized or regional disease. A classification for the clinical staging of r h a b d o m y o s a r c o m a is presented. REFERENCES
1. Pinkel, D., and Pickren, J.: Rhabdomyosarcoma in children, J. A. M. A. 175: 293, 1961. 2. Edland, R. W.: Embryonal rhabdomyosarcoma. Five year survival of a patient treated by radiation and chemotherapy, Am. J. Roentgenol. 99: 400, 1967. 3. Nelson, A. J., III: Embryonal rhabdomyosarcoma. Report of twenty-four cases and study of the effectiveness of radiation therapy upon the primary tumor, Cancer 22: 64, t968. 4. Pratt, C. B., James, D. H., Jr., Holton, C. P., and Pinkel, D.: Combination therapy including vincristine (NSC-67574) for malignant solid tumors in children, Cancer Chemother. Rep. 52: 489, 1968.
7 94
Brief clinical and laboratory observations
5. Haddy, T. B., Nora, A. tI., Sutow, W. W., and Vietti, J. J.: Cyclophosphamide treatment for metastatic soft tissue sarcoma. Intermittent large doses in the treatment of children, Am. J. Dis. Child. 114: 301, 1967. 6. Sutow, W. W., Berry, D. H., Haddy, T. B., Sullivan, M. P., Watkins, W. L., and Windmiller, J.: Vincristine sulfate therapy in children with metastatic soft tissue sarcoma, Pediatrics 38: 465, 1968. 7. James, D. H., Jr., Hustu, O., Wrenn, E. L., Jr., and Johnson, W. W.: Childhood malignant tumors. Concurrent chemotherapy with dactinomycin and vincristine sulfate, J. A. M. A. 197: 1043, 1966.
Triple
(45,x/46, x x c46, x x) mosaicism in a pbenotypic
/emale Richard L. Neu, M.S., Tadashi Kajii, M.D., Mary L. Voorhess, M.D., and Lytt I. Gardner, M.D.* SYRACUSE~
N. Y.
RINO CHROMOSOMES in m a n were first described by L e v a n 1 in cytologic preparations m a d e from m a l i g n a n t tissue. Since that time ring chromosomes have been observed in patients with leukemia, 2-4 in patients after irradiation, 5-s a n d in in vitro hum a n cell line cultures subjected to cold treatment2 From the Genetic and Endocrine Unit, Department o[ Pediatrics, State University o[ New York, Upstate Medical Center at Syracuse.
These studies were aided by Grants Nos. AM-02504 and T1-AM-5277 [rom the National Institute of Arthritis and Metabolic Diseases, and by Research Career Program Award No. 5-K3-CA-14, 289 and Research Grant No. CA-06312 from the National Cancer Institute and No. 5-TO-2-CH-1081 [rom the National Institutes o[ Health. ~Address [or reprints: 750 E. Adams St., Syracuse, N. Y. 13210.
The Journal o/ Pediatrics May 1969
8. Sitarz, A. L., Heyn, R., Murphy, M. L., Origenes, M. L., Jr., and Severo, N. C.: Triple drug therapy with actinomycin D (NSC-3053), chlorarnbucil (NSC-3088), and methntrexate (NSC-740) in metastatic solid tumors in children, Cancer Chemother. Rep. 45: 45, 1965. 9. Meadows, D., and Johnson, W.: Irreversible fibrosis and telangectasia of the urinary bladder associated with long term cyclophosphamide therapy (Abst.), Southern M. J. 59: 1475, 1966.
A n u m b e r of cases of self-perpetuating ring chromosomes in m a n have been described; these will be discussed later in this paper. T o our knowledge, 7 patients have been reported with a cell line having a ring form of a n X chromosome, i n addition to the p a t i e n t presented in this report 1~ (Table I ) . T h e description of our case follows. CASE
REPORT
The proposita was first seen at 6~62 years of age because she was only 102.5 cm. tall (height age of 41N years). The skeletal proportions were normal, as was her bone age. Her pedigree revealed a large number of very short people in her father's family. It was thought at that time that the patient represented either primordial dwarfism (familial) or ovarian agenesis with dwarfism. The only evidence for the latter was a poorly developed jaw and chin. The patient also had a palate with a rather high arch and incomplete syndactyly of the second and third toes on each foot. She was seen again at the age of 13 years. Her development had been normal except for retarded linear growth. Her school records showed her to be a B student. Menarche had not yet occurred. At that time she was 126.2 cm. in height, had early breast development, and a small amount of axillary and pubic hair. At age 149A2 years, the patient had the first of 5 normal menstrual periods, after which they ceased. At 16 years of age (Fig. 1) she was found to have a negative buccal smear, and chromosome analysis revealed an abnormal sex chromosome
Brief clinical and laboratory observations
Response of childhood rhabdomyosarcoma to combination chemotherapy Charles B. Pratt, M.D. MEMPHIS,
TENN.
R I - t A B D O M Y O S A R C O M A ~ one of the more common malignant solid tumors of children, remains largely a fatal disease in spite of surgery, radiotherapy, or chemotherapy? Early spread of the tumor occurs both by infiltration and through blood and lymphatic vessels9 Aggressive surgical attacks on these tumors h a v e failed to produce a significant increase of cures? These tumors of children are rather sensitive to radiotherapy, with predictable tumor control following treatment with a tumor dose of about 6,000 r in 6 weeks, z' 3 Dactinomycin, cyclophosphamide, and vincristine have been used in the treatment of rhabdomyosarcoma in recent years. 4 Dactinomycin alone produced tumor regressions in 10 of 38 patients with rhabdomyosarcoma. More frequent and extensive responses were obtained when dactinomycin was administered concurrently with radiotherapy, but the contribution of dactinomycin to these results could not be ascertained because rhabdomyosarcomas are responsive to radiotherapy?, z, 4 Cyclophosphamide effected tumor regression in 21 of 37 patients with rhabdomyosarcoma,~' ~ while vincristine had beneficial effects in 10 of 20 patients with this tumor. 4, 6 In the past, James and associates reported objective responses in 6 patients receiving vincristine and dactinomycin concurrently. Four of 5 paFrom the St. Jude Children's Research Hospital and University of Tennessee Medical Units. Supported by United States Public Health Service Research Grants Nos. CA 07594 and CA 08480, and by American Lebanese Syrian Associated Charities (ALSAC). Address: St. ]ude Children's Research Hospital, P. O. Box 318, Memphis, Tenn. 38101.
79 1
tients treated by Sitarz and associates s had responses following administration of combination chemotherapy consisting of dactinomycin, chlorambucil, and methotrexate. A chemotherapy plan employing a combination of these agents was chosen with the hope of producing tumor regression in a greater number of patients with rhabdomyosarcomas. It was anticipated that there would be greater destruction of tumor than could be expected with a single agent and that triple interference with tumor cell metabolism might prevent emergence of drug-resistant neoplasm. M A T E R I A L S AND M E T H O D S Seven children with advanced rhabdomyosarcoma, aged 2 to 16 years, previously untreated with chemotherapeutic agents, were treated with vincristine, dactinomycin, and cyclophosphamide in a designed plan used as part of the total management of their basic disease. Following biopsy or more definitive surgery, dactinomycin, 0.6 mg. per square meter, was administered intravenously twice weekly for 4 doses concurrently with vincristine, 1.5 mg. per square meter, intravenously once weekly for 6 weeks. After the 6 weekly injections of vincristine, this agent was alternated at weekly intervals with cyclophosphamide, 300 mg. per square meter, intravenously. Radio-
Table I. Clinical staging of childhood rhabdomyosarcoma Stage
I
Description
I
Localized disease, completely resectable
II
Regional disease A. Completely resectable B. Nonresectable or partially resectable, e.g., pelvic lymph node involvement from sarcoma botryoides, infiltration of base of skull from nasopharyngeal primary
III
Generalized disease A. Distant metastases with normal bone marrow (pulmonary metastases or disease above and below the diaphragm) B. Distant metastases with positive bone marrow (pulmonary metastases may or may not be present)
79 2
Brie[ clinical and laboratory observations
The Journal of Pediatrics May 1969
Table II. Effects of vincristine, dactinomycin, and cyclophosphamide in patients with rhabdornyo Patient No. 1
Age (years) 69/52
Sex F
Primary site Pharynx
Extension or metastases Skull, antrum, bone marrow
Clinical stage of disease III B
2
15"~2
F
Orbit
Sinuses, lung, bone marrow
III B
3~
2~2
M
Mastoid-nasopharynx
Skull, brain
4
93A2
F
Face
Skull, brain, orbit, bone marrow
III B
5
4
M
Gluteal area
Lungs
III A
Lymph nodes, orbit, skull, brain, lung
IIIA
6
12~z
F
Neck
7
161A2
F
Interosseous muscle of Bone marrow, lymph hand nodes, breasts
IIB
III B
RT= radiotherapy. ~This patient received vlncristine and dactinomycinand measurable regression which followedby radiotherapy. He did not return therapy was administered concurrently with chemotherapy, as was necessary for best clinical management. D r u g therapy was modified or temporarily withheld in the presence of hematopoietic depression or severe neurotoxicity. Serious hematopoietic toxicity was defined as reduction of the circulating leukocyte count to levels below 2,000 per cubic millimeter or platelet count to below 100,000 per cubic millimeter. Accordingly, the dosage of dactinomycin or cyclophosphamide was halved or withheld. Administration of vincristine was temporarily interrupted when there was complete loss of deep tendon reflexes, extensor weakness, paralysis of peripheral nerves, or troublesome paresthesias. Complete history, physical examination, radiographic survey including films of the bony skeleton, skull, and chest, and excretory urogram were performed on each patient. Verification of pathologic diagnosis was obtained when necessary by electron microscopy and histochemical techniques. Hemogram, bone m a r r o w aspiration, liver and kidney function studies, and appropriate bacteriologic studies were routinely performed before initiation of therapy.
Each patient was evaluated as to the primary t u m o r site, extent of disease at time of diagnosis, metastatic lesions, bone m a r r o w involvement, and radiographic evidence of disease. Clinical staging of the disease was then defined as in Table I. Response to therapy was re~orded for each area of measurable tumor and was quantitated in relation to the clinical staging of disease and the extent and duration of response. Grading of response was as defined previously. 4 RESULTS
AND DISCUSSION
Pertinent data concerning the patients, clinical staging of disease, treatment, and response are summarized in Table II. Each of the 7 patients with rhabdomyosarcoma could be evaluated for the effects of the chemotherapeutic agents. Complete or partial responses were obtained in each of these patients. O n e patient with bone marrow involvement achieved a complete response which lasted for 7.5 months. Another patient (Patient No. 7) h a d complete clearing of rhabdomyoblasts from the bone marrow, but other metastatic lesions were only partially reduced in size. Median duration of
Volume 74 Number 5
Brie[ clinical and laboratory observations
793
sarcoma Previous treatment
Concomitant therapy RT to pharynx, 5,600 r
Response Partial
Duration o[ response months 3.5
Survival [rom diagnosis (months) 5.5
RT to orbit bones for pain, 2,700 r
Partial
1.5
5.5
RT to skull, 4,400 r
Partial
4.5
17.0
RT to cheek, 1,800 r
Complete
7.5
17.0
RT to pelvis, 3,500 r
Partial
18.0
29.0
Mastoidectomy
Partial excision neck, 4,400 r
RT to left lung metastasis, 3,460 r
Partial
6.0
40.0
Mid-forearm amputation
RT to breasts, 3.400 r
Partial
3.0
22.0
for follow-up until he had evidence of progressive disease. At that time he received cyelophosphamide.
response for the g r o u p was 4.5 months. T h e m e d i a n d u r a t i o n of survival from diagnosis was 17 months, which equals the m e d i a n survival time of all children with r h a b d o m y o s a r c o m a seen at this institution. Neurologic toxicity associated with the a d m i n i s t r a t i o n of vincristine o c c u r r e d in each of these 7 patients. E a c h of the patients experienced nausea following a d m i n i s t r a t i o n of dactinomycin. O n l y 2 patients h a d modification of d r u g t h e r a p y , one because of absence of deep t e n d o n reflexes, one because of leukopenia. T h r o m b o c y t o p e n i a , w h i c h occ u r r e d in one patient, was n o t life t h r e a t e n ing in severity. Fibrosis of t h e u r i n a r y b l a d d e r was f o u n d at p o s t m o r t e m e x a m i n a t i o n in one p a t i e n t 2 H e h a d e x p e r i e n c e d no urin a r y t r a c t symptoms d u r i n g the p e r i o d of t r e a t m e n t with cyclophosphamide. T h e response of these patients with far a d v a n c e d disease indicates the consistent antineoplastic effect of this c o m b i n a t i o n of c h e m o t h e r a p e u t i c agents on r h a b d o m y o s a r coma. F o r this reason, c o m b i n a t i o n chemot h e r a p y with these t h r e e agents m i g h t be a useful a d j u n c t to surgery a n d / o r r a d i o t h e r a p y in the t r e a t m e n t of localized o r resectable regional disease.
SUMMARY
Seven patients with far a d v a n c e d r h a b d o m y o s a r c o m a were t r e a t e d with c o m b i n a t i o n c h e m o t h e r a p y consisting of vincristine, dactinomycin, a n d c y c l o p h o s p h a m i d e . O n e patient with bone m a r r o w involvement h a d a complete response lasting 7.5 months. Partial responses were o b t a i n e d in 6 patients. T h e responses of these patients indicate that this c o m b i n a t i o n of agents m a y be a valuable a d j u n c t to surgery a n d / o r r a d i o t h e r a p y in t r e a t i n g localized or regional disease. A classification for the clinical staging of r h a b d o m y o s a r c o m a is presented. REFERENCES
1. Pinkel, D., and Pickren, J.: Rhabdomyosarcoma in children, J. A. M. A. 175: 293, 1961. 2. Edland, R. W.: Embryonal rhabdomyosarcoma. Five year survival of a patient treated by radiation and chemotherapy, Am. J. Roentgenol. 99: 400, 1967. 3. Nelson, A. J., III: Embryonal rhabdomyosarcoma. Report of twenty-four cases and study of the effectiveness of radiation therapy upon the primary tumor, Cancer 22: 64, t968. 4. Pratt, C. B., James, D. H., Jr., Holton, C. P., and Pinkel, D.: Combination therapy including vincristine (NSC-67574) for malignant solid tumors in children, Cancer Chemother. Rep. 52: 489, 1968.
7 94
Brief clinical and laboratory observations
5. Haddy, T. B., Nora, A. tI., Sutow, W. W., and Vietti, J. J.: Cyclophosphamide treatment for metastatic soft tissue sarcoma. Intermittent large doses in the treatment of children, Am. J. Dis. Child. 114: 301, 1967. 6. Sutow, W. W., Berry, D. H., Haddy, T. B., Sullivan, M. P., Watkins, W. L., and Windmiller, J.: Vincristine sulfate therapy in children with metastatic soft tissue sarcoma, Pediatrics 38: 465, 1968. 7. James, D. H., Jr., Hustu, O., Wrenn, E. L., Jr., and Johnson, W. W.: Childhood malignant tumors. Concurrent chemotherapy with dactinomycin and vincristine sulfate, J. A. M. A. 197: 1043, 1966.
Triple
(45,x/46, x x c46, x x) mosaicism in a pbenotypic
/emale Richard L. Neu, M.S., Tadashi Kajii, M.D., Mary L. Voorhess, M.D., and Lytt I. Gardner, M.D.* SYRACUSE~
N. Y.
RINO CHROMOSOMES in m a n were first described by L e v a n 1 in cytologic preparations m a d e from m a l i g n a n t tissue. Since that time ring chromosomes have been observed in patients with leukemia, 2-4 in patients after irradiation, 5-s a n d in in vitro hum a n cell line cultures subjected to cold treatment2 From the Genetic and Endocrine Unit, Department o[ Pediatrics, State University o[ New York, Upstate Medical Center at Syracuse.
These studies were aided by Grants Nos. AM-02504 and T1-AM-5277 [rom the National Institute of Arthritis and Metabolic Diseases, and by Research Career Program Award No. 5-K3-CA-14, 289 and Research Grant No. CA-06312 from the National Cancer Institute and No. 5-TO-2-CH-1081 [rom the National Institutes o[ Health. ~Address [or reprints: 750 E. Adams St., Syracuse, N. Y. 13210.
The Journal o/ Pediatrics May 1969
8. Sitarz, A. L., Heyn, R., Murphy, M. L., Origenes, M. L., Jr., and Severo, N. C.: Triple drug therapy with actinomycin D (NSC-3053), chlorarnbucil (NSC-3088), and methntrexate (NSC-740) in metastatic solid tumors in children, Cancer Chemother. Rep. 45: 45, 1965. 9. Meadows, D., and Johnson, W.: Irreversible fibrosis and telangectasia of the urinary bladder associated with long term cyclophosphamide therapy (Abst.), Southern M. J. 59: 1475, 1966.
A n u m b e r of cases of self-perpetuating ring chromosomes in m a n have been described; these will be discussed later in this paper. T o our knowledge, 7 patients have been reported with a cell line having a ring form of a n X chromosome, i n addition to the p a t i e n t presented in this report 1~ (Table I ) . T h e description of our case follows. CASE
REPORT
The proposita was first seen at 6~62 years of age because she was only 102.5 cm. tall (height age of 41N years). The skeletal proportions were normal, as was her bone age. Her pedigree revealed a large number of very short people in her father's family. It was thought at that time that the patient represented either primordial dwarfism (familial) or ovarian agenesis with dwarfism. The only evidence for the latter was a poorly developed jaw and chin. The patient also had a palate with a rather high arch and incomplete syndactyly of the second and third toes on each foot. She was seen again at the age of 13 years. Her development had been normal except for retarded linear growth. Her school records showed her to be a B student. Menarche had not yet occurred. At that time she was 126.2 cm. in height, had early breast development, and a small amount of axillary and pubic hair. At age 149A2 years, the patient had the first of 5 normal menstrual periods, after which they ceased. At 16 years of age (Fig. 1) she was found to have a negative buccal smear, and chromosome analysis revealed an abnormal sex chromosome