Chemotherapy with actinomycin D influences the growth of the spine following abdominal irradiation.
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Age Factors↗
Biomedical subjects
W H Wallace
Publications and source records attributed to W H Wallace.
Irradiation-induced growth failure.
GH deficiency, skeletal disproportion and early or precocious puberty may complicate irradiation to the head or axial skeleton in childhood. Certain cohorts of children are at particular risk, including those irradiated for brain tumours and various haematological malignancies. Both GH deficiency and impaired spinal growth may result in short stature, whereas the occurrence of early puberty in association with GH deficiency reduces the time available for GH therapy. The age of the child at irradiation is critical in that, in younger children, the central nervous system is more radiosensitive, the severity of the subsequent skeletal disproportion is greatest and the onset of puberty earliest. It is the very young craniospinally-irradiated child who is most at risk of extreme short stature.
Age Factors↗
A novel variant of growth hormone (GH) insufficiency following low dose cranial irradiation.
OBJECTIVE: We aimed to investigate the effect of low dose (1800 cGy) prophylactic cranial irradiation on physiological growth hormone secretion. DESIGN: We performed an analysis of 24-hour serum GH profiles using 20-minute sampling. PATIENTS: Forty-four children were studied, of whom 21 were long-term survivors of acute lymphoblastic leukaemia and 23 were normal children. They were further subdivided into prepubertal, pubertal and post-pubertal groups. MEASUREMENTS: GH profiles were analysed by autocorrelation, Fourier transformation and spectral analysis of stationarized data, and peak detection using the Pulsar peak detection program. RESULTS In the normal children, there was a significant increase in the median (range) area under the curve (AUC) of the GH profile between the prepubertal and pubertal groups (62 (11-124) and 137 (142-158) IU/I/h respectively, (P less than 0.01)). There was also a change in the spectral analysis through puberty. The dominant frequencies were spread widely in the prepubertal and post-pubertal groups but sharply focused in the pubertal group. In the cranially irradiated children there was no significant increase in AUC between the prepubertal (62(13-110) IU/I/h) and pubertal groups (92 (14-163) IU/I/h). The wide range of dominant frequencies persisted in the pubertal cranially irradiated group due to the presence of additional high frequency pulses. The impression of a disturbance of the periodicity of GH secretion in the cranially irradiated pubertal group was further supported by the finding that the autocorrelation function in this group alone was not significantly different from that which would arise from random data. CONCLUSIONS: A novel form of GH insufficiency has been observed after low dose irradiation in childhood in which an abnormality of periodicity and a quantitative reduction in GH secretion appears restricted to puberty.
Adolescent↗
Abdominal irradiation in childhood; the potential for pregnancy.
OBJECTIVE: To investigate the impact of premature ovarian failure due to whole abdominal radiotherapy (DXT) in childhood on uterine physical characteristics and blood flow and measuring the uterine response to exogenous sex steroid replacement. DESIGN: A comparative observational study SUBJECTS: 10 women with premature ovarian failure due to treatment with whole abdominal irradiation in childhood. A comparison group of 22 women with premature ovarian failure who had not received whole abdominal DXT. MAIN OUTCOME MEASURES: Uterine length and uterine blood flow measurement plus serial assessment of endometrial thickness during a cycle of exogenous sex steroid replacement. RESULTS: Uterine length was significantly less (P less than 0.01) in women who had been exposed to whole abdominal DXT in childhood (mean 4.1 cm, 2SE 0.8) compared with a mean of 7.3 cm (2SE 0.6) in the comparison group. The three women in the DXT group who were studied serially had no increase in endometrial thickness in response to physiological sex steroid replacement therapy and most of the 10 irradiated women had no detectable uterine blood flow with Doppler ultrasound. CONCLUSIONS: Uterine musculature and blood flow are irreversibly affected by high dose irradiation in childhood. Non-invasive assessment of this nature may predict potential for pregnancy following ovum donation and embryo transfer.
Adult↗
Relationship between urinary and serum growth hormone and pubertal status.
Urinary growth hormone (uGH) excretion and serum growth hormone concentrations have been compared in three groups of children. Group 1 consisted of 21 children who had had cranial irradiation as part of their treatment for acute lymphoblastic leukaemia; group 2, 18 normal children; and group 3, 12 boys with constitutional delay in growth and puberty who were in early puberty. Children in groups 1 and 2 each had a 24 hour serum growth hormone profile (sampling every 20 minutes) and concurrent urine collection. The 12 boys in group 3 had a total of 21 profiles (sampling every 15 minutes for 12 hours) and concurrent urine collections. In the prepubertal children (n = 17), in both groups 1 and 2, there was a significant correlation between mean serum growth hormone and total uGHng/g creatinine. There were also significant correlations between total uGHng/g creatinine and both peak serum growth hormone and mean amplitude of the pulses in the growth hormone profile. In the pubertal children (n = 22), in groups 1 and 2, whether combined or in separate groups, there was no significant correlation between total uGHng/g creatinine and mean serum growth hormone, peak serum growth hormone, or mean amplitude of the pulses in the growth hormone profile. In group 3 there were significant correlations between total uGHng/g creatinine and both the mean serum growth hormone and mean amplitude of the pulses in the profile. Therefore uGH estimations appear to correlate well with serum growth hormone profiles in children who are prepubertal or in early puberty, but not in those further advanced in pubertal development. These results may reflect a variation in the renal handling of growth hormone during pubertal development. uGH estimation may be an unreliable screening investigation for growth hormone sufficiency in mid to late puberty.
Adolescent↗
Endocrine deficit after fractionated total body irradiation.
Endocrine function was assessed in 31 children (17 boys) after fractionated total body irradiation used in the preparative regimen for bone marrow transplantation. Endocrine dysfunction was present in 25 children. Fifteen of 29 had growth hormone insufficiency 0.9-4.9 years after total body irradiation, yet only three of the 15 had received previous cranial irradiation. Five of 30 had thyroid dysfunction: two with a low thyroxine and raised thyroid stimulating hormone (TSH) concentration and three with a raised TSH and normal thyroxine concentration. Thus the incidence of thyroid dysfunction (16%) is much lower than that reported after single fraction total body irradiation (39-59%). In only two children were abnormalities of the hypothalamic-pituitary-adrenal axis demonstrated. The majority of pubertal children assessed (n = 15) showed evidence of gonadal damage. All the pubertal girls (n = 5) had ovarian failure, although there was evidence of recovery of ovarian function in one girl. All seven boys in late puberty showed evidence of damage to the germinal epithelium, and two of three in early puberty had raised follicle stimulating hormone concentrations. Despite the use of a fractionated total body irradiation regimen, endocrine morbidity is substantial and children undergoing such procedures will require long term endocrine review and management.
Adolescent↗
Final height in girls with untreated constitutional delay in growth and puberty.
During a 10-year period, 23 girls compared to 118 boys presented with constitutional delay in growth and puberty. Of these girls, 15 were followed to final height to determine the outcome of the untreated condition in terms of both growth and psychological well-being. At presentation chronological age was 13.2 (1.7) years [mean (S.D.)], bone age delay 2.7 (0.9) years, standing height standard deviation score (SDS) -3.4 (0.9), and predicted adult height (PAH) SDS -1.3 (0.7) (Tanner-Whitehouse II method). Final height SDS was -1.5 (0.8) measured at 18.9 (2.6) years of age. Mean age at menarche was 15.6 (0.9) years. There was no significant difference between final adult height (FH) and PAH but there was a significant difference between FH and target height (P less than 0.001). Psychological questionnaires revealed no significant difference in self-esteem, marital or employment status between the patient and control groups. There was no significant correlation between self-esteem and FH but 80% felt their growth delay had affected success either at school, work or socially. Of the patients, 50% would have preferred treatment to advance their growth spurt. This study demonstrates that girls with constitutional delay in growth and puberty reached their PAH, although this was lower than the midparental heights. The girls also experienced significant distress due to delayed growth and puberty and treatment to advance growth should be considered more frequently.
Adolescent↗
Episodic ACTH and cortisol secretion in normal children.
The aim of this study was to determine the normal relationship between ACTH and cortisol secretion in children. Fourteen children (nine male, five female; median age 11.3 years) were hospitalized and blood samples were taken every 20 min for 24 h. A circadian rhythm was observed with median 0900 h and midnight ACTH values of 1.80 and less than 0.97 pmol/l, and for cortisol 296 and 62 nmol/l respectively. The median (range) areas under the curve for ACTH and cortisol were 29.7 (9.0-53.8) pmol/l/h and 5114 (3562-8630) nmol/l/h respectively. There were no significant differences detected for ACTH and cortisol secretion between males and females, or between prepubertal (n = 9) and pubertal subjects (n = 5). Using a novel form of time series analysis we have shown that both ACTH and cortisol are secreted with a dominant periodicity of 0.7-1.0 h, representing 24-34 secretory episodes of ACTH and cortisol in 24 h. For cortisol, but not ACTH, there is a significant secondary periodicity of 2-3.2 h. To look for shared periodicities we have used the technique of coherency. This reveals that for six of the children ACTH and cortisol are secreted with a significant shared periodicity of 0.8-1.0 h, and for a further five children a similar secondary shared periodicity is present. Therefore in normal children ACTH and cortisol secretion are interdependent and episodic but are not influenced by either pubertal status or gender.
Adolescent↗
Male fertility in long-term survivors of childhood acute lymphoblastic leukaemia.
To study long-term testicular function following the treatment of acute lymphoblastic leukaemia (ALL) in childhood, 37 young adult males were assessed at two separate time points. The initial assessment was made by a wedge testicular biopsy after completion of treatment (median 9.7 years; range 4.1-16.3 years) and the subsequent assessment (median 18.6 years; range 15.4-26.8 years) consisted of the clinical examination of pubertal stage, measurement of serum gonadotrophins and testosterone and, in 19 patients, semen analysis. All 37 men completed pubertal development normally and had a testosterone concentration within the normal adult range. Six men showed evidence of severe damage to the seminiferous epithelium, five were azoospermic and one, who did not provide semen for analysis, had a reduced mean testicular volume (11 mls; normal greater than or equal to 15 mls) and a raised basal FSH level (13 UI 1-1; normal less than or equal to 6 IU 1-1). All six men with germ-cell damage had received either cyclophosphamide or both cyclophosphamide and cytosine arabinoside as part of their chemotherapy regimen. Approximately 10.7 years earlier all 37 men had undergone a testicular biopsy after completion of their chemotherapy. Morphological damage to the seminiferous epithelium had been calculated by estimating the tubular fertility index (TFI), which is the percentage of seminiferous tubules containing identifiable spermatogonia (age-matched normal = 100%).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Effect of abdominal irradiation on growth in boys treated for a Wilms' tumor.
To study the effect of abdominal irradiation on spinal growth in childhood we have measured final height, sitting height, and leg length in 30 male survivors of a Wilms' tumor. Twenty-one patients received whole abdominal irradiation by either megavoltage therapy (MV: n = 11) or orthovoltage therapy (OV: n = 10); the remainder received flank irradiation. To examine the effect of the adolescent growth spurt on the irradiated spine we have followed prospectively seven patients who received whole abdominal irradiation and nine patients who received flank irradiation through puberty. Compared to a normal population there is a modest reduction in median final standing height SDS (H.SDS: -1.15) accompanied by a marked reduction in median final sitting height SDS (S.HT SDS: -2.41) with no apparent effect on median subischial leg length SDS (SILL.SDS: 0.04). This reduction in spinal growth is reflected by a strongly positive disproportion score (DPS; [SILL SDS-S.HT SDS] + 2.81). The incidence of scoliosis after abdominal irradiation has been low (10%). During puberty there is a significant fall in median sitting height SDS after both whole abdominal (median fall: -0.9, P = 0.02) and flank irradiation (median fall: -1.85, P = 0.01), and this is reflected in a significant increase in disproportion (DPS: whole abdominal; median rise +1.4, P = 0.02: flank, median rise +1.34, P = 0.01). After MV irradiation there is a significant correlation between the degree of disproportion and the age at treatment (P less than 0.0005). The younger the patient is at treatment the more severe is the restriction on spinal growth and the shorter and more disproportionate they become as an adult. The estimated eventual loss in potential height from abdominal irradiation at the age of one is 10 cm and at five years is 7 cm.
Abdomen↗
Final height in boys with untreated constitutional delay in growth and puberty.
To determine the natural history and psychological impact of the growth pattern in boys with constitutional delay in growth and puberty (CDGP), 43 boys presenting with short stature due to CDGP were followed up to final height. At presentation mean (SD) chronological age was 14.0 (1.9) years, bone age delay 2.7 (1.0) years, standing height standard deviation score (SDS) -3.4 (0.6), and predicted adult height SDS -1.3 (0.7). Final adult height SDS was -1.6 (0.9), measured at 21.2 (2.6) years. There was no significant difference between final height and predicted adult height, but there was a significant difference between final height and measured mid-parental height. Psychological questionnaires showed no significant difference in self esteem, marital, or employment state between the CDGP group and a control group. There was no correlation between self esteem and final height, but 25 felt their growth delay had affected their success either at school, work, or socially and 20 would rather have had treatment to advance their growth spurt. This study supports the more frequent use of active medical treatment to advance growth in boys with CDGP, and shows that although boys with CDGP reach their predicted heights, this is short for their families.
Adolescent↗
Gonadal dysfunction due to cis-platinum.
Gonadal function was studied in 15 patients 12 pubertal or postpubertal, and three prepubertal, who had been treated during childhood for nonmetastatic osteosarcoma of the long bones by chemotherapy regimens that included cis-platinum and adriamycin. Of seven postpubertal female patients assessed (mean age at diagnosis 16.5 years), three were amenorrhoeic and showed evidence of ovarian damage with raised gonadotrophin levels and a low serum oestradiol concentration. One patient who had regular periods had a raised luteal-phase follicle-stimulating hormone (FSH) concentration suggestive of gonadal dysfunction. Severe oligospermia or reduced testicular volumes in the presence of raised gonadotrophin levels were observed in three of the five pubertal males (mean age at diagnosis 13.25 years). A reliable assessment of gonadal function was not possible in three male patients who remained prepubertal at the time of study. The median total dose of cis-platinum received by those patients with gonadal damage (median dose, 490 mg) was significantly higher than in those patients with normal gonadal function (median dose, 300 mg) (P = 0.01). In the boys the damage to the testes was primarily directed at the germinal epithelium. Leydig cell function was intact and the males progressed spontaneously through puberty. In the girls, unlike the boys, there was evidence of reversibility of gonadal damage with time. This is the first study to show gonadal dysfunction due to cis-platinum and adriamycin therapy in childhood.
Adolescent↗
Ovarian failure following abdominal irradiation in childhood: natural history and prognosis.
Ovarian function has been reviewed sequentially since 1975 in 53 patients treated in childhood between 1942 and 1985 for an intraabdominal tumour with surgery and external abdominal radiotherapy (XRT). Of 38 patients who received whole abdominal XRT (20-30 Gy), 27 failed to undergo or complete pubertal development (pubertal failure) and a premature menopause (median age 23.5 years) occurred in a further ten. Of 15 patients who received flank XRT (20-30 Gy), ovarian function (median age at last assessment 15.2 years) was normal in all but one in whom pubertal failure occurred. In only one patient, who developed pubertal failure after whole abdominal XRT and required sex steroid replacement therapy (HRT) to achieve normal secondary sexual characteristics, has there been evidence of reversibility of ovarian function with a documented conception at the age of 22.7 years. Five patients who developed pubertal failure required bilateral augmentation mammoplasties despite sex steroid replacement therapy. Four patients have had documented conceptions, all received whole abdominal XRT (20-26.5 Gy) and subsequently developed a premature menopause. There have been no live births, with all miscarriages occurring in the second trimester. The outlook for normal ovarian function following whole abdominal XRT is poor, flank XRT introduced intermittently from 1972, has resulted in less pubertal failure but the possibility of a premature menopause may with time become a reality.
Abdominal Neoplasms↗
Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte.
Ovarian function has been studied sequentially since 1975 in 19 patients treated in childhood for an intra-abdominal tumour with surgery and whole abdominal radiotherapy (total dose 30 Gy). Eleven patients received chemotherapeutic agents that are not known to cause gonadal dysfunction. All but one patient have developed ovarian failure with persistently elevated gonadotrophin levels (FSH and LH greater than 32 IU/litre) and low serum oestradiol values (less than 40 pmol/litre) before the age of 16 years. The majority (n = 12) did not progress beyond breast stage 1 without sex steroid replacement therapy. As the number of oocytes within the ovary declines exponentially by atresia from approximately 2,000,000 at birth to approximately 2000 at the menopause, we have been able to estimate that the LD50 for the human oocyte does not exceed 4 Gy.
Abdomen↗
Comparative performance information in the dean's letter.
Comparative medical school performance information, including the presence of a summative "dean's code" statement, was identified by selective content analysis of 310 dean's letters. There was a significant increase in the report of comparative information over the ten year study period, and correlation with residency in-training evaluations showed that this information may be useful to housestaff selection committees.
Clinical Competence↗
Identification of eubacteria isolated from leaf cavities of four species of the N-fixing azolla fern as arthrobacter conn and dimmick.
The nutritional and physiological characteristics of 15 isolates from four species of the Azolla fern were determined. Although some minor variation existed in levels of urease activity, ability to utilize xylose, and formation of N(2) gas from NO(3), all 15 isolates were rather similar and believed to represent a single species. These eubacteria exhibited aminopeptidase activity and became viscous when treated with KOH, similar to gram-negative organisms; however, the absence of lipopolysaccharide and 2-keto-3-deoxyoctonate in cell walls indicated that they are truly gram-positive organisms. They are unusual because peptidoglycan could not be detected during most of their growth cycle. The presence of lysine as the major diamino acid in cell wall hydrolysates, the inability to hydrolyze cellulose, and the distinctive developmental pattern with rods and "V" forms present during log phase, becoming progressively shorter until cocci dominated during stationary and death phases, indicated that these organisms belong to the genus Arthrobacter Conn and Dimmick. With the exception of the inability to hydrolyze gelatin, their characteristics are consistent with those of the type species, Arthrobacter globiformis Conn and Dimmick.
Journal Article↗
Internal topography of major nerves of the forearm and hand: a current view.
Fresh cadaver nerves were examined by serial cross-sections and microdissection with the operating microscope. The findings are compared with those of previous authors, primarily Sydney Sunderland. Our study confirms and amplifies Sunderland's findings: although it is true that funicular prexus formation and interchange takes place in the nerves of the human forearm, these connections are not of such a degree as to preclude operative procedures such as intraneural neurolysis, fascicular nerve repair, and interfascicular nerve grafting. Individual branches and bundles can be identified and traced within the main nerve trunk for considerable distances without significant trauma to conducting fibers. This arrangement lends itself to the application of modern microneurosurgical techniques. Clinical applications of these findings in the repair, lysis, and grafting of the major nerves of the forearm are described. The possibility of using such branches as the dorsal cutaneous branch of the ulnar nerve(if irreparably damaged) as a donor nerve for grafting is noted.
Animals↗
Factor VIII antibodies in rheumatoid arthritis. Effect of cyclophosphamide.
Three patients with rheumatoid arthritis had bleeding and bruising and were found to have circulating antibodies specifically directed against factor VIII. Review of the literature indicates that this is an unusual but serious complication of rheumatoid arthritis. In two of our three cases, disappearance of the factor VIII antibody coincided with the oral administration of cyclophosphamide; in the third patient, antibody titers declined several weeks after cyclophosphamide therapy was discontinued. Our collected experience involving 11 nonhemophilic patients with factor VIII antibodies indicates that a good response to cyclophosphamide therapy may be expected if the antibody titer is less than 10 Bethesda units at the initiation of treatment. While optimum treatment of these patients is not yet established, we suggest an initial trial of prednisone and, if there is no response, then therapy with cyclophosphamide.
Aged↗