Restoration of ovarian function after chemotherapy for osteosarcoma.

AIM: To evaluate ovarian function after modern intensive multi-agent chemotherapy for osteosarcoma given during childhood or adolescence. METHODS: After discontinuation of treatment, 10 female osteosarcoma survivors were followed up for 1.5-14 (median 4.6) years. Their age at diagnosis was a median of 12.9 (range 6-15) years and at the last follow up 18.6 (range 16-22). The main follow up included recording of their pubertal and menstrual status and of sex hormone determinations. RESULTS: Prior to diagnosis, 5/10 had had their menarche, and one had it while on therapy. At discontinuation of chemotherapy, ovarian function had severely deteriorated; none of the girls experienced regular menstrual cycles. However, during follow up, significant restoration of ovarian function was evident. At the last follow up, 9/10 patients were menstruating spontaneously. During follow up, four patients, three of whom had received high doses of alkylating agents, presented with clear hypergonadotrophism with high FSH levels (14.4-132 IU/l). Three of these four patients initiated menstruation after their gonadotrophin levels normalised. CONCLUSIONS: The modern multi-agent chemotherapy applied for osteosarcoma impairs ovarian function. Normalisation of ovarian function is common, even in cases with severe hypergonadotrophic hypogonadism, but may only occur after several years off chemotherapy. Regular assessment of ovarian function and cautious use of hormone replacement therapy are important in patients with chemotherapy induced gonadal damage.     

Ovarian function following the treatment of childhood acute lymphoblastic leukaemia

Ovarian function was assessed in 40 long term survivors who had received standard United Kingdom Acute Lymphoblastic Leukaemia (UKALL) protocols and were in first clinical and haematological remission. A menstrual and pregnancy history was taken (median age at assessment: 18.8 (12–34.7) years) and the acquisition of adult secondary sexual characteristics confirmed in each patient. Basal bloods were taken for follicle stimulating hormone (FSH), luteinizing hormone (LH), and serum oestradiol estimations. Serum progesterone concentration was measured in those patients who were in the luteal phase of their menstrual cycle at assessment. In addition, menstrual cycle profiles of salivary progesterone concentrations were derived from daily samples in 12 patients. All patients achieved adult sexual development; median age at menarche was early at 12.4 (9.0–14.6) years and 37 of them have regular menses. Ten patients have had 14 live births, and evidence of ovulation was seen in a further 11 patients assessed in the luteal phase of the menstrual cycle. Four patients had damaged ovaries, two of whom show evidence of ovulation; three of the four received craniospinal irradiation and one received cyclophosphamide as part of her chemotherapy regimen. None of these patients has yet developed total ovarian failure or required sex steroid replacement therapy. The medium term outlook for ovarian function is good for the majority of childhood ALL survivors. The spinal component of craniospinal irradiation is a major risk factor for ovarian damage, and cyclophosphamide may be a contributory factor. A premature menopause remains a possibility if significant follicular depletion has occurred at the time of cytotoxic treatment. © 1993 Wiley-Liss, Inc.     

Ovarian function after bone marrow transplantation performed before menarche

AIM—To examine the long term effect of bone marrow transplantation (BMT) on ovarian function in girls.
METHODS—Eighteen girls who underwent BMT before menarche, had been disease free for more than six years, and were over 14 years of age at the time of study were investigated. The preparative regimen consisted of irradiation and chemotherapy. The occurrence of menarche and changes in basal serum follicle stimulating hormone (FSH) concentrations were studied.
RESULTS—Twelve patients achieved menarche at a median age of 12.8 years. Age at transplant was significantly younger in patients who achieved menarche than in those who did not (mean (SD), 7.2 (0.5) v 11.1 (1.7) years). Basal FSH began to rise to menopausal concentrations after 10 years of age, and the girls who did not experience menarche had a sustained rise in FSH concentrations. Among those with raised FSH concentrations, five girls experienced menarche while serum FSH values were decreasing and four achieved menarche while FSH remained raised.
CONCLUSIONS—The high incidence of menarche suggests a favourable outcome of ovarian function in girls who undergo BMT at a young age.

     

Long-term complications following bone marrow transplantation in children

Abstract Seventeen children who underwent bone marrow transplantation (BMT) between 1975 and 1985 and survived for more than 2 years were evaluated for growth and development. The patients had a follow up of 2.1-13.1 years. Prior to transplant, children with malignancy had received multi-agent chemotherapy and nine had also received central nervous system irradiation. Transplant preparation for malignancy (group 1; n = 13) included high-dose cyclophosphamide (CPA) 120–200 mg/kg and total body irradiation (TBI) 10–13.2 Gy, whereas conditioning for non-malignant disorders (group 2; n = 4) included high-dose CPA 200 mg/kg with or without busulphan. Patients in group 1 showed a steady decline in height velocity following initial chemotherapy and cranial irradiation and the decline was even greater following BMT. Growth hormone (GH) deficiency developed in eight of nine children tested, hypergonadotrophic hypogonadism developed in 11 who reached puberty, thyroid hormone abnormalities were encountered in four out of 10 tested and 11 of 13 developed cataracts. Patients in group 2 did not show decline in linear growth rate, thyroid hormone abnormalities or cataracts after BMT. The only child tested had normal GH levels and the two patients who reached puberty showed delayed but complete gonadal recovery. Our data demonstrate that TBI leads to significant late effects on growth and gonadal function. Contrary to previous reports, a high incidence of cataract formation is observed after fractionated TBI. Conditioning regimens without TBI should be considered in children undergoing BMT.     

Gonadal function following chemotherapy for childhood Hodgkin's disease

Gonadal function was assessed in 101 postpubertal subjects after chemotherapy for childhood Hodgkin's disease. All had received ChIVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) chemotherapy alone, with no radiotherapy below the diaphragm. Gonadotropin levels were available in 46 (79.3%) male and 32 (74.4%) female subjects. The mean age at diagnosis in the male cohort was 12.2 years (range 8.2–15.3) and in the females 13.0 years (9.0–15.2). The males and the females were studied at a median of 6 years (range 2.5–11.1) and 4.3 years (range 1.9–11.5) from diagnosis, respectively. Forty-one (89.1%) male subjects had elevated follicle-stimulating hormone (FSH) levels, confirming severe germinal epithelial damage. Germinal epithelial damage was seen in subjects up to 10 years out of therapy. Subtle Leydig cell dysfunction was identified in 24.4% with raised luteinizing hormone (LH) levels. All subjects, however, progressed spontaneously through puberty. Seventeen (53%) women had raised gonadotropin levels, with variable estradiol levels. Of these, 10 subjects presented with symptomatic ovarian failure and 6 received hormone replacement therapy (HRT). Nine women had 11 successful pregnancies, two of whom had previously had symptoms of ovarian failure with one requiring HRT. A much higher prevalence of ovarian failure has been observed, than has previously been considered in the prepubertal and pubertal female following combination chemotherapy. These conclusions have important implications for future counseling, management, and research in this population. © 1996 Wiley-Liss, Inc.     

Diminished ovarian reserve in adolescent cancer survivors treated with heavy metal chemotherapy

The extent to which heavy metal chemotherapy results in treatment-related ovarian damage is controversial. Anti-Mullerian hormone (AMH) levels measured more than 1 year after cancer therapy completion were abstracted from the medical records of 39 female survivors of childhood cancer aged 11 years and older, whose only gonadotoxic exposure was heavy metal chemotherapy. One-fifth of survivors who received cisplatin had AMH levels indicative of diminished ovarian reserve at last measurement. There was an observed clustering of low AMH in patients diagnosed in the peripubertal age range (i.e., 10–12 years). These findings may support a small, but present, risk of gonadal damage after heavy metal chemotherapy.     

Ovarian function after bone marrow transplantation performed before menarche.

AIM: To examine the long term effect of bone marrow transplantation (BMT) on ovarian function in girls. METHODS: Eighteen girls who underwent BMT before menarche, had been disease free for more than six years, and were over 14 years of age at the time of study were investigated. The preparative regimen consisted of irradiation and chemotherapy. The occurrence of menarche and changes in basal serum follicle stimulating hormone (FSH) concentrations were studied. RESULTS: Twelve patients achieved menarche at a median age of 12.8 years. Age at transplant was significantly younger in patients who achieved menarche than in those who did not (mean (SD), 7.2 (0.5) v 11.1 (1.7) years). Basal FSH began to rise to menopausal concentrations after 10 years of age, and the girls who did not experience menarche had a sustained rise in FSH concentrations. Among those with raised FSH concentrations, five girls experienced menarche while serum FSH values were decreasing and four achieved menarche while FSH remained raised. CONCLUSIONS: The high incidence of menarche suggests a favourable outcome of ovarian function in girls who undergo BMT at a young age.     

Limitations and uses of gastrojejunal feeding tubes

Background: Gastrostomy feeding is a well established alternative method to long term nasogastric tube feeding. Many such patients have gastro-oesophageal reflux (GOR) and require a fundoplication. A transgastric jejunal tube is an alternative when antireflux surgery fails, or is hazardous or inappropriate. Aims: To review experience of gastrojejunal (G-J) feeding over six years in two regional centres in the UK. Methods: Retrospective review of all children who underwent insertion of a G-J feeding tube. Results: There were 18 children, 12 of whom were neurologically impaired. G-J tubes were inserted at a median age of 3.1 years (range 0.6–14.7) because of persistent symptoms after Nissen fundoplication (n = 8) or symptomatic GOR where fundoplication was inappropriate. Four underwent primary endoscopic insertion of the G-J tube; the remainder had the tube inserted via a previous gastrostomy track. Seventeen showed good weight gain. There was one insertion related complication. During a median follow up of 10 months (range 1–60), four experienced recurrent aspiration, bilious aspirates, and/or diarrhoea. There were 65 tube related complications in 14 patients, necessitating change of the tube at a median of 74 days. Jejunal tube migration was the commonest problem. Five died from complications of their underlying disease. Conclusions: Although G-J feeding tubes were inserted safely and improved nutritional status, their use was associated with a high rate of morbidity. Surgical alternatives such as an Roux-en-Y jejunostomy may be preferable.     

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.     

Osteosarcoma After Hematopoietic Stem Cell Transplantation in Children and Adolescents: Case Report and Review of the Literature

Osteosarcoma as a secondary malignancy after hematopoietic stem cell transplantation (HSCT) is very rare. We present a case and review of 18 other cases reported to date. Our patient underwent HSCT for myelodysplastic syndrome at the age of 4 years. She developed osteosarcoma 13 years later. She underwent surgery after three courses of neoadjuvant chemotherapy followed by chemotherapy and mifamurtide. She has no evidence of disease 28 months after termination of chemotherapy. In 18 other cases of secondary osteosarcoma in the literature, 15 had received total body irradiation, eight had received alkylating agents, and six had received etoposide. The median interval from HSCT to the onset of osteosarcoma was 6.5 years (range 2.5–15.3), which confirms that children undergoing HSCT should be followed up for many years. In conclusion, osteosarcoma must be included in the differential diagnosis among solid tumors that may develop following HSCT.     

Unilateral multicystic dysplastic kidney: long term outcomes

Aims

To report the long term follow up of children with antenatally detected unilateral multicystic dysplastic kidney (MCDK) with documentation of complications, involution rate with time, and renal function at 10 years.

Methods

Data were retrieved from a prospective regional registry of patients with MCDK between 1985 and 2004. Children were followed using a common protocol of investigation with follow up ultrasound scans (USS) at 2 (165 patients), 5 (117 patients), and 10 years (43 patients).

Results

Serial USS showed that 33% of the MCDK kidneys had completely involuted at 2 years of age, 47% at 5 years, and 59% at 10 years. No patients developed hypertension, significant proteinuria, or malignancy, but two developed pelviureteric junction obstruction in the contralateral kidney. Twenty seven of 143 children (19%) had vesicoureteric reflux (VUR) (96% mild to moderate VUR) into the contralateral kidney with no difference in the incidence of urinary tract infections or renal scarring between those with or without VUR. The mean estimated glomerular filtration rate (GFR) was 86.4 ml/min/1.73 m² (range 48–125) in 31 of 43 patients followed to 10 years.

Conclusions

Conservative management of unilateral MCDK is justified with clinical review and infrequent USS but longer term follow up continues in the 41% still with renal remnants at 10 years and those with impaired GFR. It is suggested that the initial micturating cystogram is deferred unless abnormal USS features are present in the contralateral kidney or ureter.     

Residual bladder dysfunction 2 to 10 years after acute transverse myelitis

OBJECTIVE: Acute transverse myelitis (ATM) is a relatively rare condition in children. The recovery rate is reported to be generally complete. In the current study, the long-term urological outcome of children with ATM was assessed. METHODOLOGY: The medical records of children with ATM admitted to Queen Mary Hospital, Hong Kong, over the last 15 years, were reviewed. RESULTS: The median age of the five children with ATM at the time of onset was 6 years (range = 2-12 years). The median length of follow up was 5 years (2-10 years). Four children recovered completely from paraparesis; two had no urinary symptoms with normal micturition. However, video-urodynamic studies 3 years after the acute onset revealed that four out of the five children, including one without any urinary symptom, suffered from residual bladder dysfunction - two from contractile neurogenic bladder and two from intermediate type of neurogenic bladder. CONCLUSION: Residual bladder dysfunction is common in children suffering from ATM despite improvement of paraparesis and apparent lack of urological symptoms. Long-term follow up of urological function in these patients is recommended.     

Height and weight pattern up to 20 years after treatment for acute lymphoblastic leukaemia

OBJECTIVE: To assess height and body mass index standard deviation scores up to 20 years after treatment for acute lymphoblastic leukaemia (ALL). SUBJECTS AND METHODS: Height and body mass index standard deviation scores were measured in 33 patients (14 boys and 19 girls) with childhood ALL at diagnosis, after the end of treatment, at final height, and at follow up 10-20 years (median, 16.2) after diagnosis. Eleven patients were treated with chemotherapy only and 22 patients were treated with chemotherapy and cranial irradiation. RESULTS: In the chemotherapy only group, height standard deviation scores were the same at follow up as at diagnosis, but there was a significant decrease in height standard deviation scores during treatment. Mean body mass index standard deviation scores increased steadily from the start of treatment until final height and continued to increase from final height until follow up. In the cranially irradiated group, mean height standard deviation scores decreased steadily from the start of treatment until follow up. Mean body mass index standard deviation scores increased continuously from the start of treatment until final height and from final height until follow up. CONCLUSION: Chemotherapy combined with cranial irradiation and chemotherapy alone might be persisting risk factors for obesity even after final/height has been attained in patients treated for childhood ALL. Chemotherapy is a risk factor for reduced final height only when administered in combination with cranial irradiation. These problems need to be recognised and dealt with at follow up examination.     

Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma

PURPOSE: To evaluate fertility in male patients with osteosarcoma after chemotherapy including high doses of alkylating agents. PATIENTS AND METHODS: Postchemotherapy fertility was evaluated in 96 male patients who received chemotherapy at the authors' institution from 1976 to 1996 for localized bone osteosarcoma of the extremities. Four drugs were administrated (doxorubicin, cisplatin, methotrexate, ifosfamide) at different doses according to six different protocols. Eleven patients were prepubertal and 85 were postpubertal at the time of chemotherapy. The median age of these patients at the time of chemotherapy was 17 years (range 10-42), the median age at the time of the interview was 27 years (range 19-53), and the median follow-up from the end of chemotherapy was 9 years (range 4-17). RESULTS: Of the 96 patients, 26 underwent sperm analysis and 20 showed oligo- or azoospermia. Patients who received high-dose ifosfamide showed a higher incidence of azoospermia. Six patients were normospermic and received no ifosfamide or lower doses of ifosfamide. Eight patients fathered a total of 12 children. No birth defects or congenital anomalies were observed in their offspring. CONCLUSIONS: The rate of sterility was related to ifosfamide dosage. It appears that pubertal maturation is not affected by chemotherapy. No congenital malformations were seen in the children of the few patients who fathered children.     

Langerhans cell histiocytosis in children less than 2 years of age

OBJECTIVE: To study the clinical profile and outcome of langerhans cell histiocytosis in children upto 2 years of life. DESIGN: Retrospective analysis. METHODS: Medical records of Children upto 2 years of age with a diagnosis of langerhans cell histiocytosis (LCH) were analyzed. Their clinical pattern, treatment modalities and outcome were studied. The patients Were categorized into 2 groups according to their clinical presentation: (i) Subject without organ dysfunction; and (ii) cases with organ dysfunction. Treatment considered of surgical intervention, radiotherapy, chemotherapy or combination of all these modalities depending upto the extent of disease. RESULTS:There were 20 children upto 2 years of age with histiocytosis during the 12 year period (January 1983 - December 1994). The median age at diagnosis was 18 months (range 52 days - 24 months). Of the twenty patients,13 patients didn't have organ dysfunction and 7 had organ dysfunction. Out of the 13 children without organ dysfunction eleven patients received treatment and all of them are alive free of disease with a median follow up of 62 months. But all children with organ dysfunction succumbed to disease within a few weeks. CONCLUSION: Children under 2 years of age with localised and or multifocal LCH without organ dysfunction have a good prognosis and they should not be exposed to aggressive form of treatment. All children with organ dysfunction require multi-agent chemotherapy.     

The role of fast neutron therapy in unresectable pelvic osteosarcoma: preliminary report

Primary osteosarcoma of the pelvic bones represents less than 10% of all osteosarcoma. despite mutilating surgical procedures or high-dose radiotherapy and neoadjuvant chemotherapy, local failures and distant metastases remain common. the 2-year actuarial survival rate is less than 50% and the disease-free survival is under 20% at 2 years. we report 4 cases of pelvic osteosarcoma treated by a combination of chemotherapy, photon beam and neutron beam radiotherapy. after a median follow-up of 24 months, all 4 patients are alive and disease free. © 1994 wiley-liss, inc.     

Cyclical combination chemotherapy and thyroid function in patients with advanced hodgkin's disease

Clinical and biochemical assessment of thyroid function was undertaken in patients with Hodgkin's disease at designated points following diagnosis. At diagnosis, two of 20 patients had either abnormally low routine thyroid indices, or elevated thyroid stimulating hormone (TSH) levels that were not due to iodine-based investigations. Following lymphography, 76.5% of patients had TSH levels that remained elevated for a median period of 3 months. No detectable thyroid dysfunction was induced during chemotherapy. Fifty-four patients were studied at a median time of 35 months after chemotherapy. One euthyroid patient had a nodular goitre, and one had abnormal thyroid indices. TSH levels were elevated in 44% of patients, although the median TSH level for the group was normal. Half the patients had abnormal TRH stimulation tests. Sixty patients were studied after irradiation and chemotherapy. Four patients had clinical thyroid dysfunction, and 10% of routine thyroid indices were abnormal. TSH levels were abnormal in 80%, with a markedly elevated median level. All thyroid releasing hormone stimulation tests were abnormal.     

Juvenile autoimmune thyroiditis. Hormonal status at presentation and after long-term follow-up

Thirty children and adolescents with the clinical diagnosis of juvenile autoimmune thyroiditis (JAT) were studied. Twenty-six patients were female and four were male. The median age at diagnosis was 12.9 years (range, 7.5 to 17.3 years). At the initial evaluation, endocrine studies revealed that 40% of the patients were euthyroid, while 33% had compensated hypothyroidism and 27% had overt hypothyroidism. Seventeen patients, 16 of whom received thyroid hormone replacement therapy for a median period of 26 months, were followed up on a long-term basis after discontinuation of therapy. Seven (87%) of eight patients who were initially euthyroid have remained so for a median period of 28 months after treatment and a median period of 50 months since diagnosis. Four (44%) of nine patients who initially had hypothyroidism (either compensated or overt) have reverted to a euthyroid state and have remained so for a median period of 33 months after discontinuation of therapy. Neither the size of the thyroid gland nor the pattern or absolute titer of thyroid autoantibodies correlated with functional status. These results indicate that individuals with euthyroid JAT may remain euthyroid for many years and that a substantial percentage of patients with hypothyroid JAT will experience resolution of thyroid dysfunction.     

迷走神经刺激治疗婴幼儿药物难治性癫的病例系列报告

背景：迷走神经刺激（VNS）治疗儿童药物难治性癫（DRE）国内年龄适应证为3岁以上,目前临床在超年龄适应证应用VNS治疗DRE婴幼儿,但其有效性和安全性研究很少。 目的：评估VNS治疗DRE婴幼儿术后的长期疗效、安全性及疗效相关因素。 设计：病例系列报告。 方法：纳入2015年3月至2021年3月于北京大学第一医院癫中心行VNS的DRE婴幼儿,且VNS术后规律程控随访至少1年、程控期间刺激电流参数＞1 mA。排除VNS期间接受新增抗癫发作治疗（癫外科手术治疗、生酮饮食、应用糖皮质激素或促肾上腺皮质激素）,因各种原因而导致VNS程控关机、中断的患儿。以患儿家长癫日记所记录的所有发作类型的频率作为主要评估依据,行随访有效率（末次随访点较VNS植入前3个月发作频率减少≥50%）和癫发作减少率、考察临床信息及程控参数对疗效和安全性的影响。 主要结局指标：VNS术后有效率和癫发作减少率。 结果：符合本文纳入排除标准的VNS治疗DRE婴幼儿25例,男16例（64%）、女9例。癫起病年龄中位数4.9月,癫病程中位数1.7年,VNS治疗前每月发作中位数555次。VNS电极植入中位年龄2.3岁。病程中曾应用抗癫发作药物（ASM）3~10种,VNS治疗前3个月应用ASM及其他治疗1~4种,能明确DRE病因12例（48%）,病程中曾诊断癫综合征18例（72%）,存在4、3、2和1种发作形式分别为4、5、6和10例,25例VNS治疗的DRE患儿均存在发育迟缓。VNS术后随访中位数2.4年。VNS术后1年癫发作率最高增加1 367%,最低减少100%,中位数减少52.8%,VNS术后2年癫发作率最高增加1 712%,最低减少100%,中位数减少59.5%。末次随访时有效率为64%,无发作率为20%（5/25）,最长随访2年5个月无发作。VNS术后1年、2年有效率均为60%（15/25,9/15）。VNS术后1年15例有效病例中1例在VNS术后2年转为无效;VNS术后1年10例无效病例中2例在术后2年转为有效。未观察到围术期相关不良反应及设备相关不良反应,4例在程控时出现刺激相关不良反应,其中2例为一过性咳嗽,2例为咽部不适,均可在短时间内耐受。疗效相关因素分析有效组（16例）和无效组（9例）临床信息、末次程控参数和术后ASM调整情况差异均无统计学意义。 结论：DRE婴幼儿VNS治疗随访1和2年有效率均可达到60%,且安全性较好;VNS治疗DRE的年龄下限仍需进一步评估。     

Second malignant neoplasm in patients with osteosarcoma of the extremities treated with adjuvant and neoadjuvant chemotherapy

We evaluated the rate of second malignancies in 1205 patients with osteosarcoma of the extremity treated at our Institution with different protocols of adjuvant and neoadjuvant chemotherapy. Twenty-six patients (2.15%) developed a second malignant neoplasm at a median of 7.6 years (1 to 25 y) after primary osteosarcoma treatment. Of these, 2 developed a third cancer which were not considered in the series. Second neoplasms were leukemia (10), breast (7), lung (2), kidney (2), central nervous system cancer (2), soft tissue (1), parotid (1), and colon (1). The rate of second neoplasms was significantly higher in female patients, and the latent period shorter in hematologic tumors compared with solid tumors. Ten of these 26 patients are disease free at a median of 7.7 years (range 1 to 15 y) after the last treatment. The rate of second malignancies observed in the osteosarcoma group was significantly higher than that observed in the control group of 1160 patients with benign tumors treated in the same period at our Institute (2.2% vs. 0.8%, P<0.009). Our study showed that the risk of second neoplasm within 15 years increased and then leveled off and that although secondary solid tumors could be explained as unrelated cases, leukemias seem to be over represented.