Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and may disrupt an effective therapy. This study assesses whether serial parametric response mapping (a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: From 2009 to 2012, 21 children, 4-18 years of age, with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiation therapy. DWI was acquired before immunotherapy and at 6-week intervals during vaccine treatment. Pseudoprogression was identified retrospectively on the basis of clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from the first vaccine to up to 12 weeks after the vaccine was halted) with prevaccine baseline values. Log-transformed fractional increased ADC, fractional decreased ADC, and parametric response mapping ratio (fractional increased ADC/fractional decreased ADC) were compared between patients with and without pseudoprogression, by using generalized estimating equations with inverse weighting by cluster size. RESULTS: Median survival was 13.1 months from diagnosis (range, 6.4-24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (P = .01) and fractional decreased ADCs (P = .0004), compared with patients without pseudoprogression. CONCLUSIONS: Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination.

Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas.

OBJECTIVE: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). METHODS: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. RESULTS: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 µg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 µg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 µg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 µg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. CONCLUSIONS: The RP2D of PI for pediatric patients with PN is 1 µg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.

Phase II evaluation of interferon-alpha-2a for progressive or recurrent craniopharyngiomas.

OBJECT: Craniopharyngiomas originate from the same cells as squamous cell skin carcinoma, which can be treated successfully with interferon-alpha (IFNalpha)-2a. The authors evaluated the activity and toxicity of systemic IFN in young patients with craniopharyngiomas. METHODS: Fifteen patients between the ages of 4.2 and 19.8 years who had progressive or recurrent craniopharyngiomas were enrolled in this study. Nine of these patients had never received external-beam radiation therapy. Therapy consisted of 8,000,000 U/m2 IFNalpha-2a administered daily for 16 weeks (induction phase) followed by the same dose three times per week for an additional 32 weeks (maintenance phase). Of the 12 patients who could be evaluated, radiological studies demonstrated a response to treatment in three with predominantly cystic tumors (one minor response, one partial response, and one complete response); one of these patients also showed improvement in visual fields. The size of the cystic component of the tumors often increased temporarily during the first several months of therapy. Three patients met the criteria for progressive disease during therapy. The median time to progression was 25 months. The need for radiation therapy in patients treated with IFN was delayed for 18 to 35 months (median 25 months) in six patients. All patients developed transient flulike symptoms shortly after receiving the first dose of IFN. Other toxicities (predominantly hepatic, neurological, and cutaneous) were seen in nine (60%) of the 15 patients during the first 8 weeks of treatment but resolved after temporary discontinuation and/or dose reduction. CONCLUSIONS: Interferon-alpha-2a is active against some childhood craniopharyngiomas; its toxicity precludes administration of high daily doses, and the optimum dose level and schedule remain to be defined.

Dose-intensive, time-compressed procarbazine, CCNU, vincristine (PCV) with peripheral blood stem cell support and concurrent radiation in patients with newly diagnosed high-grade gliomas.

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2-22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n = 6), glioblastoma (n = 4), anaplastic astrocytoma (n = 2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m2 and vincristine 1.5 mg/m2 on day 0, and procarbazine 150 mg/m2 on days 1-7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.

Pineal and nonpineal supratentorial primitive neuroectodermal tumors.

Pineal region supratentorial primitive neuroectodermal tumors (SPNETs; pineoblastomas) and nonpineal SPNETs are rare tumors that historically have carried a very poor prognosis. With multimodality therapy, including maximal surgical resection, craniospinal radiation therapy and chemotherapy, the survival for patients with pineal PNETs has significantly improved. Chemotherapy alone, at least in conventional doses, appears to be insufficient treatment for younger children with pineoblastomas, in whom there is almost universal rapid tumor progression and death. Survival of patients with nonpineal SPNETs remains in the order of 30-35% despite multimodality therapy. Unlike those with pineal SPNETs, a significant percentage of infants with nonpineal SPNETs who undergo gross total surgical resection followed by chemotherapy will be long-term survivors. This article gives an overview of the natural history, prognostic factors and treatment of both pineal and nonpineal SPNETs.

Imaging the central nervous system effects of radiation and chemotherapy of pediatric tumors.

New developments in radiotherapy and chemotherapy have resulted in significant improvements in survival from childhood tumors. Stereotactic radiosurgery and other conformed field radiotherapy treatments allow precise localization of tumors. Through small beam sizes, these new radiation techniques deliver steep dose gradients at the field edges permitting the prescribed dose to be given to the tumor while avoiding vital structures only millimeters away. Newer chemotherapy regimens allow radiotherapy to be postponed until the child's brain can better tolerate radiation. The MR imaging and CT scans appearance of treated childhood brain tumors and the new developments in radiation and chemotherapy are discussed.

Dose-intensification of procarbazine, CCNU (lomustine), vincristine (PCV) with peripheral blood stem cell support in young patients with gliomas.

BACKGROUND: The regimen of procarbazine, CCNU, and vincristine is active against gliomas. Previous attempts at dose-intensification have been unsuccessful because of delayed and cumulative myelosuppression. We sought to determine whether peripheral blood stem cell (PBSC) infusions would allow dose-escalation and time compression. PROCEDURE: Eleven patients, age 2.8-35.9 years, with newly diagnosed (n = 10) or recurrent (n = 1) gliomas underwent PBSC harvesting after mobilization with G-CSF. Chemotherapy consisted of CCNU 130 mg/m2 on day 0, vincristine 1.5 mg/m2 on days 0 and 7, and procarbazine 150 mg/m2 on days 1-7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered 28 days apart or when counts recovered. Involved field radiation was administered to newly diagnosed high-grade glioma patients following recovery from chemotherapy. RESULTS: Compared to the standard PCV regimen given every 6 weeks, dose intensity received was 1.7- and 1.8-fold greater for CCNU and procarbazine. Chemotherapy was delivered on time in 33/41 (80.5%) courses. Four courses (9.8%) were complicated by absolute neutrophil counts < 200/microL; platelet nadirs < 50,000/microL occurred in two courses (4.9%). Fever with neutropenia complicated three courses. Eight of 9 patients with measurable disease had an objective decrease in tumor size and/or decreased enhancement. Median survival for patients with high-grade gliomas (n = 6) was 13 months. CONCLUSIONS: Dose-intensification of PCV is possible using PBSCs.

Feasibility of sequential high-dose chemotherapy and peripheral blood stem cell support for pediatric central nervous system malignancies.

BACKGROUND: The outlook for many brain tumors remains poor. Increased dose intensity has been correlated with response rate and survival in many solid tumors. PATIENTS AND METHODS: Ten children with recurrent or newly diagnosed brain tumors were treated with four sequential courses of high-dose single agent chemotherapy with peripheral blood stem cell (PBSC) support. PBSC harvesting was undertaken prior to chemotherapy and following the first course of chemotherapy (3.6 g/m2 etoposide). Each course of chemotherapy consisted of a single drug followed 48 hours later by PBSC reinfusion. Three patients were treated on Regimen A: etoposide, carboplatinum 1.95 g/m2, cyclophosphamide 5 g/m2, and thiotepa 300 mg/m2; three patients were treated on Regimen A' with carmustine 600 mg/m2 replacing cyclophosphamide; four patients received Regimen B: etoposide, carboplatinum 1.95g/m2, cyclophosphamide 7 g/m2, and thiotepa 900 mg/m2. RESULTS: No course of chemotherapy was complicated by >14 days of neutropenia. Platelet recovery was more prolonged, particularly in patients who had previously received craniospinal irradiation. Non-hematologic toxicity was severe with three toxic deaths including two patients who developed hemolytic-uremic syndrome and respiratory failure. Two of three patients with primitive neuroectodermal tumors had a partial response; no responses were observed in patients with high-grade gliomas. CONCLUSIONS: Administration of multiple courses of high-dose chemotherapy with PBSC support is feasible in this patient population and successfully mitigates hematologic toxicity. Non-hematologic toxicity becomes prohibitive as chemotherapy doses are escalated.

Treatment of standard risk medulloblastoma with craniospinal irradiation, carboplatin, and vincristine.

BACKGROUND: Improved outcome for children with medulloblastoma requires new treatment protocols which incorporate chemotherapeutic agents that are capable of eradicating minimal residual disease in the primary posterior fossa site and in the leptomeninges and whose toxicities are tolerable. PROCEDURE: We treated 25 children with nondisseminated medulloblastoma with complete or near complete surgical resection of the posterior fossa tumor, 3,600 cGy craniospinal irradiation (CSRT) and 5,400 cGy posterior fossa irradiation followed by adjuvant chemotherapy with carboplatin and vincristine. RESULTS: The estimated 3-year progression-free survival (PFS) was 0.73 (S.E. +/- 0.09) compared with a 3-year PFS of 0.69 in historical controls treated with surgical resection and CSRT but without chemotherapy. Six relapses occurred outside the posterior fossa and one relapse occurred both in the posterior fossa and in the lateral ventricle. The major acute toxicities were myelosuppression, anorexia and neuropathy. CONCLUSIONS: Our experience with this adjuvant chemotherapy regimen with carboplatin and vincristine, as used by us, does not encourage its adoption in future clinical trials.

Testing the hypothalamic-pituitary-adrenal axis in survivors of childhood brain and skull-based tumors.

The objective of this study was to determine whether a low dose of ACTH (0.2 microg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors. Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-microg i.v. bolus), a low dose ACTH test (0.2 microg/kg i.v. bolus), an insulin tolerance test, and a single dose metyrapone test. Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion. In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.

Phase II evaluation of topotecan for pediatric central nervous system tumors.

BACKGROUND: Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS: Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS: There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS: Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors.

Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group.

PURPOSE: To describe the biologic and clinical features of children with primitive neuroectodermal tumors (PNETs) arising in the pineal region (pineoblastomas) and evaluate prospectively the efficacy of radiation therapy (RT) and/or chemotherapy. PATIENTS AND METHODS: Between 1986 and 1992, 25 children with PNETs of the pineal region were treated as part of a Childrens Cancer Group study. Eight infants less than 18 months of age were nonrandomly treated with eight-drugs-in-1-day chemotherapy without RT. The remaining 17 patients were treated with craniospinal RT and randomized to receive either vincristine, lomustine (CCNU), and prednisone or the eight-drugs-in-1-day regimen. RESULTS: Of 24 completely staged patients, 20 (83%) had localized disease at diagnosis. All infants developed progressive disease a median of 4 months from the start of treatment. Of the 17 older patients treated with RT and chemotherapy, the Kaplan-Meier estimate of progression-free survival (PFS) at 3 years is 61% +/- 13%. This is superior to the PFS of children with other supratentorial PNETs (P = .026). Following RT, 12 of 17 patients (70.6%) had a residual pineal region mass, which persisted for as long as 5 years before resolving; only four subsequently developed progressive disease. CONCLUSION: (1) Eight-in-1 chemotherapy without RT appears to be ineffective therapy for young children with PNETs of the pineal region. (2) For children more than 18 months of age at diagnosis treated with craniospinal RT and chemotherapy, the PFS is superior to that of children with other supratentorial PNETs. (3) A residual enhancing mass following RT is not predictive of treatment failure.

Restrictive lung disease following treatment for malignant brain tumors: a potential late effect of craniospinal irradiation.

PURPOSE: To examine the effects of lomustine (CCNU), a commonly used nitrosourea, and craniospinal radiation therapy on the subsequent development of restrictive lung disease (RLD) following treatment for malignant brain tumors. PATIENTS AND METHODS: Pulmonary function testing with measurement of lung volume, spirometry, and diffusion capacity was performed in 28 patients who had received CCNU and/or radiation therapy as treatment for a malignant brain tumor. The median age at the time of treatment was 11.4 years (range, 3.9 to 36.7) and radiation therapy was completed 6 months to 11.6 years (median, 2.6 years) before testing. Patients were divided into four groups based on prior therapy. Group 1 received involved-field irradiation and a CCNU-containing chemotherapy regimen (n = 7); group 2, craniospinal irradiation with a boost to the primary tumor site and a CCNU-containing chemotherapy regimen (n = 6); group 3, craniospinal irradiation with a boost to the primary tumor site and a non-CCNU-containing chemotherapy regimen (n = 7); and group 4, craniospinal irradiation with a boost to the primary tumor site without chemotherapy (n = 8). RESULTS: Fourteen patients (50%) had findings consistent with RLD. One of seven patients (14.3%) who received CCNU without spinal irradiation had RLD, whereas 13 of 21 (61.9%) who received spinal irradiation with or without CCNU had RLD (P = .038), including four of eight patients treated with craniospinal irradiation alone. Logistic regression analysis showed that only spinal irradiation was a significant predictor for RLD. Patients who received spinal irradiation were 4.3 times more likely to have RLD than those who did not receive spinal irradiation. CONCLUSION: Spinal irradiation may be a risk factor for the development of RLD.

Melanotic neuroectodermal tumor of infancy.

We present a case of malignant melanotic neuroectodermal tumor of infancy arising in the skull and secondarily invading brain. The central tumor was hyperintense to brain on T1-weighted images and hypointense to brain on T2-weighted images. This appearance corresponded to the surgical and histologic findings of melanin-containing tumor.

Comparison of cardiac function tests after anthracycline therapy in childhood. Implications for screening.

BACKGROUND: Numerous methods for evaluating cardiac function after cardiotoxic therapy have been suggested. A practical algorithm for screening a large patient population is needed. METHODS: Seventy-three patients (median age, 15.3 years [range, 9-29 years) who received anthracyclines (median dose, 300 mg/m2 [range, 50-750 mg/m2) for a childhood malignancy underwent a battery of commonly used tests of cardiac function: (1) echocardiographic shortening fraction (ESF); (2) resting and exercise radionuclide scan (multiple gaited acquisition [MUGA]); (3) electrocardiogram (ECG); (4) 24-hour Holter monitor, and (5) questionnaire concerning exercise tolerance. RESULTS: Patients with an abnormal resting ejection fraction on MUGA were more likely to have an abnormal ESF (P = 0.023), prolongation of the QTc interval (P = 0.014), and complaints of "difficulty" with exercise (P = 0.04). An abnormal results for a resting study was not predictive of an abnormal MUGA exercise response. There was no association between the presence of significant dysrhythmia on Holter monitor and any resting test. An algorithm was developed using a normal ESF and QTc interval, and a negative history of exercise intolerance to identify patients who need not undergo a MUGA. With the use of such an algorithm, 29 of the 73 patients would not have undergone the MUGA, only 2 of whom had an abnormal resting ejection fraction. CONCLUSION: Patients at risk for cardiac damage after cancer therapy who have normal ESF and QTc interval results and no history of exercise intolerance are unlikely to have abnormal MUGA results. Significant dysrhythmia may be present in the absence of other abnormalities.

Cardiac dysfunction following spinal irradiation during childhood.

PURPOSE: Although spinal irradiation used in the treatment of CNS malignancies includes a portion of the heart in the radiation field, cardiac effects have not been previously reported. PATIENTS AND METHODS: We compared patients treated for malignancy in childhood with spinal irradiation (n = 26) with patients treated with mediastinal/flank irradiation (n = 47) that included the heart in the radiation field. All patients were more than 1 year from completion of radiation therapy. Patients underwent at least two of the following cardiac evaluations: (1) ECG; (2) 24-hour ambulatory ECG; (3) echocardiogram; and (4) exercise-testing using cycle ergometry. RESULTS: Twelve of 16 patients (75%) in the spinal irradiation group with an assessable exercise test achieved a maximal cardiac index (MCI) below the fifth percentile as compared with 13 of 40 patients (32%) who had received mediastinal/flank irradiation (P = .007). Furthermore, after adjusting for normal heart growth, radiation and anthracycline doses, and follow-up time, the group of patients who received spinal irradiation had significantly higher estimated posterior wall stress (P = .002), expressed as the natural logarithm of the ratio of end-diastolic left ventricular internal diameter (LVID) to left ventricular posterior wall thickness (LVPWT), than the group who had received mediastinal/flank irradiation. Finally, eight of 26 patients (31%) in the spinal group had pathologic Q-waves in the inferior leads versus three of 47 (6.4%) in the mediastinal/flank group (P = .001). CONCLUSION: Patients who have received spinal irradiation for pediatric malignancies appear to be at risk for significant cardiac dysfunction. The asymmetric distribution of radiation to a growing heart, as given with spinal irradiation, may be the cause of these findings.

Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults.

Transient electrocardiographic changes and arrhythmias are known to be acute manifestations of cardiotoxicity secondary to cancer therapy with anthracyclines or cardiac irradiation. However, despite the known risk of late cardiac dysfunction in survivors of childhood cancer therapy, the risk of clinically important electrocardiographic abnormalities and arrhythmias after treatment is unknown. Standard 12-lead and 24-hour ambulatory electrocardiograms were recorded in 73 patients who received anthracyclines alone, 24 who received cardiac irradiation alone, and 27 who received both anthracyclines and cardiac irradiation. The mean age of the patients was 15 years. Mean cumulative anthracycline dose was 282 mg/m2 in patients who received anthracyclines alone and 244 mg/m2 in patients who received both anthracyclines and cardiac irradiation. Analysis of the 12-lead and 24-hour electrocardiograms demonstrated increased frequency of QTc prolongation, supraventricular premature complexes, supraventricular tachycardia, ventricular premature complexes, couplets and ventricular tachycardia (all p less than 0.001) when compared with an age-matched healthy population. Most patients had abnormalities limited to single supraventricular or ventricular premature complexes; however, potentially serious ventricular ectopy, including ventricular pairs and ventricular tachycardia, were noted in patients with cumulative doses greater than 200 mg/m2. Electrocardiographic abnormalities and arrhythmias are not limited to the acute phase of treatment with anthracyclines and cardiac irradiation. Survivors of childhood malignancy who received anthracyclines or cardiac irradiation, or both, probably should undergo ambulatory electrocardiographic monitoring as part of their follow-up to detect potentially life-threatening arrhythmias.

Pulsatile secretion of luteinizing hormone in children.

The gonadotropin secretory patterns of 22 sexually immature children were analyzed in detail to determine whether pulsatile secretion occurs before the onset of puberty. Eight endocrinologically normal children, 13 children with isolated GH deficiency, and 1 girl with 45X gonadal dysgenesis were divided into 2 groups according to bone age. Group A children had bone ages less than 10 yr, and group B had bone ages between 10-11.5 yr. Blood samples were drawn every 20 min for periods of 3-11 h during both the day and night; in addition, 12-h urine collections were made for gonadotropin determinations. Mean nocturnal concentrations of LH and FSH were significantly greater than daytime values in 8 of 15 and 5 of 15 children in group A and in 6 of 7 and 1 of 7 in group B, respectively. Nocturnal urinary excretion of LH and FSH was significantly greater in group A children. Eight children in group A, including 4 whose bone ages were less than 5 yr, and 4 group B children had discernible LH pulses. LH pulses were detected during the day and night in both groups. LH pulse amplitude was greater during the night in both groups, but was greatest in group B (A, 1.9 +/- 0.2 mIU/ml; B, 3.0 +/- 0.3 mIU/ml). In children who demonstrated pulsatile secretion, LH pulse frequency appeared to be similar during the day and night and was slightly faster in the older children (A, every 3 h; B, every 2 h). These studies demonstrated that LH is secreted in a pulsatile manner well before the onset of puberty. Furthermore, the gonadotropin secretory pattern characteristic of early puberty results from the amplification of an already existing circadian pattern of gonadotropin secretion.