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J S Taylor,
J W Langston,
W E Reddick,
P B Kingsley,
R J Ogg,
M H Pui,
L E Kun,
J J Jenkins,
G Chen, J J Ochs,
R A Sanford,
R L Heideman
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ABSTRACT: Delayed cerebral necrosis (DN) is a significant risk for brain tumor patients treated with high-dose irradiation. Although differentiating DN from tumor progression is an important clinical question, the distinction cannot be made reliably by conventional imaging techniques. We undertook a pilot study to assess the ability of proton magnetic resonance spectroscopy (1H MRS) to differentiate prospectively between DN or recurrent/residual tumor in a series of children treated for primary brain tumors with high-dose irradiation.
Twelve children (ages 3-16 years), who had clinical and MR imaging (MRI) changes that suggested a diagnosis of either DN or progressive/recurrent brain tumor, underwent localized 1H MRS prior to planned biopsy, resection, or other confirmatory histological procedure. Prospective 1H MRS interpretations were based on comparison of spectral peak patterns and quantitative peak area values from normalized spectra: a marked depression of the intracellular metabolite peaks from choline, creatine, and N-acetyl compounds was hypothesized to indicate DN, and median-to-high choline with easily visible creatine metabolite peaks was labeled progressive/recurrent tumor. Subsequent histological studies identified the brain lesion as DN or recurrent/residual tumor.
The patient series included five cases of DN and seven recurrent/residual tumor cases, based on histology. The MRS criteria prospectively identified five out of seven patients with active tumor, and four out of five patients with histologically proven DN correctly. Discriminant analysis suggested that the primary diagnostic information for differentiating DN from tumor lay in the normalized MRS peak areas for choline and creatine compounds.
Magnetic resonance spectroscopy shows promising sensitivity and selectivity for differentiating DN from recurrent/progressive brain tumor. A novel diagnostic index based on peak areas for choline and creatine compounds may provide a simple discriminant for differentiating DN from recurrent or residual primary brain tumors.
International Journal of Radiation OncologyBiologyPhysics 01/1997; 36(5):1251-61. · 4.11 Impact Factor
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ABSTRACT: Malignant pediatric tumors of the central nervous system (CNS) have a poor prognosis, with local failure rates as high as 50%. In an attempt to improve local tumor control, we used stereotactic interstitial therapy with 125I implants in patients with recurrent/secondary or newly diagnosed CNS malignancies. Catheters were placed using computed tomography (CT) guidance; computerized dosimetry was completed with the aid of orthogonal films. Implants delivered 1,000 cGy/day to the tumor periphery (0.5 cm beyond the boundary of enhancement on CT scans), to a total dose of 60 Gy. Hyperfractionated external beam irradiation (HEBI), started 2-4 weeks after removal of implants, delivered total doses of 66-70.4 Gy in 110-cGy fractions twice daily to a 3-cm margin around the implant volume. Eight of the 11 patients with newly diagnosed tumors also received 48.4 Gy HEBI to the craniospinal axis. Tumor regression was noted at 2 months after implantation in the 4 patients treated for recurrent/secondary tumors; local progression was subsequently documented in 2 cases at 6 and 20 months after implantation, while a third patient died 6 months after implantation with no evidence of local recurrence. The remaining recurrent/secondary tumor patient has no evidence of active recurrence 15 months after implantation. Local control was maintained in 9 of the 11 patients treated for primary tumors for a median of 27 months (range 15 to 48+ months). The two local failures occurred at 5 and 7 months after implantation. Six patients are alive without evidence of progressive disease (median = 23 months after implantation). There were no severe acute toxicities, but 7 patients later developed histologically confirmed tumor necrosis. Quality of life assessment (QLA) following initial primary therapy with implantation was evaluated utilizing an established criteria and found to be excellent with only one child showing marked QLA score decrease which was related to neurosurgical intervention for radiation-induced necrosis and dysfunctional family social situation. This small series suggests that stereotactic 125I implantation followed by HEBI merits further evaluation in selected children with supratentorial malignant lesions.
Pediatric Neurosurgery 02/1995; 22(6):289-97; discussion 98. · 0.70 Impact Factor
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ABSTRACT: Short stature and obesity have been reported among long-term survivors of childhood acute lymphocytic leukemia (ALL). We examined factors that contribute to these adverse sequelae.
Serial height and weight measurements were analyzed for 91 long-term survivors who were treated for ALL between 1967 and 1975 at a single institution. These patients were all younger than 12 years at diagnosis, were in continuous complete remission, had reached final height, and had height and weight measurements within 1 year of age 18 years. They had received craniospinal (n = 33) or cranial irradiation (n = 58) to total doses of 24 Gy as CNS prophylaxis. Standard deviation scores (SDS) were used to reflect the deviation of height and weight measurements from population means, and the body mass index (BMI; weight divided by height squared) was used in assessing obesity at age 18 years.
Short stature (less than fifth percentile) was seen in 41 patients (45%), and obesity (BMI greater than or equal to 24 kg/m2) in 35 (38%). Regression formulae were developed that explain 65% and 62% of the variability in patient height and BMI, respectively.
Risk factors were identified for abnormally short stature, which was defined to be a decrease of 1.5 SDS in height from diagnosis to age 18 years. These factors include younger age and above-average height for age at diagnosis (height SDS greater than 0), craniospinal irradiation, and greater decrease in height SDS during antileukemic therapy. Risk factors for obesity at age 18 years include weight SDS greater than 0 and greater than height SDS at 1 year after the end of chemotherapy.
Journal of Clinical Oncology 02/1992; 10(1):128-33. · 18.37 Impact Factor
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ABSTRACT: Significant growth retardation was found in 115 survivors of childhood acute lymphoblastic leukemia (ALL) who had completed their growth. These children were diagnosed before 12 years of age and treated on four protocols in a single institution; all received either cranial (n = 78) or craniospinal (n = 37) prophylactic irradiation. Patients' heights at diagnosis were within expected ranges, but final heights were greater than or equal to 1 SD below population means in 74% of cases and greater than or equal to 2 SD in 37%. Effects on growth were more pronounced for children who had received craniospinal irradiation, but decrements were also significant in the cranial irradiation group, with adult heights greater than or equal to 2 SD below population norms in 32%. Growth retardation was significantly greater (P less than .0001) in children who had earlier disease onset. Growth deceleration occurred not only during chemotherapy but during a later period that followed an interval of improved growth in many cases. Thus, late decrements in growth may be missed in studies that do not follow patients until they have attained final heights. These findings indicate that abnormally short stature among survivors of ALL merits further clinical and research attention.
Journal of Clinical Oncology 04/1991; 9(3):400-5. · 18.37 Impact Factor
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J J Ochs
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ABSTRACT: Therapy for occult or overt meningeal leukemia produces subclinical or clinical neurotoxicity in a variable proportion of children with acute lymphoblastic leukemia (ALL). The type, frequency, and permanence of these central nervous system (CNS) changes depend primarily on the therapy itself, although the contribution of additional factors, such as young age, may be substantial. Neurotoxicity in patients who have received 2,400 cGy cranial irradiation plus 5 concurrent doses of intrathecal methotrexate as CNS prophylaxis has been characterized more fully than the CNS changes accompanying other forms of therapy. Cross-sectional studies using cranial computed tomography scans to evaluate structural changes in the brain have shown ventricular dilatation in 15%, white matter hypodensity in 3.5%, and calcifications in 8%. The principal neuroendocrine effect is decreased growth velocity during therapy and adolescence, with significant decreases in final height in approximately one-third of children. Secondary cerebral gliomas with a poor prognosis are being reported with increasing regularity, but the true risk of this complication is still unknown. Use of parenteral methotrexate as the sole method of CNS prophylaxis is associated with transient focal white matter hypodensity. Neuroendocrine and neuropsychologic sequelae associated with this therapy are minimal; however, much of the available information is based on patients treated with regimens that had unacceptably high CNS relapse rates or whose length of follow-up was brief. With more aggressive, and hence more effective, prophylaxis with intrathecal methotrexate, spinal cord myelopathy may become a significant new area of neurotoxicity. Clinically significant CNS toxicity develops in the majority of patients who receive treatment for meningeal relapse. The leukemia itself is a prime contributing factor to this neurotoxicity. In patients who are subsequently cured of leukemia, acute neurotoxicity consists mainly of seizures; the most significant sequelae appearing after the cessation of therapy consists of significant drops in full scale IQ.
The American journal of pediatric hematology/oncology 02/1989; 11(1):93-105.
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Haematology and blood transfusion 02/1987; 30:156-60.
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Medical and Pediatric Oncology 02/1986; 14(3):177-81.
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ABSTRACT: We assessed the influence of an initial isolated meningeal relapse on treatment outcome in 839 children with acute lymphoblastic leukemia (ALL) who were admitted to St Jude Children's Research Hospital (Memphis) from mid-1967 through mid-1979. The patients were entered in a series of five clinical trials (Total Therapy Studies V through IX), each designed to test one or more modifications of treatment for ALL. Two groups were compared: 699 children who received CNS prophylaxis (2,400-rad craniospinal irradiation or 2,400-rad cranial irradiation plus intrathecal methotrexate) v 56 who did not. Our results, obtained with a time-dependent covariate model and a matching technique, indicate a 2 to 3.5-fold increase in the risk of hematologic relapse or death among patients who experienced an isolated CNS relapse compared with similar patients (matched for leukocyte count and length of complete remission) who remained free of CNS involvement. Of the 107 children with an initial isolated CNS relapse, 89 (83%) have died or have had a subsequent relapse. There was no detectable difference in the rate of hematologic relapse or death after a CNS relapse between patients who had received preventive therapy and those who had not. We conclude that CNS prophylaxis is important both for the prevention of initial CNS leukemia and for reducing the risk of hematologic relapse or death subsequent to a CNS relapse.
Journal of Clinical Oncology 07/1985; 3(6):776-81. · 18.37 Impact Factor
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ABSTRACT: The frequency and types of major CNS toxicity and morbidity were analyzed in 107 children with acute lymphoblastic leukemia (ALL) following an isolated primary CNS relapse. Seventy-nine (73%) have had multiple subsequent marrow or CNS relapses requiring intensive and prolonged therapy to the CNS. Median survival time is two years. Of these 79 patients, two thirds have had one or more types of major CNS toxicity, including epileptiform seizures (35), moderate to severe structural abnormalities (24 of 27 evaluated), major motor disabilities (9), blindness (2), CNS infection (6), cranial nerve palsies (2), and intracranial lymphoma (2). The remaining 28 patients (26%) have had no or one additional CNS relapse and have received therapy for a median of eight years. One half of this surviving group of patients have had major CNS toxicity, including seizures (9), major motor disability (2), and intracranial calcifications (12/19). When neuropsychologic evaluations were compared between the 28 survivors and 50 of their contemporaries who had been in initial continuous complete remission, the CNS survivors had significantly lower Full Scale IQ scores (83 +/- 16 v 99 +/- 14, P = less than .001) with similarly lower measures of academic performance. The relative contributions of meningeal leukemia itself and intrathecal or radiation therapy to these effects cannot be determined. Since major CNS sequelae occurred in the majority of patients who had a primary isolated CNS relapse, and the frequency of CNS relapse is dependent on the efficacy of the method of CNS prophylaxis, the best method of avoiding major CNS sequelae is the most effective form of CNS prophylaxis.
Journal of Clinical Oncology 06/1985; 3(5):622-6. · 18.37 Impact Factor
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ABSTRACT: Features of seizures in children with acute lymphoblastic leukaemia were examined in relation to the type of treatment received for central nervous system prophylaxis. Of the 1289 patients in the study, 132 (10%) had experienced one or more seizures. In 96 the seizures had not been associated with any recognisable aetiology and, with 3 exceptions, had been generalised or focal motor in type. Status epilepticus had occurred in one-third of the group with seizures. Initial seizure rates among patients in continuous complete remission were significantly related to the method of central nervous system prophylaxis. Those who had received intrathecal methotrexate repeatedly with or without moderate doses of methotrexate intravenously or prior prophylactic cranial irradiation had a 20-fold higher seizure risk during remission induction, and a 37-fold higher risk during the 6th to 12th month of therapy, than did those who had received irradiation and only five intrathecal injections of methotrexate early in the course of treatment. Other clinical factors associated with an increased frequency of seizures were escalation of intravenous methotrexate dosage following cranial irradiation and treatment of meningeal leukaemia with intrathecal methotrexate. Parenterally administered methotrexate thus seems to increase susceptibility to seizure development in childhood leukaemia patients.
The Lancet 01/1985; 2(8417-8418):1422-4. · 38.28 Impact Factor
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ABSTRACT: Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.
Cancer treatment reports 01/1984; 67(12):1123-6.
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ABSTRACT: Cranial computed tomography (CT) was used to estimate the frequency and permanence of brain abnormalities in 108 consecutive children with acute lymphoblastic leukemia (ALL). Fifty-five patients received cranial irradiation (1,800 rad) with intrathecal methotrexate (RT group) and 53 patients received intravenous and intrathecal methotrexate without irradiation (IVIT group). Continuation treatment included sequential drug pairs for the RT group and periodic IVIT methotrexate for the other group. After 12 to 24 months of serial evaluation, five (9%) of the 55 patients in the RT group have had CT scan abnormalities, compared to 10 (19%) of 52 in the IVIT group (p = 0.171). Fourteen of the 15 patients with CT scan abnormalities had focal or diffuse white-matter hypodensity; these have reverted to normal in most cases, reflecting a dynamic process. While such CT findings are of concern and may be an early indicator of central nervous system toxicity, this remains to be proven. Therapy should not be altered on the basis of abnormal CT scans alone but in the context of the entire clinical situation.
Journal of Clinical Oncology 01/1984; 1(12):793-8. · 18.37 Impact Factor
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ABSTRACT: Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.
Cancer 06/1980; 45(9):2274-8. · 4.77 Impact Factor
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ABSTRACT: Eight patients with advanced metastatic osteogenic sarcoma were treated with cis-dichlorodiammineplatinum(II) (DDP). Prior to DDP, seven patients had amputations and all had received adjuvant adriamycin (ADR) therapy. In addition, prior to DDP, six patients had received high-dose methotrexate. There was one complete response (pulmonary metastases) and four partial responses (three metastases in the lungs and one in the bone). One additional patient, with local recurrence of osteogenic sarcoma of the mandible following initial resection and adjuvant ADR, was retreated with surgery and DDP and is disease-free for greater than 3 years. The cumulative dose ranged from 300 to 660 mg/m2. Toxicity included irreversible kidney damage in two patients, transient severe hematologic suppression in two patients, and nausea and vomiting in all patients. DDP is a new effective agent in the treatment of osteogenic sarcoma.
Cancer treatment reports 03/1978; 62(2):239-45.
