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Purpose: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. Methods and Materials: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35%) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. Results: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group ( p = 0.3, log-rank test). Variables predicting longer survival were younger age ( p = 0.006), lower grade ( p = 0.0006), higher Karnofsky Performance Scale (KPS) ( p = 0.0005), and smaller tumor volume ( p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group ( p Conclusion: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Purpose The spine can be treated with an electron beam when its maximum posterior depth is within the therapeutic range of electrons. Electron fields treated at extended source-to-surface distances (SSDs), however, have larger penumbras and narrower therapeutic isodose widths relative to those at the standard SSD of 100 cm. We investigated the use of tertiary collimation close to the patient surface for these fields to sharpen the penumbra, minimizing dose to normal tissue and maximizing target coverage. Methods and materials Using film dosimetry in a polystyrene phantom, we measured the dose distribution for electron fields at extended SSD under varying collimation conditions. Beam penumbra and therapeutic width as a function of depth, SSD, applicator insert size, and tertiary collimator opening were determined. We also measured the dose distributions in the junction region for various gaps between x-ray fields and an electron field as used for craniospinal irradiation. Results Measurements show that tertiary collimation close to the skin surface reduces penumbra width (lateral distance between the 90 and 20% isodose lines) by 56% and increases therapeutic isodose width (lateral width of the 90% isodose curve) by 25% at a depth of dmax relative to standard collimation. These numbers change to 23 and 13%, respectively, at an average depth of the spine. When lateral brain and posterior spine fields are used to irradiate the entire craniospinal axis, tertiary collimation aids in reducing the volume of the hot spot in the junction region by as much as 10% without compromising target coverage. Conclusions Tertiary collimation for extended SSD electron fields is preferable to standard collimation in order to minimize dose to normal tissue and increase target coverage. This technique can be applied to both spinal and craniospinal irradiation. Support structures for the tertiary blocking are needed because the weight of the lead is usually too great for placement on the skin.

Purpose: Anemia during radiation therapy independently predicts poor outcome in patients with cervical cancer. Despite a randomized trial demonstrating red cell transfusions improve local control and survival, many patients are not transfused due to toxicity concerns. This study evaluates the efficacy of recombinant human erythropoietin (r-HuEPO) in reversing anemia in patients undergoing radiation therapy. Methods and Materials: Twenty patients with criteria of anemia (Hgb n = 7), IIA ( n = 1), IIB ( n = 9), and IIIB ( n = 3), ranging in ages from 23–75 years (median 43), were included in this Phase I/II study. Fifteen were treated with r-HuEPO (200 U/kg/day) and ferrous sulfate 5–10 days prior to initiation of external beam radiation therapy, continuing until Hgb was ≤ 14 g/dL or completion of radiation therapy. Five patients were treated with ferrous sulfate alone. An additional 61 historical controls meeting eligibility criteria were analyzed. All received external beam radiation therapy and two intracavitary cesium applications. Cisplatinum chemotherapy (20 mg/m 2 /week) was given as a radiosensitizer in 14 r-HuEPO patients, 4 concurrent controls, and 17 historical controls. Results: A marked reticulocytosis was seen in the r-HuEPO group, but not the study controls. In the r-HuEPO group, the mean ± SD serum Hgb rose +30% over the course of radiation therapy from a baseline of 10.3 ± 1.04 g/dL to 13.2 ± 1.7 g/dL. Average increase in Hgb was 0.5 g/dL per week. Average Hgb during RT was 13.4 g/dL. In study and historical controls, mean initial Hgb levels were 10.7 ± 1.04 g/dL and 11.1 ± 1.3g/dL, respectively, remaining unchanged over the course of radiation therapy. Average Hgb levels during radiation therapy were 11.1 g/dL in study controls and 11.4 g/dL in historical controls, significantly lower than r-HuFP0 patients ( p = 0.0001). Erythropoietin was well tolerated. There were no significant differences in white blood counts ( p = 0.6) or platelet counts ( p = 0.4) between r-HuEPO patients and both control groups. No patients had blood pressure changes during r-HuEPO therapy. The only possible side effect was deep venous thrombosis, occurring in two patients who were withdrawn from r-HuFP0 therapy. Two additional patients developed deep venous thrombosis 9 and 10 days after radiation therapy and r-HuFP0 were completed. Conclusion: Erythropoietin appears to be both safe and effective at raising Hgb levels in anemic cervical cancer patients receiving radiation therapy and chemotherapy.

We have compared the RNA expression of two oncogenes, H-ras and c-myc, with normal human lymphocytes, normal human T-cells, and human T-cell acute lymphoblastic leukemia (ALL). T-cell ALL RNA was derived from two human T-cell lines (MOLT-3 and CEM) and from five children with T-cell ALL. The RNA expression of H-ras and the third exon of c-myc was determined by northern hybridization. RNA from both MOLT-3 and CEM overexpressed both H-ras and the third exon of c-myc compared to normal lymphocytes and normal T-cells. T-cell ALL samples from four of five children overexpressed H-ras, while three of five patient samples overexpressed the third exon of c-myc when compared to normal lymphocytes and normal T-cells. Additional information on the oncogene expression of T-cell ALL may prove to be useful in the diagnosis and treatment of T-cell ALL.

PURPOSE: This Children’s Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent ± 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% ± 9% of patients improved. The neuroradiographic response rate for regimen B was 19% ± 8% for chemotherapy and 23% ± 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% ± 5% (estimate ± SE) at 1 year and 6% ± 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P < .05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

We have explored the RNA oncogene expression by three human acute lymphoblastic leukemia lines, NALM-6, MOLT-3, and REH. We compared such expression with that of normal human lymphocytes. Marked differences in the RNA expression of the third exon of c-myc, v-myb, v-Hras, N-ras, v-fes, and v-fos were found. We noted minimal or no differences in the RNA expression of v-abl, B-lym, v-erb-B, c-ets, v-fms, v-kras, v-mos, v-raf, and v-sis.

The iron-binding proteins lactoferrin (LF) and H-ferritin have been implicated in the negative regulation of myelopoiesis in vitro and in vivo. The present studies evaluated the functional activity of affinity-purified LF from polymorphonuclear neutrophils (PMN) of patients with chronic myelogenous leukemia (CML) and LF/H-ferritin-cell interactions in a nonleukemic patient with LF deficiency with normal levels of circulating blood leukocytes. Affinity-purified CML-PMN-LF was found to be qualitatively deficient as a suppressor of the release of colony-stimulating factors from mononuclear blood cells, adding to previous information from our group documenting defective LF-cell interactions in CML. LF was detected by immunoradiometric assay in PMN of the patient with LF deficiency, but at a much lower level than normal. This LF was found, however, to be active as a suppressor molecular against the patient’s cells and normal donor cells. Patient cells were as responsive as normal cells to effects of purified milk LF. Decreased LF levels in this patient were associated with increased levels of monocyte H-ferritin inhibitory activity, consistent with the known suppressive effects in vitro of LF on H-ferritin release from monocytes. Patient marrow hematopoietic progenitor cells were as responsive as progenitors from normal donors to suppression by purified H-ferritin and prostaglandin Ei. These results are consistent with a role of LF and H-ferritin in the control of myelopoiesis in this patient.

Pancreatic tumors are rare in children. Over a 20-year period we have treated 13 children with pancreatic neoplasms. There were eight boys and five girls (age range, 4 months to 12 years). Seven tumors were benign, including five insulinomas, and two cystadenomas. Six lesions were malignant (rhabdomyosarcoma, 2; pancreatic carcinoma, 4). Children with insulinoma presented with hypoglycemia and irrational behavior. Three had abnormal insulin:glucose ratios ( greater than 1.0). The tumor was detected by computed tomography scan in three cases, at the time of surgery in one, and with intraoperative ultrasound in one. Surgical treatment included tumor enucleation in four cases and 80% pancreatectomy in one. Mucinous cystadenomas were observed in two patients, ages 4 months and 10 months. Tha latter infant underwent cyst excision alone, resulting in malignant recurrence at 18 months of age and death. The 4-month-old child had a distal pancreatectomy and is alive at 6 years. Two of the four children with pancreatic cancer had unresectable tumors at diagnosis, and were treated by biopsy (ductal adenocarcinoma), irradiation, and chemotherapy. Length of survival was 6 months and 9 months. Two others (ages 4 and 12 years) underwent 85% distal pancreatic resection for pancreatoblastoma and a pancreatoduodenectomy for papillary carcinoma, respectively. The latter is alive and tumor-free at 20 years of follow-up. The former underwent hepatic lobectomy for a 3.0 x 3.0 cm solitary liver metastases and is alive at 6 years with no evidence of disease. One child with rhabdomyosarcoma died of progressive disease, the other is alive with residual disease despite resection and chemotherapy. Most insulinomas can be treated by enucleation.(ABSTRACT TRUNCATED AT 250 WORDS)

We have developed a computerized system for the quantification of video images of cell migration patterns obtained in the chemotaxis under agarose assay. This system allows either manual or automatic measurement of standard parameters of chemotaxis, as well as quantification of three new parameters which reflect mean cell movement and chemokinesis. The parameters of mean cell population movement are not obtainable by the traditional analysis of the chemotaxis under agarose assay. Our system operates on an inexpensive microcomputer, is easy to use and provides data output in a format that is directly transferable to standard statistical packages.

The short-term and long-term effectiveness of central parenteral nutrition (CPN) versus peripheral parenteral nutrition (PPN) in improving muscle mass (arm muscle area [AMA]) was evaluated for 24 malnourished children with newly diagnosed Stage IV neuroblastoma (n = 14) or Stages II-V Wilms' tumor (n = 10). Patients were randomized to either CPN or PPN plus enteral nutrition (EN: intense nutrition counseling, oral foods, and supplements) for 4 weeks followed by EN until week 10. Oncologic treatment was similar for each tumor type. Dietary, anthropometric, and biochemical measurements were obtained at weeks 0, 4, and 10. During weeks 1 through 4, energy (CPN: means 100 +/- 4; PPN: means 96 +/- 4% of healthy children) and protein (CPN: means 2.5 +/- 0.1; PPN means 2.7 +/- 0.2 g/kg) intakes of the two groups did not differ. The AMA increased (P less than 0.05) with 4 weeks of CPN but not with PPN; changes thereafter with EN were not significant. Weight (P less than 0.05) and triceps skinfolds (P less than 0.01) increased with 4 weeks of PN in both groups and decreased with EN thereafter (P less than 0.01) but were higher at week 10 than diagnosis. Increases in albumin in both groups reached significance at week 10 (P less than 0.05). These data show that CPN improves AMA in malnourished children with neuroblastoma or Wilms' tumor when energy and protein intakes are adequate. The AMA gains can be maintained thereafter with EN.

PURE red-cell aplasia is a syndrome characterized by severe anemia, reticulocytopenia, and an absence of erythroid precursor cells in bone marrow that is otherwise normal. This failure of erythropoiesis has been shown to be antibody-mediated in almost half the patients with the adult form of red-cell aplasia.1 2 3 4 Immunosuppressive agents such as corticosteroids, cyclophosphamide, and antithymocyte globulin have been used to treat immunologically mediated red-cell aplasia.2 , 5 6 7 8 Results of in vitro assays for hematopoietic progenitor cells may assist in predicting which patients will respond to immunosuppressive therapy.9 10 11 Red-cell aplasia in children usually differs from the disorder in adults. There is a constitutional . . .

Twenty-one children with Stage II neuroblastoma diagnosed between 1973 and 1983 were analyzed retrospectively. Median age at diagnosis was eleven months (1 week to 153 months). Primary tumor was above the diaphragm in 67% and below the diaphragm in 33%. All patients underwent surgical resection and pathologic diagnosis was neuroblastoma in 76% and ganglioneuroblastoma in 24%. Regional lymph nodes were positive in three of eleven patients sampled. Sixty-seven percent had gross residual disease, and thirty-three percent had microscopic residual disease. Seventeen patients received postoperative irradiation and none has relapsed (median follow-up 57 months). Four patients received surgery alone (median follow-up 24 months); one local relapse occurred in this group and was subsequently treated with irradiation. All patients are alive and disease free, with a median length of follow-up of 55 months. Radiation dosage was 1000-1800 rad in patients less than 12 months of age, and 1800-3000 rad in those greater than 12 months of age at diagnosis. The high disease-free survival rate in both groups of patients, but especially in the group receiving adjuvant irradiation, emphasizes the need for a controlled, prospective study to determine which Stage II neuroblastoma patients, if any, would be benefitted by postoperative irradiation.

Benefits and risks of nutrition support were evaluated in 31 malnourished children with newly diagnosed Wilms' tumor managed according to the third National Wilms' Tumor Study protocol. Patients were classified at diagnosis as being at high nutritional risk (HNR, n = 19) or low nutritional risk (LNR, n = 12). Ten HNR patients were randomized to central parenteral nutrition (CPN) and nine HNR patients were randomized to peripheral parenteral nutrition (PPN) plus enteral nutrition (EN) for 4 weeks of initial intense treatment and EN (nutritional counseling, oral foods and supplements) thereafter. Thirteen HNR patients (seven CPN, six PPN) completed the protocol. Twelve LNR patients received EN; 11 Stage I malnourished patients were randomized to 10 or 26 weeks of chemotherapy. Dietary, anthropometric, and biochemical data were determined for HNR patients at weeks 0-4, 6, 13, 19, and 26 and for LNR patients at weeks 1, 2, 5, and 26. In HNR patients, adequate parenteral nutrition support reversed protein energy malnutrition (PEM), and prevented chemotherapy and radiotherapy delays due to granulocytopenia. CPN was superior to PPN in reversing PEM: energy intake, weight gain, and retinol binding protein were higher (P less than 0.05). LNR patients lost weight and fat reserves in the first 2 weeks of treatment; depletion persisted at week 5, and 25% had chemotherapy delays. Thereafter, EN reversed PEM in patients with both chemotherapy regimens. These data suggest that CPN is preferable during initial intense treatment for HNR patients, and that, although EN is ineffective in preventing depletion and treatment delays in the first 5 weeks of treatment for LNR patients, it is effective thereafter.

Magnetic resonance imaging has been used to evaluate 10 children with lymphomas and was able to identify disease in all 10 cases and monitor response to therapy in all three patients with follow-up studies. It could not distinguish between the different histological types of lymphoma. The image intensity of a diseased spleen in one case was different from that of five other normal spleens in six children with Hodgkins disease. Magnetic resonance imaging compared well with computed tomography and it was especially good at identifying blood vessels.

Neutrophil function was studied in a patient with polymorphonuclear leukocyte (PMN) glycoprotein-180 deficiency and in her parents. PMNs of the patient had abnormal chemotaxis, phagocytosis, adherence, surface charge, and membrane-associated events of activation. Selective defects to C3b, immunoglobulin G (IgG), phorbol myristate acetate (PMA) and N- formyl-methionyl-leucyl-phenylalanine (FMLP) are described, although C3b receptor density was normal. The parents were found to have abnormal adherence to nylon-wool fibers, abnormal transmembrane potential depolarization with PMA, and reduced amounts of glycoprotein- 180 in their PMNs. These studies provide further evidence that the oxidative burst has several different pathways for activation. They demonstrate that the absence of a single PMN surface glycoprotein is associated with a broad spectrum of PMN functional abnormalities. Finally, the observations made in the parents support an autosomal recessive mode of inheritance.

There are conflicting reports on the appearance of blood and blood clot as seen in the human body by MRI. This study was designed to show the in vitro MR signal intensity of human blood products in the fresh state and to evaluate the serial MRI changes that occur over time (2 weeks). T1 relaxation times were also measured. Anticoagulated whole blood, plasma, serum, white blood cell concentrates, platelet concentrates, lysed red cells, red cell concentrates, and blood clot were studied. The results show that plasma and serum have similar T1 values, as do lysed and intact erythrocytes. T1 of serum and plasma rose initially and then fell with the aging of the samples. T1 of red blood cells, clot, and packed red blood cells decreased for the first 48 hr and then remained constant for 7 days before increasing to the initial values by 2 weeks. Platelets and white blood cells had little influence on the MR image. However, temperature had a significant effect on T1 and signal intensity. In vivo clots are complex mixtures of whole clot, lysing clot, serum, and plasma influenced in various ways by the adjacent normal or diseased tissues. The chemical and physical properties of the mixture change constantly. Because of the clot's complex nature, determining the age of a hematoma from the appearance of clots on the MR image may not be possible.

Raynaud's phenomenon occurred in a 2-year-old girl 17 months after starting multiagent chemotherapy for an endodermal sinus tumor of the vagina. Symptoms began 2 months after receiving her final dose of bleomycin, and gradually resolved over a 6-month period despite continuing vinblastine. Chemotherapy-associated Raynaud's phenomenon appears to be unusual in young children, although mild episodes of vasospasm may not be reported by children or their parents. Specific questions regarding symptoms of Raynaud's phenomenon should be asked of all children receiving vinblastine and bleomycin therapy.

We measured serial urine levels of hypoxanthine, xanthine, and uric acid in 19 children with acute lymphocytic leukemia (ALL) receiving allopurinol therapy during tumor lysis; four of these children developed acute renal failure. The urinary excretion of uric acid rose moderately from 447 +/- 251 micrograms/dl glomerular filtrate before chemotherapy to 778 +/- 463 micrograms/dl glomerular filtrate during tumor lysis (P less than 0.05) whereas the urinary excretion of hypoxanthine (17.9 +/- 15 to 292 +/- 213 micrograms/dl glomerular filtrate) and xanthine (74 +/- 62 to 1091 +/- 1085 micrograms/dl glomerular filtrate) rose dramatically (P less than 0.001). The urinary excretion of uric acid, hypoxanthine, and xanthine per deciliter of filtrate was significantly higher (P less than 0.001) in those who developed acute renal failure than in those who did not, but the highest urine concentration of these purine metabolites did not differ in the two groups. In all 19 children, the highest urine concentration of uric acid and hypoxanthine during tumor lysis did not exceed the solubility limit of each in an alkaline urine specimen. In contrast, the peak urine concentration of xanthine exceeded its solubility limit in an alkaline urine specimen in 16 of 19 children. The urine sediment during the period of tumor lysis was examined by diffuse reflectance infrared spectroscopy; precipitated xanthine was found in sediment from eight of the 19 children, was significantly (P less than 0.001) associated with a urine xanthine level greater than 350 mg/dL, and occurred with equal frequency in those who did or did not develop acute renal failure. We conclude that urinary excretion of hypoxanthine and xanthine increases dramatically whereas uric acid excretion rises moderately in children undergoing tumor lysis while receiving allopurinol, that acute renal failure occurs in children with a higher purine load per deciliter of glomerular filtrate, but that factors other than tubular precipitation of purine metabolites are likely to be involved in the pathogenesis of renal failure during tumor lysis.

• One hundred thirty-nine children with neoplasms were studied using magnetic resonance imaging (MRI). This procedure was as accurate as computed tomography in predicting tumor histology, except that MRI was unable to detect small areas of tumor calcification. Magnetic resonance imaging could accurately identify the organ of origin of tumor masses and differentiate soft tissue from fat, fluid, or hemorrhage. In addition, MRI was helpful in planning surgery in many cases: (1) It was better than computed tomography in defining the size and extent of soft-tissue tumor masses. (2) It was accurate in defining the extent of the spread of bone sarcomas in the bone marrow. (3) Without requiring the injection of intravenous contrast agents, it accurately defined displacement, encasement, or invasion of major abdominal blood vessels by Wilms' tumors and neuroblastomas. As a means of evaluating pediatric neoplasms, MRI is noninvasive, painless, and well tolerated by children, and it uses no radiation. ( Arch Surg 1986;121:522-529)

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