Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients.

PURPOSE: We report survival, prognostic factors, and treatment efficacy in low-grade glioma. PATIENTS AND METHODS: A total of 379 patients with histologic intracranial low-grade glioma received post-operative radiotherapy (n = 361) and intraarterial carmustine (BCNU) chemotherapy (n = 153). Overall survival and prognostic factors were evaluated with the SPSS statistical program (SPSS Inc, Chicago, IL). RESULTS: Median survival (all patients) was 100 months (95% confidence interval [CI], B7 to 113); in age group 0 to 19 years (n = 41), 226 months; in age group 20 to 49 years (n = 263), 106 months; in age group 50 to 59 years (n = 49), 76 months; and for older patients (n = 26), 39 months. Projected survival at 10 and 15 years was 42% and 29%, respectively. Patient age, World Health Organization (WHO) performance status, tumor computed tomography (CT) contrast enhancement, mental changes, or initial corticosteroid dependency were significant independent prognostic factors (p < .05), while histologic subgroup, focal deficits, presence of seizures, prediagnostic symptom duration, tumor category, and tumor stage were not. Patients aged 20 to 49 years with no independent negative prognostic factors (n = 132) had a median survival time of 139 months versus 41 months in patients with two or more factors (n = 33). Patients who presented with symptoms of expansion (n = 97) survived longer when resected (P < .03); otherwise no survival benefit was associated with initial tumor resection compared with biopsy. Intraarterial chemotherapy and radiation doses more than 55 Gy were not associated with prolonged survival. Among 66 reoperated patients, 45% progressed to high-grade histology within 25 months. CONCLUSION: Prognosis in low-grade glioma following postoperative radiotherapy seems largely determined by the inherent biology of the glioma and patient age at diagnosis.

Bone marrow examination in neuroblastoma patients: a morphologic, immunocytochemical, and immunohistochemical study.

Bone marrow examination was performed at the time of diagnosis, before initiation of therapy, and during follow-up of 14 consecutive patients with neuroblastoma who were treated at the National Hospital in Oslo. A total of 30 bone marrow specimens were examined by conventional histology, by immunohistochemistry with selected monoclonal antibodies to neuroblastoma cells (UJ 13A, UJ 167.11, PI 153/3, and A2B5) applied on trephines, and by morphologic evaluation of smears in addition to immunocytochemistry of aspirated bone marrow cells. The study confirmed the value of immunohistochemistry and immunocytochemistry for the detection of bone marrow involvement in neuroblastoma. Immunohistochemistry performed on bone marrow trephines was a slightly better adjunct than immunocytochemistry on aspirated bone marrow cells.

[Better survival in neuroblastoma?]. / Bedred overlevelse ved neuroblastom?

This study compares the five year absolute survival rates among neuroblastoma patients treated at the National Hospital, Oslo, during two periods of time, 1985-90 and 1967-81. The treatment regimens differed, the main difference was more radical operations and more intensive chemotherapy during the period 1985-90 (n = 27) than in 1967-81 (n = 58). The intensified treatment was accomplished without operative mortality and without lethal complications associated with the cytostatic medication. For localized neuroblastoma the survival rate rose from 64% to 93%. The results obtained for disseminated neuroblastoma (Evans' stage IV) remained poor, however, with survival rates of 0% in 1967-81 and 17% in 1985-90.

Vitamin C and thiol reagents promote the in vitro growth of murine granulocyte/macrophage progenitor cells by neutralizing endogenous inhibitor(s).

Growth of murine hemopoietic cells in culture requires the presence of a stimulator of stem cell proliferation, "colony stimulating factor" (CSF). A widely used source of CSF is lung conditioned medium (LCM). We have earlier shown that the great variability of CSF activities in different batches of LCM is due to varying amounts of inhibitor(s). The present study expands the observation that the addition of ascorbic acid to the murine bone marrow soft agar assay system removes the inhibitory activity. The vitamin probably acts as an antioxidant or free radical scavenger, since addition of reduced (but not oxidized) glutathione, cysteine, dithiothreitol or 2-mercaptoethanol to the cultures also inactivates the endogeneous inhibitor. Cysteine and glutathione gave the highest colony numbers, were active at concentrations present in body fluids and did not inhibit colony growth even at concentrations ten times higher than optimum. No synergistic effects could be observed between the different antioxidants. At optimum concentration (usually 0.45 mmol/l) the otherwise bell-shaped dose-response curve for conditioned medium changed to a sigmoid curve. Antioxidants had no growth promoting effect in the absence of CSF. The presence of cysteine or vitamin C revealed CSF-like activity in conditioned media of tissues not considered to be potent producers of such factors. It has been reported that individual batches of foetal calf serum contain different levels of reduced glutathione, and we suggest that one of the batch variable growth regulators in foetal calf serum may be reduced glutathione. The results indicate a possible physiological role of antioxidants in granulopoiesis and suggest that cysteine or reduced glutathione should be freshly added to culture systems assaying CSF and/or granulocyte macrophage progenitor cells.

Endogenous inhibitors of human granulocyte/macrophage colony forming cells in vitro are inactivated by free radical scavengers.

Granulocyte/macrophage colony forming cells (GM-CFC) require colony stimulating factors (CSF) for growth in vitro. Crude preparations of CSF also contain inhibitors. To investigate whether this inhibition involves free radicals, the following scavenging agents were tested on human GM-CFC grown in agar: cysteine, reduced glutathione, dithiothreitol, sodium selenite, alpha-tocopherol, superoxide dismutase, catalase and ascorbic acid. All except ascorbic acid and catalase had enhancing and stabilising effects on colony formation. The colonies also contained more cells but no changes in cell composition were detected. Cysteine, the most extensively tested substance, was active at concentrations present in body fluids and enhanced colony formation without an exogenous source of CSF. Our results are consistent with an imbalance between the production and removal of free radicals generated in the human GM-CFC assay in vitro. This hampers investigation of regulators of granulopoiesis and results in underestimation of GM-CFC, but can be alleviated by the addition of free radical scavengers.

[Psychological and neurologic long-term consequences of brain tumors in children. A pilot study]. / Psykologiske og neurologiske langtidsvirkninger av hjernesvulst hos barn. En pilotstudie.

Brain tumor is one of the most common forms of cancer in children. The therapy includes surgical interventions, radiation of the central nervous system and chemotherapy. Combining these methods of treatment has remarkably improved the survival of children with certain brain tumours (e.g. medulloblastoma). However, long-term studies have revealed serious psychological and somatic consequences of the disease and the treatment. This paper presents the results of a pilot study of nine children with brain tumor. The patients were examined using a battery of neuropsychological methods (Luria's Neuropsychological Investigation, WISC-R), a semi-structured interview (Child Assessment Schedule), a parent report form (Achenbach Child Behaviour Checklist) and a clinical neurological examination. The most striking finding from this investigation was in the psychosocial field. Except for one child, all the patients showed an introvert reaction pattern with a tendency towards anxiety, depression and social withdrawal. All the children showed some neurological and neuropsychological deficits. Except in the case of two mentally retarded children, cognitive functions were within the lower normal range. Specific learning, memory and fine-motor disabilities were found in more than half of the patients. The investigation suggested that both fine-motor and mental performance was detrimentally affected by increased speed. This seems to be an area of special interest for further studies.

Inhibitory activity in mouse lung-conditioned medium studied in the agar assay for bone marrow colony-forming cells: removal by vitamin C.

The growth of granulocyte/macrophage colony-forming cells (CFC) from bone marrow, with mouse lung-conditioned medium (LCM) as source of colony-stimulating factor, was tested in five strains of mice. Maximum stimulation of growth was usually obtained at a LCM dilution of 1:5 (final concentration, 1.8% vol/vol). Higher concentrations nearly always caused inhibition. The inhibitory activity was resistant to heating (56 degrees C, 30 min) and was not removed by dialysis, but could be extracted with chloroform, suggesting a lipophilic inhibitor of high molecular weight. On gel filtration (Sephadex G50) the stimulatory activity eluted in the first fraction, whereas the inhibitory activity could not be recovered. Ascorbic acid reduced or prevented the inhibition (optimum concentration, 0.45 mmol/l), and provides a convenient means of stabilizing the CFC agar assay system. In physiological conditions the vitamin might influence the responsiveness of CFC to growth-regulating factors.

Psychological outcome in children treated for brain tumor.

The cognitive and psychosocial functions of 16 children with brain tumor, treated with wholebrain or local radiotherapy, were studied. Fifteen nonirradiated children with acute lymphatic leukemia (ALL) served as a comparison group. Mean Wechsler Intelligence Scale for Children--Revised Full Scale IQ score and mean Visual-Motor Integration Test (Beery VMI) standard score were significantly decreased in the brain tumor group. The Achenbach checklists were filled in by mothers (Child Behavior Checklist, CBCL) and teachers (Teacher's Report Form). Overall adjustment was rated lower in the children with brain tumor. Although most of the children in the ALL group were well adapted, one third of them had low CBCL Social Competence scores relative to nonclinical norms. On a visual analog scale a significantly decreased tempo was assessed by mothers and teachers in the children with brain tumor, and low speed and hypoactivity seemed to limit the majority of these children in school and daily life activities.

Management of pediatric pontine gliomas.

We present 36 consecutive patients with intrinsic glioma of the pons. Tumors with exophytic expansion were excluded. There were 16 females and 20 males, ranging in age from 2 to 13 years, median 6 years. The most common presenting symptoms were cranial nerve dysfunction, unsteadiness of gait, and hemiparesis. Computed tomography (CT) showed a hypodense (17/21) or isodense (4/21) expansion of the pons. Five tumors had areas of contrast enhancement. Following information about prognosis and possible types of management, parents decided for or against radiation therapy: twenty-four children underwent irradiation and 12 did not. Median survival among children receiving a full course of irradiation was 280 days, compared to 140 days in an equivalent group of non-irradiated children. Hemiparesis presenting without cranial nerve symptoms and contrast enhancement on CT scan were poor prognostic factors, whereas sex, age, and duration of symptoms at diagnosis were unrelated to prognosis.

Human granulopoiesis in vitro--medium-dependent growth regulation by a granulocyte-derived inhibitor.

A number of reports have indicated that mature blood granulocytes produce regulators that inhibit proliferation of progenitor cells in the bone marrow. However, this concept of negative feedback of granulopoiesis is still controversial. To examine whether conflicting results may depend upon the experimental set-up, we have compared colony formation by human bone marrow cells in different growth media. Unmodified McCoy's medium, which in feeder layer cultures supports the formation of large numbers of colonies, was a poor growth medium in cultures supplied with crude or recombinant colony stimulating factor (CSF). The colony formation improved when the medium was supplemented with defined additives. In CMRL 1066 cultures, granulocyte extract (GRE) consistently caused a strong inhibition of colony formation. In contrast, with unmodified McCoy's medium, granulocyte extract enhanced colony formation in a dose-dependent manner. The enhancing effect of granulocyte extract coincided with low colony numbers in the control cultures. The stimulatory effect of granulocyte extract in McCoy's medium, switched to strong inhibition when thymidine, a component of CMRL 1066 medium, was added. The inhibitory and stimulatory activities were found in the same molecular weight fractions (30-60 kD) after gel filtration. Both modulators in granulocyte extract appeared to be independent of monocytes and T lymphocytes in the bone marrow, as shown by removal of these cells with magnetic microspheres coated with specific monoclonal antibodies. The present work shows that regulation of cell proliferation in vitro depends strongly on culture conditions, such as choice of medium. It appears that thymidine acts as co-factor for the inhibitor in granulocyte extract.

Pharmacokinetics of oral 6-mercaptopurine: relationship between plasma levels and urine excretion of parent drug.

Plasma levels and cumulative urine excretion of 6-mercaptopurine (6-MP) were measured using a specific and sensitive high-performance liquid chromatographic assay in seven children with acute lymphoblastic leukemia (ALL) as well as in one healthy volunteer. The dose of 6-MP varied in the range of 25-75 mg/m2 of body surface area and was administered with a standard breakfast. A 4- to 11-fold variation between individuals was found in the pharmacokinetic parameters: peak concentration, time to reach peak, area under the plasma concentration-time curve (AUC), and fraction of dose excreted in the urine. Three repeated determinations in one individual revealed that AUC also varied more than sixfold following an overnight fast. In three individuals, the reducing agents glutathione (10 mg/kg) and ascorbic acid (15 mg/kg) were coadministered with 6-MP to evaluate their possible role in the protection of 6-MP from oxidation and degradation in the intestinal lumen. No consistent effect was observed, however, on the AUCs of either of these agents. A clear relationship was found between AUCs and the 24-h urinary excretion of unchanged drug (r = 0.9381), indicating that determinations of 6-MP in the urine may replace the painful procedure of repeated blood sampling. Further studies are necessary to determine the factors contributing to the unpredictable plasma levels following oral doses of 6-MP and to determine the value of pharmacokinetic monitoring in ALL patients.

Prognostic factors in neuroblastoma. Clinical, histopathologic, and immunohistochemical features and DNA ploidy in relation to prognosis.

Tumor samples from 58 patients diagnosed and treated for neuroblastoma or ganglioneuroblastoma in a single institution from 1967 to 1981 were included in a study of prognostic factors. Histopathology, certain immunohistochemical markers, and DNA ploidy were evaluated along with clinical variables such as tumor stage, primary site, and patient's age at diagnosis. Children under 1.5 years of age at diagnosis had a much better prognosis than did older ones, and this variable was the best prognostic indicator. Tumor Stages I to II and IVS, primary tumor site above the diaphragm, and tumor differentiation were also related to a better prognosis. The Shimada classification was of no additional prognostic value in our study. Neither was the immunohistochemical marker pattern, but it was sometimes helpful in establishing the tumor diagnosis. Tumor-cell ploidy, however, seemed to afford additional prognostic information because the 11 patients with aneuploid tumors under the age of 1.5 years at diagnosis all survived in contrast to only five of nine patients with diploid tumors in the same age group. It is possible that this was due to a better response to treatment in the aneuploid group. Our results suggest that patients with diploid neuroblastomas of undifferentiated histology and those over the age of 1.5 years at diagnosis might be selected for more intense treatment.

Cure of infantile myofibromatosis with severe respiratory complications without antitumour therapy.

UNLABELLED: The prognosis of infantile myofibromatosis (IMF) depends on the organs involved: the prognosis is very poor if vital viscera are affected, but excellent if there is no visceral involvement. We report the case of a boy presenting with a pathological fracture at the age of 6 weeks. Progressive osteolytic lesions in the whole skeleton until the age of 8 months led to respiratory failure due to a softened thoracic wall requiring mechanical ventilation for 11 months. No pulmonary, laryngeal or other visceral involvement was found. In spite of the rapidly progressing disease and serious complications only supportive therapy was given. The lesions subsided gradually leaving slight deformities but normal function. At the age of 3.5 years the boy has an excellent quality of life. CONCLUSION: This case illustrates that even in progressing, complicated multifocal infantile myofibromatosis (without visceral involvement) the lesions can resolve without antitumour treatment if high quality intensive care is supplemented.

Severe aplastic anaemia in the Nordic countries: a population based study of incidence, presentation, course, and outcome.

PURPOSE: Incidence data for severe aplastic anaemia (SAA) in children are scanty and vary. Few population based studies have been reported. A retrospective and prospective study was conducted to determine the incidence and course of SAA. PATIENTS AND METHODS: All children with a diagnosis of SAA in the Nordic countries from 1982 through 1993 were registered and have been followed up since 1987. RESULTS: A total of 101 children were diagnosed with SAA. The mean annual child population was 4.31 million. A constant incidence of 1.95/million children/year was found: 2.4 for boys and 1.5 for girls. A non-significant increase of cases occurred from November to March. Possible aetiological agents were noted in 29%. The actuarial survival was 79% after one year and 68% after five years without significant difference between boys and girls. CONCLUSION: The incidence of SAA in the Nordic countries remains stable with a preponderance among boys. SAA has still a high initial mortality and a risk of late deaths.

Neurobehavioral response of infants after paracervical block during labour.

30 parturient women were randomized into a group receiving paracervical block (PCB) and a control group. The infants were tested by a neurobehavioral examination immediately after birth, after 3 hours and 3 days. The examiner was unaware of the obstetrical management of the patients. No clinically significant differences could be detected between the two groups. Arterial and venous pO2, pCO2 and pH from the umbilical cord showed no differences between the groups.

[Autologous bone marrow transplantation in children--experience with neuroblastoma]. / Autolog beinmargstransplantasjon hos barn--erfaringer ved neuroblastom.

Autologous bone marrow transplantation permits the use of greatly intensified cytoreductive therapy for cancer. Since 1983 seven children with disseminated neuroblastoma (stage IV) were treated by this method. Five were treated in first, and one in second complete remission; one child was in partial remission. Tumor cell purging of the marrow inoculum was performed in five cases. All children had engraftment and were discharged from hospital free of disease. Relapse was observed in three children within two years. Four children remain healthy at follow-up 5-77 months after autotransplantation. We describe and discuss indications, methods, side effects and results.

Ependymoma in children and young adults (0-19 years): report of 25 consecutive cases.

The objective of this retrospective study was to evaluate the relative effect of surgery and radiotherapy (RT) on the survival of 25 consecutive children and young adults treated for ependymoma [18 in the posterior fossa (PF), 2 in supratentorial locations (ST) and 5 in intraspinal locations (IS)]. Five-year survival rates for patients with PF, ST and IS tumors were 28%, 0% and 100%, respectively. Total tumor resection was a positive prognostic factor in the case of PF tumors. No patients with subtotal removal of a PF tumor survived for longer than 5 years. The effect of RT on survival of patients with PF ependymomas in this series was uncertain. No patients with PF ependymoma had disseminated disease at diagnosis, and all tumor recurrences were local. Based on these observations, we see no indications for craniospinal RT of PF ependymomas, except in rare cases of disseminated disease. If RT is given, it should only be targeted to the tumor site. The two patients with ST ependymoma died within 3.8 years after primary treatment. Our series of ST ependymomas does not allow any specific treatment recommendations. One patient with IS ependymoma was cured by surgery alone. Four patients with IS ependymoma had documented residual tumor after surgery. RT induced remission in these patients. For IS ependymomas we recommend no RT if total tumor removal can be documented. In patients with subtotal removal of IS ependymomas local RT is effective and should be given.

Characterization of a new malignant human T-cell line (PFI-285) sensitive to ascorbic acid.

A new malignant human T-cell line-labelled PFI-285-has been isolated from a boy with malignant lymphoma. Morphologically, the cells had characteristics of malignant lymphoid cells. The cells presented surface antigens as early cortical lymphocytes and proliferated non-adherently as single cells, independent of T-cell growth factor (IL-2), in liquid culture. The cells had undetectable levels of receptors for IL-2, were not clonogenic in soft agar, but did form tumors in nude mice. Their establishment and continuous growth in vitro was dependent on the number of cells inoculated and on the growth medium used. Cytogenetic alteration, HTLV-1 or reverse transcriptase activity were not detected. The production of known T-cell derived lymphokines such as IL-2, B-cell growth factor(s), alpha-interferon or granulocyte/macrophage colony stimulating or inhibiting factor(s) was not detected. The cells had 5-8% natural killer (NK)-cell activity against NK-cell sensitive target cells (K562) and were not sensitive for NK cells. A most unusual characteristic was the pronounced sensitivity of the cells to ascorbic acid. Concentrations down to 50 mumol/l killed the cells within hours.

Radio-iodobenzylguanidine scintigraphy of neuroblastoma: conflicting results, when compared with standard investigations.

Seventy-one patients with neuroblastoma (NB) and 25 patients with other neoplastic or nonneoplastic diseases were studied with MIBG scintigraphy. Sensitivity and specificity at diagnosis were 94% and 88%, respectively. Of 52 patients with NB studied during follow-up, 14 had on one or several occasions conflicting results, when the findings at MIBG scintigraphy were compared to standard investigations (SI: CT scan, bone scan, x-ray, and ultrasound). The correlation of MIBG scintigraphy and SI to clinical outcome were in these 14 patients not significantly different. Adding VMA-excretion measurements did not significantly improve the predictive value of MIBG scintigraphy or SI. Patients with tumor-suspected lesions only at MIBG scintigraphy should be followed closely and the nature of the lesions should be explored through biopsy.