Pulmonary abnormalities at long-term follow-up of patients with Langerhans cell histiocytosis.

BACKGROUND: In Langerhans cell histiocytosis (LCH) pulmonary involvement, which is often initially asymptomatic, may contribute to significant morbidity and mortality. To determine the long-term prognosis, a cross-sectional study was undertaken. PROCEDURE: Forty-one patients with > or = 5 years follow-up after the diagnosis of LCH were interviewed and underwent physical examination, blood tests, a chest X-ray and a high-resolution CT (HRCT) of the lungs. All patients included had been referred to the Department of Pediatrics at the Karolinska Hospital in Stockholm between July 1962 and February 1990 (median follow-up 16 years). Biopsies from all patients were reviewed and confirmed to be consistent with LCH. Information on previous clinical features including treatment and the results of chest X-rays were also collected for risk factor analysis. RESULTS: Radiographic abnormalities of the lungs (cysts and/or emphysema), found in 10/41 (24%) at follow-up, were classified into five groups according to the extent of the cysts. These patients had more often suffered from multisystem than from single-system disease (P = 0.01), were significantly older at diagnosis (P < 0.001), and had been more heavily treated with chemotherapy and/or radiotherapy. They were also more frequently smokers (P < 0.0001) and 7/10 (70%) had suffered lung involvement at diagnosis. At the time of diagnosis of the pulmonary involvement, 4/10 (40%) patients had respiratory symptoms, but only 2/10 (20%) had symptoms at follow-up. CONCLUSIONS: Ten (24%) of the 41 patients had abnormal findings on radiological examination of the lungs at long-term follow-up and seven are or had been smokers. It is of great importance that patients with LCH be informed about smoking-related pulmonary morbidity. Prolonged monitoring of the lungs for smokers and patients with known pulmonary involvement is recommended.

Intralesional steroids in Langerhans cell histiocytosis of bone.

Langerhans cell histiocytosis may involve single or multiple organ systems. Bone involvement is the most common feature. We have examined retrospectively the effects of 20 intralesional injections of steroids into bone in seven patients seen at our department from 1988 to 1993. Most of these injections (75%) relieved the symptoms, and no side-effects were observed. However, injections into the jaw were seldom effective. Our results suggest that the dose of the steroids administered is of importance.

Expression of nerve growth factor receptor mRNAs and clinical response to retinoic acid in neuroblastoma.

Four children with advanced or relapsed neuroblastoma were treated with oral 13-cis-retinoic acid 0.75 mg/kg/day. Clinical response to retinoic acid was noted only in the two children with tumors coexpressing trk protooncogene mRNA, encoding an essential part of the nerve growth factor (NGF) high affinity receptor, and low affinity NGF receptor gene (LNGFR) mRNA. Clinical stage or age, plasma neuropeptide Y, tumor DNA ploidy and N-myc amplification did not as accurately predict response to retinoic acid as NGF receptor mRNAs. In vitro data have shown that retinoic acid up regulates LNGFR expression and NGF sensitivity via interaction with specific regulatory elements in the LNGFR gene promoter. We hypothesize that part of the therapeutic effect of retinoic acid in neuroblastoma in vivo may be exerted via increased NGF receptor expression and NGF sensitivity. Analysis of trk and LNGFR mRNA may be useful to predict clinical response to retinoic acid in these children.

Variability of 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute leukemia.

The effects of some environmental and genetic factors on the inter- and intraindividual variations of 6-mercaptopurine (6-MP) pharmacokinetics were studied in children on oral remission maintenance therapy for acute lymphoblastic leukemia or non-Hodgkin's lymphoma. Blood samples were obtained 0-4 h after drug intake. 6-MP concentrations were determined in plasma and in erythrocyte concentrates. The influence of food on the pharmacokinetics was examined in a prospective study of 15 children. Each child was examined four times, twice in the fasted state and twice after intake of a standardized, milky, breakfast. There were pronounced inter- and intraindividual variations. Food intake seemed to reduce these variations but there were no significant changes in peak concentrations and area under the plasma concentration vs time curves (AUC) between the fasted and fed states. Food intake reduced the time to peak concentration both in plasma, from 1.8 h to 1.1 h (P less than 0.01) and in red blood cells, from 1.8 h to 1.3 h (P less than 0.01). Retrospective subdivision of the patients indicated a tendency for different pharmacokinetic patterns according to dose; five out of seven patients receiving greater than 70 mg m-2 had a higher AUC in the fasting state, while five out of eight patients receiving less than 70 mg m-2 had a higher AUC in the fed state. The cytochrome P-450-dependent hydroxylation capacity was evaluated with debrisoquine but no correlation was found to the pharmacokinetics of 6-MP.

6-Mercaptopurine in cerebrospinal fluid during oral maintenance therapy of children with acute lymphoblastic leukemia.

In three children receiving oral remission maintenance therapy for acute lymphoblastic leukemia, the concentrations of 6-mercaptopurine (6-MP) in cerebrospinal fluid (CSF), plasma and red blood cells were compared. CSF samples were obtained from an Ommaya reservoir previously inserted for treatment of CNS relapse. At the time of the study, the children were all in remission and had been on oral 6-MP (42-63 mg m-2) once daily for at least 24 weeks. Immediately before dose intake on the day of study (about 24 h after last dose), the concentrations of 6-MP in CSF, plasma and red blood cells were rather similar and below 20 ng ml-1 in all patients. After dose intake, the concentrations in plasma and in red blood cells increased to 40-200 ng nl-1 within 0.5-4 h. In contrast, the concentration of 6-MP in the CSF remained fairly constant around 4-10 ng ml-1 throughout the time period studied (up to 4 h). It is concluded that 6-MP can be detected in CSF during oral maintenance therapy and that the drug has different pharmacokinetic profile in CSF to that in plasma and red blood cells. Further studies are necessary to evaluate the significance of the 6-MP concentrations obtained in CSF for the prevention of CNS relapse.

Large interindividual variations in the pharmacokinetics of oral 6-mercaptopurine in maintenance therapy of children with acute leukaemia and non-Hodgkin lymphoma.

The concentrations of 6-mercaptopurine were studied in plasma and red blood cells from 10 children with acute leukaemia or non-Hodgkin lymphoma receiving oral maintenance therapy. The doses varied between 25 and 79 mg/m2 body surface once daily. Large interindividual differences were found in the concentrations both in plasma and in red blood cells. There was no clear relationship between the dose administered and the concentrations obtained. However, in each patient the concentrations in plasma and in red blood cells were very similar. In most patients, the peak concentrations were reached 1-2 hours after dose intake and the concentrations then declined with half-lives less than 1 hour. Further studies are necessary to evaluate the potential value of drug level monitoring in optimizing treatment with oral 6-mercaptopurine.

[Erroneous diagnosis of nephroblastoma (Wilm's tumor) based on SIOP data]. / Oshibochnyi diagnoz nefroblastomy (opukholi Vil'msa) po materialam SIOP.

Available films of 21 cases of erroneously diagnosed Wilms' tumor in the European Wilms' material have been studied. The diagnosis has been reassessed and the reasons for agreement in 6 cases and disagreement in the remaining 15 are discussed. General diagnostic recommendations are given to help secure optimal diagnostic information.

Veno-occlusive disease and peliosis of the liver complicating the course of Wilms' tumour.

Veno-occlusive disease (VOD) of the liver was diagnosed in 8 patients with Wilms' tumour and peliosis hepatis (PH) in one. Fever of obscure origin, vague abdominal pain, hepatomegaly or hepatosplenomegaly, severe anaemia or sudden, unexplained drop in haemoglobin, thrombocytopenia, increasing serum transaminase levels, jaundice and ascites recorded within the first weeks or months of tumour diagnosis should arise suspicion of non-metastatic vascular hepatopathy. General or focal decreased accumulation of isotope at liver scintigraphy belong to the early radiologic findings. Sonography and CT may show a generalized irregular echogenicity or attenuation but no unequivocal metastases. One patient with PH had multiple low attenuating foci in both liver lobes and angiographically abnormal pooling of contrast medium in the liver. It is important to recognize these conditions as alternatives to suspected liver metastases, which as a rule develop much later yet on occasions may have very similar radiologic appearances. Therefore the relation in time between tumour diagnosis, initial operation and development of obscure hepatic manifestations is of critical significance for the recognition of VOD or PH. In these patients chemotherapy and irradiation must be discontinued without delay. If the disorders are adequately treated the prognosis may be considered fair.

Early results of a trial of the Oka-strain varicella vaccine in children with leukaemia or other malignancies in Sweden.

Nineteen children with acute lymphoblastic leukaemia or other malignancies, aged 3-13 years, with negative histories of varicella-zoster virus (VZV) and of whom 5 were still on regular maintenance chemotherapy, were vaccinated with the Oka-strain varicella vaccine. Mild systemic reactions, involving low-grade fever of a few days duration, were recorded in 4 of the vaccinees. Two of them also developed an extremely sparse rash. A mild local reaction at the vaccination site was observed in 1 child. Conversion rates for circulating VZV antibody, measured at 4-6 weeks and 4-6 months after vaccination using an indirect immunofluorescence test, were 8/12 (67%) and 5/9 (56%), respectively. Markedly lower antibody conversion rates of 5/18 (28%) and 5/14 (36%) were found by means of the enzyme-linked immunosorbent assay method. Corresponding conversion rates for cell-mediated immunity against VZV, determined using a specific lymphocyte stimulation technique, were 9/17 (52%) and 12/14 (86%), respectively.

Renoprival growth following treatment of unilateral Wilms' tumour.

The renal growth pattern following uninephrectomy for Wilms' tumour was analysed in 18 boys and 18 girls by means of a comparison between renal parenchymal and body surface area. No straightforward correlation was noted between age at nephrectomy, chemo- and radiation therapy applied, and subsequent renoprival dimensions. Five years on average after operation, a mean renal size corresponding to approximately 125 per cent of the normal for one of two healthy kidneys was recorded. However, wide variations in size were observed, but only 10 patients had a compensatory growth of the remaining kidney equivalent to that seen in patients nephrectomized for unilateral, non-malignant renal disease.

Spontaneous regression of stage IV neuroblastoma.

Neuroblastoma presenting with wide spread osseous metastases (stage IV) is generally considered incurable. However, rare cases of spontaneous regression and cure are on record. This report deals with such a case in which an infant received steroids as sole treatment for developing skeletal pain. Established metastases to the brain, scalp and skeleton disappeared. Today 4 1/2 years later the patient is free from symptoms and signs of tumour.

Growth of renoprivals following uninephrectomy for Wilms' tumour: application and suitability of a method of assessment.

In an attempt to evaluate the long-term renoprival growth in patients uni-nephrectomized for Wilms' tumour, renal length was related to the length of the lumbar segment L1-L3. The results of this study indicated that spinal growth retardation, secondary to applied adjuvant treatment, invalidated employment of the method for this particular purpose. A computerized analysis showed no straight-forward correlation between age at operation, chemotherapy utilized, irradiation and the post-treatment renoprival growth as established by substitution of the observed L1-L3 length with a mathematically corrected value. Emergent figures exclude significant compensatory growth of the remaining kidney.

Paravertebral widening in a case of recurrent Wilms' tumour.

In infants and children the association of paravertebral widening and abdominal tumour has been regarded as typical of neuroblastoma. However, a paraspinal mass may develop in other malignant tumours too, but seems to be extremely rare in nephroblastoma. The fourth case so far on record is reported. Microscopically the tumour was of the sarcomatous clear cell variant.

Lymph node invasion and prognosis in nephroblastoma.

Five hundred and twelve children with Wilms' tumor Stages I, II, and III registered to the International Society of Pediatric Oncology (SIOP) nephroblastoma trial were analyzed as to the prognostic value of metastatic lymph node involvement. The lymph nodes of 300 patients were submitted for microscopic examination; malignant invasion was reported in 15%. The disease-free and the actuarial survival rates for patients with metastatic lymph node invasion were significantly worse than for those without metastatic lymph node involvement. Radical lymph node dissection neither improved the cure rate nor decreased the rate of abdominal recurrence in patients with lymph node metastases.