Peripheral blood stem cell (PBSC) collection in extremely low-weight infants.

While PBSC collection has become a safe procedure for adults, only a few reports exist about its efficacy, safety and feasibility in paediatric patients, especially extremely low-weight infants. We describe successful PBSC collection in three infants of less than 10 kg body weight (BW; range: 6.92-9.4 kg) suffering from stage IV neuroblastoma. Harvest of PBSC started after mobilisation with high-dose chemotherapy and G-CSF, as soon as 1.0% CD34+ cells were detected. Collections were performed using a Baxter CS-3000 Plus separator primed with a mixture of irradiated, white cell-depleted and CMV-negative packed red cells resuspended in 5% human albumin and diluted with saline to match the patient's haematocrit. Performing a median of four, (4-7, median, range) procedures we collected at least 4 x 10(8)/kg BW nucleated cells (NC) from all three patients. The infants were not sedated and showed no serious side-effects. All three children were successfully transplanted with myeloid engraftment in 8 (7-9) days, independence from red cell support was achieved in 15 (10-20) days and from platelet transfusions in 25 (14-29) days after PBSC infusion. We conclude that PBSC harvesting using continuous flow cell separators is safe, even in low-weight infants of less than 7 kg BW.

Recombinant human granulocyte-macrophage colony-stimulating factor in septic neutropenic pediatric cancer patients: detection of circulating hematopoietic precursor cells correlates with rapid granulocyte recovery.

Cycling intensive chemotherapy currently used to treat pediatric solid tumors induces severe neutropenia. Prolonged neutropenia is a major risk factor for septic death which occurs in up to 5% of febrile or septic neutropenic episodes. We treated 18 neutropenic pediatric cancer patients (eight females, 10 males) during 30 febrile and/or septic episodes with single daily doses of E. coli-derived non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF, 5 micrograms per kg of body weight). The cytokine was administered for a median period of 6.5 days (2-12 days). Analysis of circulating hematopoietic progenitor cells was performed at day 1 (baseline) and day 5 of rh-GM-CSF treatment and included flow cytometric CD34 analysis as well as the methylcellulose-based clonogenic assay. Prompt hematopoietic recovery and resolution of septic problems was observed in all children. The counts of leukocytes (WBC), absolute neutrophils (ANC), and platelets (PLT) rose above 1,000/microL, 1,000/microL, and 50,000/microL within 4 days (0-9), 5.5 days (2-13), and 6 days (0-14), respectively. Faster granulocyte recovery and improved recruitment of circulating hemopoietic precursors was observed in children with detectable amounts (> 0.1%) of CD34-positive mononuclear cells prior to rh-GM-CSF treatment. We conclude that, to some extent, the efficacy of rh-GM-CSF treatment in neutropenic cancer patients is influenced by the hematopoietic recovery status on the progenitor cell level. Although they respond more slowly to the treatment, patients without circulating CD34-positive progenitor cells may gain most from growth factor therapy. Rh-GM-CSF can be safely administered to febrile and/or septic neutropenic children treated for cancer.

Cardiac troponin T and creatine kinase MB mass concentrations in children receiving anthracycline chemotherapy.

Anthracyclines (doxorubicin, daunorubicin, and derivatives) are among the most effective antineoplastic drugs for pediatric cancer with dose-limiting acute and long-term cardiotoxicity. The exact mechanism of the development of cardiomyopathy is still not clear. Anthracyclines may induce subclinical acute myocardial injury leading to lysis of a limited number of myocytes. Alternatively, myocytes may experience a transient loss of cytoplasmic membrane integrity. Both conditions may lead to a transient efflux of small amounts of cytoplasmic enzymes and other proteins specific to the heart muscle fibers. To test these hypotheses we assayed plasma creatine kinase (CK) MB mass and cardiac specific troponin T (TnT). CKMB may be released even in case of reversible cell membrane injury, while prolonged elevation of TnT is the most sensitive and specific marker of limited myocardial necrosis. Thirty-five anthracycline-containing chemotherapy courses in 22 children with cancer were analyzed. CKMB mass and TnT concentrations were within the normal range in all children before anthracycline therapy. Within 72 hours from anthracycline therapy no increment of one of these two marker proteins was detected (ANOVA for repeated measures, P = 0.94 [TnT] and 0.25 [CKMB]). We conclude that only minimal if any acute necroses of cardiac myocytes occur after anthracycline therapy. Even membrane integrity appears to be maintained within the first 3 days after anthracycline therapy, in the absence of electrocardiographic or echocardiographic signs of acute cardiotoxicity.

Methotrexate osteopathy in infants with tumors of the central nervous system.

Methotrexate osteopathy, previously reported as a complication of maintenance-therapy for acute lymphoblastic leukemia, is characterized by osteopenia, particularly involving the lower extremities, thick, dense provisional zones of calcification, growth arrest lines, and corner fractures resembling scurvy. In attempts to postpone radiotherapy in infants under three years of age, the multicentric German therapy protocol for childhood central nervous system tumors (HIT-89 protocol) has employed high cumulative methotrexate doses. Here we describe osteopathy in three patients as a toxic side effect after administration of cumulative methotrexate doses of 20 g/m2, 80 g/m2 and 135 g/m2. The high prevalence of this adverse effect in infants with tumors of the central nervous system may be attributed to the long-term therapy with high cumulative methotrexate-doses. Both factors may favor intracellular accumulation of methotrexate and formation of methotrexate-polyglutamates and may be responsible for bone toxicity. Apparently the susceptibility of the rapidly growing skeletal structures of infants under three years of age to this toxic side effect of methotrexate is remarkably high.

Prognostic significance of myeloid-associated antigen expression on blast cells in children with acute lymphoblastic leukemia. The Austrian Pediatric Oncology Group.

The prognostic significance of expression of myeloid-associated antigens in childhood acute lymphoblastic leukemia (myA+ALL) was evaluated. From 1984 to 1990, 251 children with immunologically verified ALL were treated in two prospective consecutive Austrian studies. Complete immunophenotyping was performed in 206 cases (82%). Out of these 175 cases were classified as B-cell precursor ALL, 31 cases as T-ALL. Expression of myeloid-associated antigens was demonstrated in 23 cases (13.1%) of childhood B-cell precursor ALL, particularly in immature (CD10 negative) forms (P < .0001), and in 1 case (3.2%) of T-ALL. CDw65 was expressed most frequently (12 cases), followed by CD13 and CD15 (5 cases each), CD33 (4 cases), and blood-group H (3 cases). Compared to myA- ALL prognosis of children with myA+ B-cell precursor ALL was poor, despite intensive multiagent chemotherapy according to BFM protocols. Remission rates were not impaired, but pEFS was 74.6% for myA- ALL, and only 37.8% for myA+ ALL (P = .0001). As demonstrated by multivariate analysis the expression of myeloid-associated antigens was the most important prognostic variable for EFS in B-cell precursor ALL, whether or not CD10 was expressed.

Precocious puberty due to a lipid-cell tumour of the ovary.

A 4-year-old girl with a lipid cell tumour of the ovary showed isosexual precocious pseudopuberty. The endocrine activity of the tumour led to elevated plasma levels of dehydroepiandrosterone sulphate, oestradiol, testosterone and androstenedione. After tumour resection the clinical signs of abnormal hormonal stimulation disappeared within 10 months. The girl developed precocious puberty again 2 years later without any sign of relapse. Therapy with luteinizing hormone releasing hormone agonist was effective although premature activation of the hypothalamic-pituitary-gonadal axis could not clearly be demonstrated by hormonal investigations.

Cold haemagglutinin disease complicating Mycoplasma pneumoniae infection in a child under cytotoxic cancer treatment.

Acute cold haemagglutinin disease, most commonly associated with underlying mycoplasma infection, is rare in children. A 3-year-old girl who developed this auto-immune disease under intensive cytotoxic treatment for rhabdomyosarcoma is presented. Clinically, a livedo reticularis skin pattern upon exposure to cold which was reversible at room temperature and a spontaneous red cell agglutination of blood samples in vitro led to the diagnosis. Together with bronchopneumonia the girl developed hyper-IgM, high antibody titres against Mycoplasma pneumoniae, as well as high titres of cold agglutinins. Laboratory signs of mild intravascular haemolysis were found. Positive direct antiglobulin test resulted from coating of red cells with C3d and C4. Three different antibodies were identified in serum: nonspecific cold agglutinins without complement activation, anti-I specific cold agglutinins with complement activation, as well as a weak biphasic Donath-Landsteiner haemolysin. Under antibiotic treatment and a short course of predisolone the clinical course was mild.

Long term remission of intrinsic brainstem gliomas: the case reports of two children.

Intrinsic brainstem gliomas carry the worst prognosis of all pediatric CNS tumors; only 10-25% of patients are expected to survive for more than two years. Over a period of four years seven intrinsic brainstem gliomas were diagnosed in children in one institution. Four of them underwent a rapidly fatal course, whilst one was diagnosed only two years ago, which is too recent for long-term evaluation. We report the case histories of the remaining two boys, who showed a favorable course of their disease. Presenting symptoms were headaches and signs of brainstem dysfunction with multiple bilateral cranial nerve palsies, ataxia and pyramidal tract signs. Diagnosis rested on neuroimaging (CAT scans and/or MRI scans). Both tumors were intrinsic brainstem gliomas, one diffuse and the other focal. They responded to treatment (radiotherapy and chemotherapy in the former patient and radiotherapy alone in the latter patient). The two boys became long-term survivors and have remained well, without evidence of disease, for more than 71 and 61 months, respectively, after completion of treatment. They are probably cured. Prompt therapy with curative intention is recommended, with consistent adherence to the chosen antitumor regimen even in poor-risk brainstem gliomas.

[Respiratory aid using a diaphragmatic pacemaker in high paraplegia]. / Atemhilfe durch Zwerchfellschrittmacher bei hoher Querschnittslähmung.

Spastic tetraplegia due to cervical medullary injury above the origin of the phrenic nerve neurons means complete respiratory paralysis. In this case a phrenic pacemaker can be considered as an alternative to long term mechanical ventilation. An implantable 8-channel stimulation device has been developed for functional electrical stimulation of the phrenic nerves. The "Karussellstimulation" provides fatigue free stimulation for 24 hours a day. We report the case of a 12 year old girl with complete ventilatory insufficiency who underwent implantation of a phrenic pacemaker. 18 month after implantation she is independent of a conventional respirator and limits rehabilitation could be achieved. Electrophrenic respiration is of value in the rehabilitation management of tetraplegic patients with ventilatory insufficiency.