Annette Ridolfi Lüthy

Predicting Adverse Events in Children With Fever and Chemotherapy-Induced Neutropenia: The Prospective Multicenter SPOG 2003 FN Study

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Predicting bacteremia in children with fever and chemotherapy-induced neutropenia.

Background. Fever and neutropenia are common clinical problems in pediatric oncology and frequently necessitate emergency hospitalization and immediate empiric broad spectrum antimicrobial therapy. Estimating the risk of bacteremia in fever and neutropenia is a challenge. The purpose of this study was to develop an algorithm predicting the risk of bacteremia and Gram-negative bacteremia in children and adolescents with fever and neutropenia, based on information accessible at presentation. Methods. We collected information available within 2 h of presentation of children with fever and neutropenia and, on outcome, from all pediatric cancer patients presenting with fever and neutropenia from 1993 through 2001 in a retrospective single center cohort study. After univariate analyses a multivariate decision tree was constructed, and its performance was evaluated by cross-validation. Results. Bacteremia was detected in 87 (24%) and Gram-negative bacteremia in 30 (8%) of 364 episodes of fever and neutropenia. At the predetermined sensitivity level, ≥95%, decision tree models reached cross-validated specificities of 37 and 43%, with negative predictive values of 96 and 99%, for bacteremia and Gram-negative bacteremia, respectively. Absence of a clinically or radiologically evident source of infection and previous episodes of fever and neutropenia were defined as two newly described factors associated with bacteremia. Conclusions. Based on this retrospective analysis, it appears that bacteremia can be predicted with clinically useful specificity at a high level of sensitivity, using clinical information available at presentation in pediatric cancer patients with fever and neutropenia.

Repression of nuclear lamin A and C gene expression in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells

The lamins A, B and C which are differentially expressed during ontogenesis and differentiation are karyoskeletal proteins forming a polymeric meshwork at the inner nuclear membrane. Using Northern blot analyses we investigated the steady state levels of the three lamin specific RNA transcripts in neoplastic cells derived from 16 untreated patients with acute lymphoblastic leukemia (ALL) or non-Hodgkins lymphoma (NHL) and in ALL and NHL established cell lines. Whereas lamin B mRNA was present in all, lamin A and C transcripts were observed in none of the malignant cell samples except one of a common-ALL patient (precursor B-ALL, cytoplasmic mu chain negative). All three lamin mRNAs were detected in normal peripheral blood lymphocytes, however, only after mitogenic stimulation with concanavalin A. Our results provide evidence that expression of lamin A and C is repressed in neoplastic blast cells derived from patients with ALL or NHL and suggest that lamin A and C gene repression is not related to cell proliferation but might be relevant to the differentiated stages of the lymphoid cells in vivo.

Fatal adenovirus hepatitis during maintenance therapy for childhood acute lymphoblastic leukemia.

Disseminated adenoviral infection with hepatitis is rare in children undergoing standard chemotherapy. We report on a 3½‐year‐old male with fatal adenovirus hepatitis receiving maintenance chemotherapy for acute lymphoblastic leukemia (ALL). Adenoviral hepatitis was proven by histology, viral culture, and PCR in a liver biopsy. Quantitative real‐time PCR in the peripheral blood showed adenoviral DNA copy number >109/ml. Despite aggressive supportive care and antiviral treatment with cidofovir, the patient died rapidly due to fulminant liver failure. Diagnostic and treatment options for adenovirus infection remain unsatisfactory for these patients. We propose suggestions for diagnosis and therapy. Pediatr Blood Cancer 2008;50:647–649.

Haemophilia due to factor VIII inhibitors in a patient suffering from an autoimmune disease: Treatment with intravenous immunoglobulin: A case report

SummaryThis paper describes a case of haemophilia due to factor VIII inhibitors occurring in a 13-year-old boy suffering from an autoimmune disease. The patient had autoantibodies to factor VIII. The haemophilia was controlled by vincristine and steroids, but this regimen had to be discontinued because of side effects, whereupon the haemophilia recurred. Treatment with intravenous immunoglobulin (IgG i.v.) produced a slow rise in factor VIII, and the factor VIII inhibitors disappeared. Although factor VIII activity was raised for only a few months and factor VIII inhibitors reappeared, immunoglobulin treatment was continued and the patient remained remained free of clinical symptoms. The mechanism of action of treatment with IgG is discussed.

Evaluation of the Fresenius cell separator AS 104 for harvesting peripheral blood stem cells in pediatric patients

In a single institution trial we carried out 35 peripheral blood stem cell harvesting procedures in 12 children with advanced malignancies to evaluate the procedures safety and the collection efficiency of the Fresenius blood cell separator AS 104 in a pediatric population. Despite a significant mean decrease of 21% (+/-8%) in systolic blood pressure after starting the procedure, all children tolerated leukapheresis without any adverse reaction. After termination of leukapheresis there was a significant decrease of all determined hematological parameters, as compared with pre-harvest values. The mean mononuclear cell recovery was 64% (+/-26%), and in 25/35 (71%) harvesting procedures the minimum progenitor number required for safe autografting could be obtained by one single leukapheresis. We conclude that the Fresenius AS 104 blood cell separator provides a high cell yield and is a safe device for leukapheresis in pediatric patients.

Cell birth and death in childhood acute lymphoblastic leukaemia: how fast does the neoplastic cell clone expand?

In 23 children with untreated precursor B‐cell acute lymphoblastic leukaemia (ALL), the daily growth rate of the malignant cell clone was calculated. Cell birth expanded the leukaemic cell clone an average 10–11% per day, programmed cell death or apoptosis reduced the leukaemic cell mass by some 4% per day. From these two variables a net increase in the size of the leukaemic cell population of 6.9 ± 7.3% (range −1.2–27.3%) per day could be calculated. The daily growth rate correlated negatively with the logarithm of the duration of clinical symptoms before the diagnosis of ALL was established (r=−0.680; P = 0.0004). A long history, especially in children with undefined bone pain and arthralgias, was associated with a very slow expansion of the neoplastic cell clone.

Fever in neutropenia in children and adolescents: Evolution over time of main characteristics in a single center, 1993–2001

Goals of workTo assess the evolution over time of main characteristics of episodes of fever in severe chemotherapy-induced neutropenia (FN) in children and adolescents with cancer treated for FN following nonmyeloablative chemotherapy, to compare the results with the experiences of other centers, and to assess the impact of the changes found on management of FN and on risk prediction rules.Patients and methodsRetrospective cohort study of all children and adolescents up to 18 years presenting with FN in a single pediatric oncology unit between 1993 and 2001.Main resultsIn 132 patients, 364 episodes of FN were reported. The relative incidence of FN increased significantly over time in patients with precursor B-cell acute lymphoblastic leukemia (PBC-ALL), reflecting the increased intensity of chemotherapy. At presentation with FN, the proportions of patients (1) with PBC-ALL versus other malignancies, (2) with other malignancies being in complete remission, (3) with a central venous catheter, and (4) with shaking chills all significantly increased over time (overall proportions, 64%, 60%, 50%, and 5%, respectively; p <0.001 for all). In 337 (93%) episodes, ceftriaxone plus amikacin was used as empirical broad spectrum antimicrobial therapy.ConclusionsThis study demonstrates that some characteristics of FN, though not necessarily its management, change over time, implying regular update of risk prediction rules. In contrast to other centers, the first-line antimicrobial therapy did not need modification because of changing resistance patterns.

Single Institution Experience with Mobilization, Harvesting, and Reinfusion of Peripheral Blood Stem Cells in Children with a Solid Tumor or Leukemia

The aim of our single center pilot study was to evaluate the feasibility of peripheral blood stem cell autotransplantation (PBSCT) in a pediatric population. Only children with solid and hematological malignancies and poor prognosis who were without a HLA-identical bone marrow donor were included in this study. Mobilization of PBSC was done by treatment with myelosuppressive chemotherapy followed by recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Circulating progenitor cells were harvested by a total of 24 leukaphereses on an AS 104 cell separator in eight patients. Seven patients had undergone conditioning with high-dose chemotherapy with or without irradiation prior to PBSCT. All patients showed a rapid hematological recovery, although reconstitution of thrombopoiesis was incomplete in three children. We conclude that PBSCT is feasible in childhood and that it results in a rapid hematologic recovery.

In childhood acute lymphoblastic leukemia the hypophosphorylated retinoblastoma protein, p110RB, is diminished, as compared with normal CD34+ peripheral blood progenitor cells.

Acute lymphoblastic leukemia (ALL) of childhood arises from dysregulated clonal expansion of immature lymphoid precursor cells that fail to differentiate into functional lymphocytes. The cell-cycling status of ALL cells shares many common features with that of normal CD34+ hematopoietic progenitor cells, such as low number of resting G0 and cycling S phase cells even though the growth fraction is high. Thus, ALL cells should be in a long G1 phase. Phosphorylation of the retinoblastoma protein is a crucial step in cell-cycle progression from G0/early G1 to late G1/S phase. We therefore analyzed the G1 distribution of these two immature cell populations by immunostaining and Western blot. Bone marrow samples from children with ALL at diagnosis as well as purified CD34+ cells, before and after in vitro stimulation with cytokines, were investigated for the expression of hypophosphorylated p110RB (early G1 phase), total retinoblastoma protein, statin (G0 phase), bromo-deoxyuridine (S phase), proliferating cell nuclear antigen, and p120 (cycling cells). Compared with unstimulated CD34+ cells (95.8 ± 1.2%) the component of ALL cells containing hypophosphorylated p110RB (16.3 ± 13.2%) was significantly reduced (p = 0.00018), whereas only a minor difference could be detected for the proportion of cycling cells (p = 0.03), and no difference in G0 and S phase cells (p > 0.05). Our results indicate that, as opposed to unstimulated CD34+ cells, the majority of ALL cells are beyond the restriction point and therefore irreversibly committed to DNA replication and mitosis.