Andreas Hirt

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.

L1 (1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with beta-thalassaemia major

Summary L1 was given to eight patients with beta‐thalassaemia major who had previously been treated with deferox‐amine (DF) for 4–10 years. The patients’ages ranged from 11 to 27 years. Serum ferritin values ranged from 1.3 to 11.5 ± 103 pg/l. L1 was given twice daily at a daily dose of 55–80 mg/kg body weight and was continued for 10 months in two patients, 9 months in three, 7 months in two patients and 4 months in one patient. As previously observed with DF, each patients urinary iron excretion (UIE) varied greatly from day to day. The mean UIE of the eight patients ranged from 11 to 49 mg/d (0.2–0.87 mmol/d) on subcutaneous DF and from 16 to 53 mg/d (0.28–0.95 mmol/d) on L1. Two patients excreted significantly more and one patient significantly less iron while on L1. If the UIE was calculated as mmol Fe/mmol creatinine there was no statistically significant difference. Serum ferritin values fluctuated widely in all, with a consistent downward trend in three, no change in four and an increase in one of two non‐splenectomized patients. This patients splenomegaly and need for transfusions continued to increase while on L1. No toxicities attributable to the drug were detected during the period of study and tolerance of the drug was excellent.

Liver iron and fibrosis during long‐term treatment with deferiprone in Swiss thalassaemic patients

Serum ferritin levels, hepatic histology and iron concentration were studied in a ‘veteran’ group of seven Swiss β‐thalassaemic patients after 93–99 months of treatment with the oral iron chelator deferiprone (L1), and another four patients who had received 54–82 months of L1 therapy. Despite continuous compliance, unexplained resurgence of serum ferritin levels occurred in 4/7 patients of the ‘veteran’ group after 4–5 years on L1. In three of these a concomitant increase of liver iron was also observed.

Focal nodular hyperplasia of the liver in children: Review of follow-up and outcome

The authors used a conservative approach to treat focal nodular hyperplasia of the liver (FNH) and were interested in the long-term results of different therapeutic approaches in order to establish the most appropriate treatment. A review of the literature was conducted, and 31 pediatric case reports were identified in which follow-up and outcome data were noted. Tumor resection was performed in 18 cases (58%), operative biopsy alone in nine (29%), vascular ligation in two, and embolization of hepatic arteries in two. The outcome appears to be good for both groups of patients, ie, those with observation alone and those with resection. More information is to be collected regarding the new procedures (embolization and ligation). This is a retrospective analysis, and data from future international prospective studies are needed.

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.

Intravenous immunoglobulin (i.v. IgG) for previously treated acute or for chronic idiopathic thrombocytopenic purpura (ITP) in childhood: a prospective multicenter study

SummaryIn a prospective multicenter study 42 thrombocytopenic (<30×109 platelets/l) children with chronic idiopathic thrombocytopenic purpura (ITP) or with acute ITP, dependent on or refractory to corticosteroids, were given 0.4 g i.v. IgG/kg body weight/day on 5 consecutive days and thereafter once a week if the platelet count fell to <20×109/l or if the patient bled. After the initial 5 days of i.v. IgG the platelets rose within a mean of 7–8 days to >30×109/l in all and to >150×109/l in 33 of 42 patients (79%). After a mean observation time of 26.6 months 26 of 42 patients (62%) showed a satisfactory long-term effect, i.e. no need for treatment for at least 6 months without bleeding and with no platelet counts below 20×109/l. No difference in response rate was found between children with chronic and those with previously treated acute ITP. These results indicate that i.v. IgG could be used to control emergency situations, e.g. to stop bleeding or to prepare a patient for surgery. I.v. IgG also represents a good alternative to treatment modalities, such as splenectomy and/or the administration of cytostatic immunosuppressants with potentially serious side effects. In addition to the expected transient rise in serum IgG levels, i.v. IgG induced a more prolonged elevation of serum IgM. Platelet associated IgG, elevated before therapy, was correlated with the clinical long-term outcome.

Serum levels of mannose-binding lectin and the risk of fever in neutropenia pediatric cancer patients

Fever in neutropenia (FN) is a frequent complication in pediatric oncology. Deficiency of mannose‐binding lectin (MBL), an important component of innate immunity, is common due to genetic polymorphisms, but its impact on infections in oncologic patients is controversial. This study investigated whether MBL serum levels at cancer diagnosis are associated with the development of FN in pediatric cancer patients.

Persisting Renotubular Sequelae after Cisplatin in Children and Adolescents

UNLABELLED Information on persisting renal sequelae after cisplatin in children and adolescents is limited. Twelve patients aged 4-20 years had been treated with cisplatin and were healthy 4-43 months after stopping chemotherapy. Plasma creatinine, calcium, albumin and hydrogen ion concentration, plasma and urinary sodium, chloride, phosphate and urate, and urinary magnesium and potassium were comparable in patients and controls. However, mean calciuria, magnesemia and potassemia were significantly reduced and bicarbonatemia increased in the patients. Calciuria, magnesemia, potassemia and bicarbonatemia were normal in 3 patients only, calciuria was below -2 SD control in 9 patients, renal magnesium deficiency was demonstrated in 5 patients (all with hypocalciuria as well), and 4 patients presented with hypokalemic metabolic alkalosis (all with magnesium deficiency and hypocalciuria). CONCLUSIONS (1) Renotubular dysfunctions persist very often after cisplatin; (2) hypocalciuria is more frequent than hypomagnesemia; (3) the most severe tubulopathy after cisplatin includes hypocalciuria, renal magnesium deficiency and hypokalemic metabolic alkalosis.

Predicting bacteremia in children with cancer and fever in chemotherapy-induced neutropenia : results of the prospective multicenter SPOG 2003 FN study

Study Aim: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance. 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 bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results: Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥3, the score—simplified into a low-risk checklist—predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%. Conclusions: This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.

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.