Role of fibrinolytic and clotting parameters in the diagnosis of liver veno-occlusive disease after hematopoietic stem cell transplantation in a pediatric population.

Hepatic veno-occlusive disease (VOD) is a severe complication after hematopoietic stem cell transplantation (HSCT). Recent studies, mainly in adults receiving HSCT, have identified an increase in the plasminogen activator inhibitor-1 (PAI-1) as a possible marker of VOD. To confirm this finding, the fibrinolytic, coagulation and liver function parameters were assayed before and weekly for 1 month after 61 HSCT performed in 53 consecutive children. Non-VOD patients had a slight increase in t-PA antigen, fibrinogen and P-selectin levels, as well as a mildly longer aPTT and a drop in antithrombin after HSCT. The 6 children with VOD (9.84%) had an early and significant increase in PAI-1 antigen and activity (p<0.0001), t-PA antigen (p<0.0001) and D-dimer (p<0.01) levels, and a decrease in plasminogen, alpha 2-antiplasmin and PT emerged 2(+/-1) days before the clinical diagnosis of VOD by comparison with mean post-HSCT values in the non-VOD patients. Significant differences were also detected for these parameters and antithrombin levels between non-VOD and VOD patients soon after the clinical onset of VOD, whereas the rise in bilirubin levels became significant only later on. In conclusion, variations in fibrinolytic test findings after HSCT, and PAI-1 in particular, may facilitate the early diagnosis of VOD in pediatric patients after HSCT.

A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Veno-occlusive disease (VOD) is one of the most frequent complications after stem cell transplantation. We conducted a prospective survey of 244 hematopoietic stem cell transplants in children to determine the incidence of VOD, its main risk factors, treatment and effect on the transplant. DESIGN AND METHODS: Two hundred and forty-four hematopoietic stem cell transplants (HSCT) performed in 220 pediatric patients from 1993 to 2003 were evaluated. The series included 127 males and 93 females with a median age of 6.7 years at the time of transplantation. RESULTS: VOD was diagnosed following 26 of the 244 transplants (cumulative incidence 11%), but a higher incidence was found in patients with at least one known risk factor for VOD (cumulative incidence 20%). In multivariate analysis, risk factors for VOD were age < 6.7 years; type of VOD prophylaxis, and busulphan-containing conditioning regimens. Routine treatment of VOD was based on supportive care and, starting from 1999, defibrotide was used. All patients were monitored with daily Doppler ultrasound-(US) for early diagnosis of inversion of portal blood flow. Twelve patients developed inversion of portal flow (9 had severe VOD; 3 had moderate VOD) and were promptly started on fibrinolytic and anticoagulant therapy with heparin and recombinant tissue plasminogen activator (rt-PA). Hepatic flow reverted to normal in all 12 patients; only 4 patients ultimately developed multiorgan failure and died. The transplant-related-mortality (TRM) rate in patients with or without inversion of portal flow was 33% vs 7%, (p=0.1). The TRM in patients with or without VOD was 19% vs 8% (p=0.001). INTERPRETATION AND CONCLUSIONS: This study showed that younger age, type of VOD prophylaxis, and busulphan-based conditioning regimens are independent risk factors for VOD. Inversion of portal flow was found in 9 of 10 patients with severe VOD. Doppler US monitoring may be helpful in early identification of the patients with VOD-induced inversion of portal flow who might benefit from therapy with heparin and rt-PA.

Parental narratives of quality of life in children with leukemia as associated with the placement of a central venous catheter.

Thirty mothers of children with leukemia were interviewed about the child's and family's daily routines using a version of the Ecocultural Family Interview. Parental narratives were analyzed qualitatively and quantitatively. Four broad dimensions, encompassing 23 subthemes, were identified: child coping (alpha=0.88), child quality of life (alpha=0.72), parental coping (alpha=0.72), and parental trust in the medical care (alpha=0.73). Two objective variables were drawn from the medical charts (time from the diagnosis, time from central venous catheter [CVC] placement). Regression analyses showed that the number of days from the CVC placement (beta=0.46) and child coping (beta=0.44) significantly predicted children's quality of life, which in turn predicted parental trust in the medical care (beta=0.31). The methodological implications of our narrative approach are discussed.

Psychosocial life achievements in adults even if they received prophylactic cranial irradiation for acute lymphoblastic leukemia during childhood.

The aim of this study was to assess life goal achievements in long-term survivors (LTS) receiving cranial radiotherapy (CRT) as central nervous system (CNS) prophylaxis for acute lymphoblastic leukemia (ALL) during childhood, compared to healthy individuals. Participants in this study were 141 LTS treated in our center from 1961 to 1990. Questionnaires were mailed to LTS. Analyses were stratified by age classes comparing LTS and a matched healthy population living in the same geographic area, as well as comparing patients treated with 24 Gy vs. 18 Gy CRT. Survivors reached the same educational level as controls. Significant differences were noted according to age and CRT dose. LTS had similar employment rates to those of controls, but lower marriage rates. Most respondents described their life positively, but as worse in the 24 Gy group. This study highlights the good life satisfaction of our LTS despite the long-term effects of the disease and its treatment.

Prospective, randomized trial of two different modalities of flushing central venous catheters in pediatric patients with cancer.

PURPOSE: There are limited prospective data on whether the method of flushing affects the complication rate of tunnelled central venous catheters (CVCs). PATIENTS AND METHODS: During a 25-month period, 203 pediatric patients who had newly placed Broviac-Hickman CVCs were randomly assigned to standard flushing with heparin solution or to experimental flushing with normal saline via a positive-pressure cap. RESULTS: Two hundred twenty-one complications were recorded among 75,249 CVC-days (2.94 per 1,000 CVC-days). A higher incidence of CVC occlusion (83 v 41 episodes; P = .0002) and bacteremia (24 v 9; P = .01) were found in the experimental arm. The cumulative probability of developing at least one CVC complication was higher in the experimental arm than in the standard arm (65.1% [95% CI, 55% to 75%] v 43.8% [95% CI, 34% to 54%], respectively; P = .01). No difference was found in either the cause or the frequency of premature removal of CVCs between the two study arms. After a median follow-up of 360 days (range, 4 to 1,073), CVC survival was similar: 77% (95% CI, 66% to 84%) for the experimental arm and 69% (95% CI, 53% to 80%) for the standard arm (P = .7). The factors associated with the occurrence of CVC complication were a diagnosis of leukemia/lymphoma, double-lumen CVC, and experimental flushing. The only factor significantly associated with premature removal of a CVC was a diagnosis of leukemia/lymphoma (hazard rate, 2.3; 95% CI, 1.1 to 4.7). CONCLUSION: An increased complication rate was found with normal saline flushing, but additional investigation is warranted to clarify whether it is related to saline use or to once-a-week flushing.

Mesenchymal stromal cells can be derived from bone marrow CD133+ cells: implications for therapy.

It is known that the bone marrow (BM) CD133(+) cells play an important role in the hematopoietic compartment, but this is not their only role. The cells indeed can take part in vascular reconstitution when they become endothelial cells (EC), in skeletal muscle fiber regeneration when there is a switch in muscle precursors, and to cardiomyocyte phenotypic conversion when differentiating in cardiomyocytes-like cells. While the role in hematopoiesis and vasculogenesis of the selected cells is well established, their ability to differentiate along multiple non-EC lineages has not yet been fully elucidated. The goal of this study is to assert whether human CD133(+)BM-derived cells are able to differentiate in vitro, besides to blood cells, cell lineages pertinent to the mesoderm germ layers. To this end, we isolated CD133(+) cells using a clinically approved methodology and compared their differentiation potential to that of hematopoietic progenitor cells (HPCs) and mesenchymal stem cells (MSCs) obtained from the same BM samples. In our culture conditions, CD133 expression was consistently decreased after passage 2, as well as the expression of the stemness markers c-kit and OCT4, whereas expression of Stage Specific Embryonic Antigen 4 (SSEA4) remained consistent in all different conditions. Expanded CD133 were also positive for HLA-ABC, but negative for HLA-DR, in accordance with what has been previously reported for MSCs. Moreover, CD133(+) cells from human BM demonstrated a wide range of differentiation potential, encompassing not only mesodermal but also ectodermal (neurogenic) cell lineages. CD133 antigen could be potentially used to select a cell population with similar characteristics as MSCs for therapeutic applications.

Musculoskeletal manifestations in pediatric acute leukemia.

BACKGROUND: In children, acute leukemia (AL) at presentation can mimic several orthopaedic pathologies, so that a variable delay of the correct diagnosis is often reported. METHODS: To define more clearly the clinical and radiological musculoskeletal manifestations of leukemia in children, 122 affected children referred from 1984 to 1999 to our Pediatric Onco-Hematologic Clinic were retrospectively reviewed. Average age at diagnosis was 6.6 years (from 7 months to 17 years). Seventy-three (60%) were boys and adolescent boys, 49 (40%) were girls and adolescent girls. One hundred two (83.6%) had acute lymphoblastic leukemia, 20 (16.4%) had acute myeloid leukemia. The mean follow-up was 8.2 years for the 104 survivors and 2.5 years for the 18 nonsurvivors. The chi2 test was used to perform the statistical analyses. RESULTS: At presentation, complaints related to the musculoskeletal system were frequent (38.3%), including pain (34.4%), functional impairment (22.9%), limping (12.3%), swelling (10.6%), and joint effusion (5.7%). At presentation, 40.2% of children had at least 1 radiographic abnormality. In order, they were osteolysis (13.1%), metaphyseal bands (9.8%), osteopenia (9%), osteosclerosis (7.4%), permeative pattern (5.7%), pathological fractures (5.7%), periosteal reactions (4.1%), and mixed lysis-sclerosis lesions (2.5%). Different from previous reports, late radiographic lesions were uncommon (5.7%), probably because of milder newer medication protocols. They included avascular necrosis (3.3%), vertebral collapses (1.6%), and osteolysis (0.8%). CONCLUSIONS: Both clinical and radiological changes had various and no uniform localization. Poor correlation was found between symptoms and radiological lesions. Survival rates in children with AL were 95.8% at 1 year, 89.6% at 3 years, 85.8% at 5 years, and 83.4% at 10 and at 13 years. Radiographic abnormalities (P = 0.400), type of leukemia (P = 0.291), sex (P = 0.245), and white blood cell count at presentation (P = 0.877) were not prognostic factors. The presence of multiple bone lesions did not affect the survival rate (P=0.632). As early diagnosis significantly decreases morbidity and mortality of AL, the orthopaedist should suspect AL in any child with unexplained persistent skeletal pain or radiographic alterations. Accurate history, general physical examination, and complete blood cell count tests should address the suspicion, which is confirmed by a peripheral and/or iliac crest bone marrow biopsy.

Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood.

PURPOSE: To study the prevalence of t(8;14) at diagnosis and the response kinetics to treatment of minimal residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) patients and determine its impact on prognosis. PATIENTS AND METHODS: A total of 68 children affected by de novo B-ALL enrolled onto the Berlin-Frankfurt-Muenster-based Italian Association of Pediatric Hematology and Oncology LNH-97 clinical protocol were studied. Bone marrow aspirate from each patient was analyzed for the presence of t(8;14)(q24;q32) by long-distance polymerase chain reaction at diagnosis, after the first chemotherapy cycle, and after subsequent cycles until negative for MRD. Morphologic and immunophenotypic analyses were reviewed centrally. RESULTS: A total of 47 patients (69%) were positive for t(8;14)(q24;q32). MRD response kinetics was determined in 39 patients. All of them reached clinical complete remission and most (31 of 39) became MRD negative after the first chemotherapy cycle. The 3-year relapse-free survival (RFS) was 38% (SE = 17%) in patients MRD positive after the first chemotherapy cycle compared with 84% (SE = 7%) in MRD-negative patients (P = .0005), whereas there was no difference in RFS for children who reached a clinical complete remission after the first chemotherapy cycle versus those who did not (RFS = 72% and SE = 9%; RFS = 79% and SE = 11%, respectively; P = .8). In multivariate analysis, MRD was shown to be predictive of higher risk of failure. CONCLUSION: Our study demonstrated that MRD carries a negative prognostic impact in B-ALL patients and suggests that a better risk-adapted therapy, possibly including the use of anti-CD20 monoclonal antibody, should be considered in selected patients.

Pediatric patients with essential thrombocythemia are mostly polyclonal and V617FJAK2 negative.

Essential thrombocythemia (ET) is rare in children, and little or no information is available about clonality or JAK2 mutations. However, the analyses in this work prove useful for the diagnosis of adult myeloproliferative disorders (MPDs). We evaluated the clonality status and V617FJAK2 mutation in 20 children affected by ET and compared them with 47 consecutive adult ET cases. Clonality was evaluated on the DNA of granulocytes and on the RNA of platelets. V617FJAK2 was analyzed by sequencing tests, allele-specific polymerase chain reaction (PCR), and digestion by BsaXI. A monoclonal pattern was found in 4 (28.5%) of 14 children and in 45% of informative adults. Heterozygous V617FJAK2 was found less frequently in children than in adults (P < .009). Only 2 girls showed both the V617FJAK2 mutation and a monoclonal pattern; one of them was the only child presenting a major thrombotic complication. In contrast to adults, most children with ET do not show either a clonal disorder or the V617FJAK2 mutation.

Isolation of mesenchymal stem cells from human vermiform appendix.

BACKGROUND: Recent findings have shown that pluripotent stem cells exist in areas outside the bone marrow (BM). Moreover, it has been demonstrated that the appendix is important for the development of mucosal gut immunity, and hematopoietic progenitors have been isolated from animal and human appendices. MATERIALS AND METHODS: Non-inflamed appendices removed during laparotomy were processed and cultured until the appearance of adherent cells. Differentiations (performed under osteogenic, adipogenic, and myogenic conditions) were confirmed by immunohistochemistry and cytochemistry. Polymerase chain reaction and cytofluorimetric analyses were performed to evidence the presence of genes and protein specific lineages in appendix-derived mesenchymal stem cells (ADMCs). RESULTS: ADMCs were present in non-inflamed appendices. ADMCs under osteogenic conditions differentiated in osteoblasts and showed increased alkaline phosphatase expression; at the gene level, we observed the expression of Core binding factor alpha 1 (Cbfa1) and osteocalcin in osteogenic induced ADMCs. Under adipogenic conditions, lipidic drops in the cytoplasm, expression of lipoprotein lipase (LpL), and peroxisome proliferator-activated receptor gamma were observed; under myogenic conditions, myotubes expressing muscle specific proteins like desmin were formed. Myogenic regulatory factor 4 and MyoD were selectively induced in the ADMCs under myogenic conditions. CONCLUSIONS: This study shows for the first time that mesenchymal stem cells can be isolated from normal appendices obtained from a pediatric and adult age group (0-18 years of age). This finding not only may further knowledge of the maturation of the intestinal immunesystem but also could indicate a new physiological role of the human vermiform appendix.

Conversational strategies with parents of newly diagnosed leukaemic children: an analysis of 4880 conversational turns.

GOALS OF WORK: Communication with parents of children newly diagnosed with cancer poses a number of problems, mostly due to the psychological effects of parental trauma. This study was designed to answer the following questions: How can we sustain the flow of communication with parents of children newly diagnosed with leukaemia so that it may become easier and more effective? What should we say to gather more reliable information from parents? How can we help empower their coping strategies? PATIENTS AND METHODS: We analysed 4880 conversational turns in individual conversations carried out between psychologists and 21 parents of children with leukaemia. The conversations were aimed at gathering information of the families' daily routines. Dialogues were audiotaped and fully transcribed. The type and frequency of speech acts present in each turn were coded along 18 categories by two independent judges (inter-rater agreement, Cohen Kappa =0.73). MAIN RESULTS: The parental speech acts expressing emotion in various ways go up to 58% of the total number of their speech acts. The lag-sequential analysis showed that such expressions are not associated with any of the interviewer's speech act. The same analysis showed that, by contrast, the interviewer's style has an effect upon the cognitive aspects of parents' conversation. Support of hope favoured parental ability to identify their coping strategies. Explicit requests, confirmations such as "sure" and key words summarizing parents' viewpoints are followed by parental factual and objective narratives. CONCLUSIONS: Based on these results, a few practical recommendations for health care professionals are given in order to better communicate with parents of children newly diagnosed with cancer.

The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation.

To assess a real-time polymerase chain reaction-based modulation of immunosuppression in patients with an increasing Epstein-Barr virus (EBV) viral load, we studied 79 paediatric allogeneic stem cell transplantations (allo-SCT) performed between January 1998 and December 2003. EBV reactivation was observed in 42 of 79 patients (53%) after a median time of 45 d from allo-SCT: 37 (88%) and five (12%) patients had received the graft from an unrelated and a related donor respectively (P = 0.001). Twenty-eight patients (67%) had a viral load > or =300 genomic copies x10(5) peripheral blood mononuclear cells (PBMC) and antithymocyte globulin was the only factor significantly associated with EBV reactivation (P = 0.001, RR 7.1). Among these 28 patients, immunosuppression was suspended and reduced in 17 and 11 patients respectively. Overall, post-transplant lymphoproliferative disease was diagnosed in one of 79 patients (1%). The pre-emptive modulation of immunosuppression in patients with EBV reactivation and a viral load > or =300 genomic copies x10(5) PBMC did not negatively influence transplant-related mortality, overall survival or event-free survival. In conclusion, EBV reactivation is frequent even in 'low risk' patients and the pre-emptive modulation of immunosuppression enables it to be managed safely, with no significant flare in graft-versus-host disease status.

Anaplastic large cell lymphoma treated with a leukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol.

BACKGROUND: Childhood anaplastic large cell lymphoma (ALCL) is a well defined entity with a rather poor prognosis. Different approaches have been adopted in the treatment of ALCL in various cooperative trials, including short high-dose intensive therapy and leukemia-like protocols. In the early 1990s, the Italian Association of Pediatric Hematology and Oncology (AIEOP) initiated a multicenter trial for the treatment of ALCL based on a modified LSA2-L2 protocol. METHODS: Thirty-four consecutive eligible children with newly diagnosed ALCL were enrolled in the AIEOP LNH-92 protocol. Treatment was comprised of an induction of remission phase, followed by consolidation and maintenance for a total duration of 24 months, independently of disease stage. RESULTS: Thirty of 34 patients (88%) achieved complete disease remission and 8 patients experienced disease recurrence. With a median follow-up of 8.4 years, the probabilities of survival and event-free survival were 85% (range, 79-91%) and 65% (range, 57-73%), respectively. Therapy was well tolerated and hematologic toxicity was the most frequent toxicity. CONCLUSIONS: The leukemia-like protocol AIEOP LNH-92 was found to be an effective treatment for childhood ALCL. Its long duration may be beneficial to specific patient subgroups, but optimal treatment duration in ALCL remains to be elucidated.

Successful treatment with the monoclonal antibody rituximab in two children with refractory autoimmune thrombocytopenia.

UNLABELLED: Rituximab is a chimeric monoclonal antibody directed against normal and malignant mature B-lymphocytes and results in prolonged and severe B-cell depletion. Recently, rituximab has been successfully used in adult and paediatric disorders of B-lymphocytes such as autoimmune haemolytic anaemia and Werlhof disease. We report on two children with chronic immune thrombocytopenic purpura (ITP) refractory to steroids and immunoglobulins who achieved complete normalisation of their platelet counts after treatment with rituximab, 375 mg/m2 given weekly in four doses. In both cases the B-lymphocyte count dropped to zero after the second dose of rituximab and an unsupported platelet count > 100 x 10(9)/l was achieved during treatment. Six and 12 months after treatment, both patients remain well with normal platelet counts. CONCLUSION: This report supports the concept that rituximab may also be a valuable therapeutic option in children with chronic immune thrombocytopenic purpura refractory to standard treatment. Controlled clinical trials are needed to evaluate the efficacy and long-term side-effects of rituximab in this group of patients.

Markers of endothelial function in pediatric stem cell transplantation for acute leukemia.

BACKGROUND: Endothelial cells and leukocytes intimately interact in inflammation and coagulation processes, so that dysregulation of their function may lead to both cellular damage and thrombosis, which may occur as complications of bone marrow transplantation (BMT). Partially conflicting evidence about endothelial markers and their relationships with clinical complications after BMT has been reported in the literature. Since almost all studies were carried out in adults, we evaluated some recent available markers of endothelial cell function in pediatric patients undergoing stem cell transplantation (SCT) for acute leukemia. PROCEDURE: We studied the variation in circulating serum endothelial-selectin (ES), leukocyte-selectin (LS), thrombomodulin (TM), von Willebrand factor (vWF), nitrate + nitrite (NO(2) (-)/NO(3) (-)), endothelin-1 (EN), and tissue factor (TF) in 21 pediatric patients undergoing SCT for acute leukemia. RESULTS: ES and LS significantly lowered following SCT and returned to pre-SCT levels 4 weeks after the procedure. NO(2) (-)/NO(3) (-) markedly increased following SCT. Also, TM and vWF increased, although such changes did not reach statistical significance. EN and TF did not appreciably change. A strong correlation was observed between white blood cell (WBC) count and both ES and LS, as well as between such selectins. TM significantly correlated with both selectins and NO(2) (-)/NO(3) (-). The pre-conditioning levels of TM and vWF in patients undergoing major complications, considered altogether, were significantly lower and higher, respectively, than in uncomplicated patients. NO(2) (-)/NO(3) (-) levels 3 and 4 weeks post-SCT were significantly lower in patients suffering from veno occlusive disease. Both selectins were significantly higher in allo- than in auto-transplanted patients 4 weeks after SCT. CONCLUSIONS: Our data support the hypothesis of severe endothelial damage after conditioning and SCT, particularly allogeneic. However, the increase in TM, which has strong anticoagulant properties, and metabolites of NO, involved also in protective actions, may reflect regeneration of the anti-thrombotic endothelial function. This could take place after transitory functional impairment, rather than pure endothelial damage.

Granulocyte transfusions from G-CSF-stimulated donors for the treatment of severe infections in neutropenic pediatric patients with onco-hematological diseases.

From March 1994 to January 2001, 15 courses of granulocyte transfusion (GTX) were administered to 13 neutropenic patients (6 male and 7 female patients; median age 7 years, range 3 months to 14 years) affected by: acute lymphoblastic leukemia (ALL) in 6 cases, acute myeloid leukemia (AML) in 5, very severe aplastic anemia in 1, and familial erythrophagocytic lymphohistiocytosis (FEL) in 1. Infections were classified as microbiologically defined and clinically defined infections in 8 and 7 episodes, respectively. Before the GTX transfusions, broad-spectrum antibacterial and antifungal therapy had been administered for a median of 12 (range 5-28) and 8 days (range 2-50), respectively, with no improvement. G-CSF was administered prior to GTX in 9 episodes of infection, with a median of 9 days of treatment (range 4-30). Leukapheresis was obtained from 15 related donors (father, 10; mother, 3; sister, 1; aunt, 1) after s.c. stimulation with G-CSF, 300 micro g daily, starting from day -3 (where day 0 was the day of the first granulocyte collection) and continuing throughout the period of GTX treatment. The donors' median white blood cell (WBC) count at leukapheresis was 31.6 x 10(9)/l (range 12-56), and the median yield was 31.39 x 10(9) WBC (range 2.96-64.73 x 10(9)), with a proportion of PMN of 90-95%. Overall, 70 GTX were administered, with a median of 4 GTX per episode of infection (range 2-11). The combination of GTX with antimicrobial therapy led to complete or partial recovery in 6 and in 3 of 15 episodes (60%), respectively. Priming of the donor with G-CSF was well tolerated, the most common side-effects being bone pain, malaise and paresthesia. All donors are alive and well after a median of 4.5 years (range 0.8-7.7) from donation. We conclude that GTX is potentially useful when the severity of the infection and the host's immunodeficiency make any other antimicrobial treatment ineffectual. Long-term safety data on the stimulation of donors with G-CSF have been reassuring to date. Further controlled studies are needed to assess the exact role of GTX in the outcome of neutropenic patients with severe infection and any criteria for patient selection and the timing of GTX administration.

Voriconazole for invasive aspergillosis in oncohematological patients: a single-center pediatric experience.

Voriconazole is a new triazole active orally and parenterally that recently proved effective in the treatment of invasive aspergillosis and in empirical antifungal therapy for persistently febrile neutropenic patients. Limited data are available for pediatric patients. We report our experience with voriconazole in seven children with invasive aspergillosis, i.e., four girls and three boys with a median age of 5 (range 2-13) years affected by acute lymphoblastic leukemia (3), acute myeloid leukemia (2), refractory anemia with excess of blasts (1), and severe aplastic anemia (1). First-line therapy in all patients was liposomal amphotericin B (AmBisome) administered at a dosage of 3-5 mg/kg day. Voriconazole was administered for a median 8 (range 2-15) weeks. Response was complete and partial in two patients, respectively, stable in one, and there was no response (failure) in two. The voriconazole treatment was well tolerated. Four patients died-two of progressive aspergillosis. Three patients are alive and well 6, 5, and 4 months after the diagnosis of aspergillosis. Voriconazole appears to be an effective salvage treatment for invasive aspergillosis in pediatric patients, with good responses in patients who recover from neutropenia or are not relapsing.

Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy.

BACKGROUND: To evaluate the effect of chemotherapy on humoral immunity to vaccine-preventable disease, the authors investigated the persistence of protective antibody titers in a group of patients who were alive and well after they were treated for pediatric malignancies. METHODS: Serum antibody levels were evaluated for polio, tetanus, hepatitis B, rubella, mumps, and measles in 192 children. The terms lack of immunity and loss of immunity, respectively, were used to describe the absence of immunity in patients who were tested only after chemotherapy and in patients who were tested both before and after chemotherapy and determined to have immunity before chemotherapy. RESULTS: Overall, the absence of a protective serum antibody titer for hepatitis B, measles, mumps, rubella, tetanus, and polio was detected in 46%, 25%, 26%, 24%, 14%, and 7% of patients, respectively. On univariate analysis, loss of antibodies against rubella, mumps, and tetanus was associated significantly with younger age (P < 0.001, P = 0.02, and P = 0.001, respectively), and loss of antibodies against measles was significantly associated with younger age and female gender (P = 0.0003 and P = 0.008, respectively). The administration of 59 booster vaccinations to 51 patients who had lost > or = 1 protective antibody titer resulted in an overall response rate of 93%. CONCLUSIONS: Chemotherapy induced different rates of loss of protective antibody titers depending on the type of vaccination administered. This finding may be responsible for the failure of vaccination programs for patients who have undergone chemotherapy. The administration of a booster dose after the completion of chemotherapy is a simple and cost-effective way to restore humoral immunity against most vaccine-preventable diseases.

Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis.

OBJECTIVE: Data on the use of combination of liposomal amphotericin B and caspofungin followed by voriconazole, as maintenance or further rescue treatment, in 10 patients with invasive mycosis are reported. MATERIAL AND METHODS: The diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkin's lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6; and possible, 1) refractory to first-line antifungal treatment (liposomal amphotericin B in all patients except one who received fluconazole). RESULTS: Rescue therapy with a combination of caspofungin and liposomal amphotericin B was well tolerated, hypokalemia, and thrombophlebitis being the most common side-effects. Combination therapy was administered for a median of 17 d, range 6-40. Among the nine patients with proven or probable mycosis, one was not evaluated because of early death caused by massive hemoptysis whilst in the remaining eight patients, the response was classified as complete, stable and failure in four, three, and one patients, respectively. Complete response was also observed in patient with possible mycosis. Eight of nine patients received voriconazole for a median of 75 d, range 42-194. Voriconazole was well tolerated although some drug interactions were observed during treatment with methotrexate and digoxin. After a median follow-up of 125 d, nine of 10 patients are alive. Overall, a favorable response to antifungal treatment (including the case of possible mycosis) was obtained in eight of 10 patients. CONCLUSION: These data suggest that medical antifungal treatment may be intensified in severely ill patients without significantly compromising patient safety. The combination of synergistic antifungal drugs as well as their sequential use warrants further investigation by a larger randomized controlled study.