Cytomegalovirus infection in pediatric allogenic hematopoietic stem cell transplantation. A single center experience.

We report a retrospective analysis of Cytomegalovirus (CMV) infection: incidence, recurrence, resistance, and subsequent disease of 81 children who underwent allogenic hematopoietic stem cell transplantation (HSCT). The recipient and/or donor's CMV serology was positive prior to transplant [recipient (R+) and/or donor (D+)]. CMV was monitored by RT-PCR starting from the first week post transplant. Forty patients showed CMV infection (49, 5%). Of them 10 manifested CMV disease leading to four deaths. In univariate analysis, factors associated with CMV infection were CMV R+ P < .01, CMV R+/D+ pair P < .01, nonbone marrow (BM) stem cell source P < .05, nonirradiation conditioning regimen P < .05, Antithymocyte globulin (ATG) P < .01. Factors associated with CMV resistance were: >1 HLA allele mismatch P < .05, CMV R +/D-pair P < .01, CMV D-P < .01, non-BM P < .05, nongenoidentical transplant P < .01. CMV disease was influenced by >1 HLA allele mismatch (P < .001), non-BM (P < .01). On multivariate analysis, CMV R+/D- (P < .05), corticosteroids ≥2 mg/kg P < .01, ATG P < .01 and non-BM (P < .05) were independent factors for CMV infection. CMV R+ transplant is associated with more CMV infection and resistance to preemptive treatment. Prolonged immune suppression (IS) worsens outcome of CMV infection and should be shortened whenever possible.

Double reduced-intensity allogeneic hematopoietic stem cell transplantation: a retrospective study from the SFGM-TC.

The purpose of this paper is to describe the outcome of patients who underwent double allogeneic hematopoietic stem cell transplantation (AHSCT) with reduced-intensity conditioning regimens (RIC). Forty-five patients who received double RIC-AHSCT between 1997 and 2006 were retrospectively studied. The predominant diagnosis was acute myeloid leukemia (AML) (n = 17). Other diagnoses were aplasic anemia (AA) (n = 5), myelodysplasic disorder (n = 5), acute lymphoblastic leukemia (ALL) (n = 4), chronic myelomonocytic leukemia (CML) (n = 3), myeloma (n = 3), non-Hodgkin lymphoma (NHL) (n = 3), chronic lymphocytic leukemia (CLL) (n = 2), Hodgkin's disease (HD) (n = 2), and chronic myelomonocytic leukemia (n = 1). Main indications for RIC-AHSCT 2 were relapse (n = 25, 56%) and early (n = 8, 18%) or late (n = 12, 26%) graft failure. Median delays to reach a neutrophil count of 0.5 × 10(9)/L and platelet counts of 50 × 10(9)/L were significantly smaller after the second AHSCT. Among 25 patients who relapsed after RIC-AHSCT 1, 14 patients (56%) presented a response improvement after RIC-AHSCT 2. In this group, 9 patients sustained a complete response and 5 patients a partial response. Moreover, among the 20 patients who had early or late graft failure following RIC-AHSCT 1, 9 (45%) finally reached an engraftment. Disease-free survival (DFS) was significantly improved after RIC-AHSCT 2. Thirteen patients (28%) died of transplant-related mortality (TRM) at a median delay of 69 days (range: 0-451) after RIC-AHSCT 2. Double RIC-AHSCT is a feasible procedure that allows a response or engraftment not observed after RIC-AHSCT 1. The main indication is relapse. However, TRM remains high.

[Disseminated nocardiosis in a child with acute lymphoblastic leukemia]. / Nocardiose viscérale disséminée chez un enfant atteint de leucémie aiguë lymphoblastique.

Nocardiosis is a rare infectious disease in children. We report here a disseminated nocardiosis in a child with acute lymphoblastic leukemia. The patient presented prolonged febrile neutropenia and nodular pneumopathy. Based on the amplification of a 16S rDNA, a PCR assay detected Nocardia sp. in the patient's bronchoalveolar lavage (BAL) fluid. Culture of BAL samples yielded Nocardia nova colonies after 2 weeks of incubation. Hepatic, splenic, renal and cerebral localisations were detected on extension checkup. trimethoprime-sulfamethoxazole and amikacine were started given the results of PCR assay, with a good response. Improvement of the patient's general condition led to complete chemotherapy under ciprofloxacine and ceftriaxone treatment, without nocardiosis reactivation. Nocardiosis is a rare complication in children with acute lymphoblastic leukemia. trimethoprime-sulfamethoxazole prophylaxis is widely used to prevent Pneumocystis jiroveci infection in children with haematologic malignancies. As Nocardia species are usually sensible, trimethoprime-sulfamethoxazole could play a role in Nocardia prophylaxis in such population. In our patient, compliance with trimethoprime-sulfamethoxazole had been low. Nocardia species are relatively fastidious growth bacteria and are difficult to isolate with classical bacteriological techniques. Molecular methods are now available, with a good sensitivity and fast results allowing to start an appropriate antibiotherapy before culture results, as early treatment is a major prognosis factor in nocardiosis. Nocardia infection should be suspected in case of nodular pneumopathy in immunocompromised children. An extension checkup should be performed to detect secondary localisations.

Inhibition of normal lymphocyte proliferation by Indirubin-3'-monoxime: a multifactorial process.

Indirubin-3'-monoxime (IO) is a derivative of Indirubin, compound of a Chinese medicinal recipe used to treat various diseases including leukemia. In this study, we investigated to what extent IO inhibits the growth of normal human lymphocytes. We defined various experimental conditions of peripheral blood lymphocyte treatment: IO introduced (i) on unstimulated lymphocytes, (ii) or on stimulated lymphocytes at the time of phytohemagglutinin stimulation (L1 protocol), (iii) 48 h after the beginning of stimulation (L2 protocol), and (iv) after nocodazole synchronization of stimulated lymphocytes. IO induces a concentration dependent cytotoxic effect yielding a characteristic sub-G1 peak in normal stimulated lymphocytes. Cell death was partly due to necrosis and apoptosis. Normal unstimulated lymphocytes remained insensitive to the cytotoxic effect of 10 microM IO treatment. A cell cycle inhibition was observed after IO treatment, stronger for the L1 than for the L2 protocol, without induction of polyploidy after Nocodazole synchronization. These cellular consequences were associated with a decrease in CDK activity, and with CDK and cyclin gene expression modifications. The inhibition of lymphocyte proliferation by IO indicates that indirubin derivatives may be potent immunosuppressive agents.

[Human herpesvirus 6 encephalitis after bone marrow transplantation]. / Un cas d'encéphalite à herpès virus humain de type 6 après transplantation de moelle osseuse.

Human herpesvirus 6 (HHV-6) encephalitis may induce neurological sequelae and death; the diagnosis is difficult because of an initially poor symptomatology and of the absence of specific biochemical, electric and radiological signs. We report on a 7-year-old boy with relapsed acute lymphoblastic leukaemia, who developed HHV-6 encephalitis after bone marrow transplantation; the patient recovered after treatment with ganciclovir.

[Thrombocytosis and essential thrombocythemia in childhood]. / Thrombocytoses et thrombocytémies essentielles de l'enfant.

Thrombocytosis is frequently observed in pediatric patients. Among them the secondary thrombocytosis are the most frequent and result from several causes. The rarely primary thrombocytosis can be either constitutive (and often familial) or acquired (essential thrombocythemia). The purpose of this article is to give diagnostic orientation and to suggest which biological tests should be performed.

Lupus nephritis in a child with AIDS.

Concomitant acquired immunodeficiency syndrome (AIDS) and lupus nephritis is an exceptional feature in white patients. A white boy with maternofetal human immunodeficiency virus (HIV) infection had no medical follow-up until he presented at 12 years of age with a nephrotic syndrome, macrohematuria, renal failure, pancytopenia, and low CD4(+) cell count. A renal biopsy revealed severe lupus nephritis (World Health Organization class IV) with specific immune deposits in the absence of any clinical sign of systemic lupus erythematosus or specific autoantibodies at the time of diagnosis. The treatment consisted of methylprednisolone pulses followed by oral prednisone; antiretroviral triple therapy was started a few weeks later, which contributed to clinical and biologic improvement. To our knowledge, this is the first case report of lupus-like nephritis in a white child with AIDS, whose outcome might be improved significantly by a combination of steroids and antiretroviral therapy.

[Metastatic osteosarcoma: prognosis factors and treatment]. / Les ostéosarcomes métastatiques; facteurs pronostiques et traitements.

Long term outcome and prognosis factors of patients with metastatic osteosarcoma were evaluated on 29 observations from 3 centres reviewed retrospectively. Twenty-nine patients less than 18 years old were treated from 1990 to 1998. Only 29 of these patients had received similar treatments associating chemotherapy and surgery, adapted according to histological and clinical response to treatment, as recommended by the SFOP. Overall survival at five years was 26%, and disease free survival 14%. Eight patients are alive, four in first complete remission (CR) and four in second CR. Three of the four patients alive in first CR had bone metastases at diagnosis. On univariate analysis, factors predicting survival are: the numbers of organs affected by metastatic lesions, the number of lung nodules and the type of surgery. This is, to our knowledge, the first report of long term survivors with bone metastases at diagnosis. Metastatic osteosarcoma prognosis remain poor. A randomised study would help to define the best possible treatment for this disease.

[Immunization for children treated for solid tumors: what are the guidelines?]. / Vaccination de l'enfant traité pour tumeur solide: quelle conduite à tenir?

There is no agreement on immunization of children treated with chemotherapy (CT) for solid tumors. Based on a review of the literature, we have attempted to establish guidelines on this subject. Except for hepatitis B vaccine, there is no argument to support the use of vaccine during CT. After a standard CT, a 3-month washout period appears to be necessary before starting an immunization program for a child not previously vaccinated, or to proceed with the recommended booster injections for diphteria anatoxin, tetanus vaccine, poliomyelitis inactivated vaccine, pertussis vaccine, and haemophilus influenza type b vaccine if the child is less than 5 years old. For mumps, measles, and rubella live vaccines, a longer post-CT washout of 6 months is suggested for the initial immunization, or for a revaccination of a child proved to be negative for all three serologies. Following high-dose CT a minimal 12-months term and a normalization of the blood lymphocytes count is necessary before planning booster injections once having checked for antidiphteria, tetanic, polio, measles, mumps, rubella and +/- haemophilus antibody titles. We don't find any reason to recommend a systematic varicella immunization in pediatric oncology. Pneumococcal vaccine is recommended in case of asplenia. Any other vaccination (BCG, influenza, yellow fever) must be evaluated individually.

[Lacidipine efficacy and safety for high blood pressure treatment in pediatric oncohematology]. / Efficacité et tolérance de la lacidipine dans le traitement de l'hypertension artérielle en onco-hématologie pédiatrique.

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.

[Deep vein thrombosis revealing myeloproliferative syndrome in two adolescents]. / Thrombose splanchnique révélatrice d'un syndrome myéloprolifératif chez deux adolescentes.

Deep vein thrombosis occurs in 30% of patients with essential thrombocythemia, but rarely at initial diagnosis. We report two pediatric patients with essential thrombocythemia revealed by atypical deep vein thrombosis. First, a 16-year-old girl presented Budd-Chiari syndrome revealed by a hemorrhagic shock. Clinical exam revealed isolated splenomegaly. A search for thrombophilia found a factor V Leiden homozygous mutation and a Jak2 mutation. Bone marrow biopsy confirmed the diagnosis of a myeloproliferative disorder. The second case, a 17-year-old girl, had a routine examination by her physician that revealed splenomegaly. Ultrasonography displayed thrombus in the splenic and portal vein. An isolated Jak2 mutation was found and a myeloproliferative disorder was confirmed by bone marrow biopsy. The diagnosis of myeloproliferative disorder was made in both patients presenting atypical venous thrombosis with a Jak2 mutation and confirmed by bone marrow biopsy. These initial presentations of myeloproliferative disorders are rare in childhood and possibly underdiagnosed.

[Dyskeratosis congenita: an update]. / La dyskératose congénitale : mise au point.

Dyskeratosis congenita is a rare inherited bone marrow failure characterized by excessively short telomeres in highly proliferative tissues. These abnormalities are due to disturbance of the telomere maintenance machinery. The clinical presentation is characterized by skin pigmentation, nail dystrophy, and mucosal leukoplakia. All these mucocutaneous features are rare in childhood: they usually appear between 5 and 10 years of age. In young children, the initial presentation can associate bone marrow failure and neurological or ocular problems: Hoyeraal-Hreidarsson and Revesz syndromes, respectively. Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer. Diagnosis is often suspected on bone marrow failure with no clinical or biological abnormalities compatible with Fanconi anemia diagnosis. The telomere length study can be helpful for diagnosis in case of aplastic anemia in children before studying gene mutations. Until now, 6 genes (DKC1, TERT, TERC, NOLA2, NOLA3, TINF2) have been identified in dyskeratosis congenita. Transmission of the disease can be autosomal recessive, autosomal dominant, or X-linked. In half of the cases, the genetic abnormality is unknown. Treatment of DC has to be adapted to each patient, from symptomatic or androgenic treatment to hematopoietic stem cell transplantation.

[Granulocytic sarcoma, a diagnostic challenge: 3 pediatric cases]. / Le sarcome granulocytaire, un diagnostic à connaître : à propos de 3 observations pédiatriques.

Granulocytic sarcoma (GS) is a rare extramedullary tumor frequently associated with acute myeloblastic leukemia (AML). We report 3 cases of pediatric granulocytic sarcomas with various locations: skin, orbit, and bowel. Cases 1 and 2 were associated with AML; case 3 was isolated. In all 3 cases, the diagnosis was delayed or initially missed. Pathology and immunohistochemistry data identified the disease. GS is treated with chemotherapy, like AML. The prognosis of GS seems better than that of isolated AML.

Influence of underlying disease on busulfan disposition in pediatric bone marrow transplant recipients: a nonparametric population pharmacokinetic study.

Busulfan is an alkylating agent used in a conditioning regimen prior to bone marrow transplantation. Busulfan has a narrow therapeutic index, giving rise to major liver toxicity (veno-occlusive disease), and a wide interpatient and intrapatient pharmacokinetic variability. This report presents the results of a population pharmacokinetic analysis leading to models based on underlying diseases requiring bone marrow transplantation. One hundred children received oral busulfan-based conditioning regimens between March 1998 and February 2006. Busulfan pharmacokinetic parameter estimates (Ka, first order absorption rate constant; Vs, volume of distribution related to the body weight; and Cl/F, apparent clearance) were estimated by using the nonparametric adaptative grid (NPAG) algorithm in patients divided into four groups according to initial diagnosis: metabolic diseases, hemoglobinopathies, hematological malignancies, and immune deficiencies. Ka and Vs did no differ significantly in the four subgroups. Cl/F and areas under the plasma concentration curve were significantly different in the four groups. Cl/F was significantly higher in the hemoglobinopathies group (P = 0.002), with a mean value of 7.78 L . h, whereas the immune deficiencies group was characterized by the lowest Cl/F (3.59 L . h). Interindividual variability was shown by high interindividual parameter percent coefficients of variation (CV%) but, nevertheless, with less diversity in the population parameter distributions for Vs in the three subgroups-metabolic diseases, hemoglobinopathies, and malignant diseases-and in Cl/F for patients with hemoglobinopathies. The fit was good for busulfan concentration predictions based on Bayesian individual posterior values, with little bias and good precision. In comparison with the overall population, the only model of subgroup presenting a greater precision was patients with hemoglobinopathies (P = 0.002). Use of these more specific models of a given disease may well result in more accurate individualization of busulfan dose regimens, especially in very sparse blood sampling situations.

Primary cardiac Burkitt lymphoma in a child.

Primary cardiac lymphoma (PCL) is a rare and usually fatal malignancy, seldom reported in children. This report describes the case of a 10-year-old boy who presented with multiple intracardiac masses which, when biopsied, proved to be small non-cleaved cell (Burkitt's) lymphoma. The first two cycles of chemotherapy according to the LMB 96 protocol were given under close cardiological supervision, with good response. The treatment was then continued with full-dose chemotherapy, without any cardiological complication. The patient who was treated by chemotherapy alone remains in complete remission 36 months after the end of treatment and can presently be considered as cured, without late cardiac effect.