[Cefepime-amikacin combination in febrile neutropenic children with malignant hemopathy or tumor]. / Association céfépime-amikacine chez les enfants neutropéniques fébriles atteints d'hémopathies ou de tumeurs malignes.

UNLABELLED: Our aim was to evaluate retrospectively the efficacy of a therapeutic strategy with a first line combination based on cefepime-amikacin in febrile neutropenic children treated with chemotherapy. PATIENTS AND METHODS: Sixty-five neutropenic febrile episodes in 43 children treated by the association cefepime-amikacin, were evaluated according to the clinical status, the depth and duration of neutropenia, the underlying disease and the initial treatment. RESULTS: Thirty-nine (60%) episodes were successfully treated by the association cefepime-amikacin. Among the 26 persisting febrile episodes, adjunction of vancomycin and amphotericin B was effective in 11 (76% of total rate success) and 5 (84% of total rate success) cases respectively. The efficacy of the first line antibiotherapy was not different as regards to the duration and the depth of neutropenia. Otherwise, febrile episodes after chemotherapy against solid tumours were rapidly controlled by the first and second line of the anti-microbial strategy. Children treated for haematological malignancies presented a lower response rate (P = 0.03). CONCLUSION: In febrile and neutropenic children treated with chemotherapy, the association cefepime-amikacin appeared to be a safe empirical treatment. In a neutropenic child, the immunodeficiency and possibly the clinical status should be the major factors of the infectious prognosis more than the duration of aplasia.

Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia.

The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft-versus-host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD > or = 2 at 3 months which was higher in group I (65 +/- 10%) than in group II (38 +/- 5%; P = 0.01). Moreover, disease-free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 +/- 10% vs. 41 +/- 6%; P = 0.005)(95% CI) and (41 +/- 10% vs. 55 +/- 6%; P = 0.002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.

Cytochromes c555 from the hyperthermophilic bacterium Aquifex aeolicus. 2. Heterologous production of soluble cytochrome c555s and investigation of the role of methionine residues.

The cycB2 gene encoding the soluble cytochrome c555s from Aquifex aeolicus, an hyperthermophilic organism, has been cloned and expressed using Escherichia coli as the host organism. The cytochrome was successfully produced in the periplasm of an E. coli strain coexpressing the ccmABCDEFGH genes involved in the cytochrome c maturation process. Comparison of native and recombinant cytochrome c555s shows that both proteins are indistinguishable in terms of spectroscopic and physicochemical properties. Since two different methionine residues are present in the sequence stretch usually providing the sixth ligand to the heme iron, site-directed mutagenesis has been performed in order to identify the methionine serving as the axial ligand. Two single mutations were introduced, leading to the replacement of each methionine by a histidine residue. Characterization of both mutants, M78H and M84H cytochromes c555s, using biochemical and biophysical techniques has been carried out. The M84H mutant exhibits spectral features identical to those of native cytochrome. Its redox midpoint potential is decreased by 40 mV. By contrast, substitution of methionine 78 by a histidine residue strongly alters the structural and physicochemical properties of the molecule which exhibits characteristics of His/His iron coordination type rather than His/Met. These results allow us to identify methionine 78 as the sixth ligand of cytochrome c555s heme iron. Preliminary results on the thermostability of the native and mutant cytochromes c555 are also reported.

Cytochromes c555 from the hyperthermophilic bacterium Aquifex aeolicus (VF5). 1. Characterization of two highly homologous, soluble and membranous, cytochromes c555.

Two distinct class I (monoheme) c-type cytochromes from the hyperthermophilic bacterium Aquifex aeolicus were studied by biochemical and biophysical methods (i.e., optical and EPR spectroscopy, electrochemistry). The sequences of these two heme proteins (encoded by the cycB1 and cycB2 genes) are close to identical (85% identity in the common part of the protein) apart from the presence of an N-terminal stretch of 62 amino acid residues present only in the cycB1 gene. A soluble cytochrome was purified and identified by N-terminal sequencing as the cycB2 gene product. It showed an alpha-peak at 555 nm, an E(m) value of +220 mV, and electron paramagnetic resonance parameters of gz = 2.89, gy = 2.287, and gx = 1.52. A firmly membrane-bound cytochrome characterized by nearly identical properties was detected and attributed to the cycB1 gene product. The very high degree of homology of its N-terminal part to cytochrome c553 from Heliobacterium gestii strongly suggests it to be anchored to the membrane via N-terminally attached lipid molecules. The two heme proteins were named cytochrome c555s (soluble) and cytochrome c555m (membranous). Electron paramagnetic resonance on partially ordered membrane multilayers suggests that the solvent-exposed heme domain of cytochrome c555m is flexible with respect to the membrane plane. Possible functional roles for both cytochromes are discussed.

Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant.

Herpes simplex virus (HSV) causes serious problems in immuno-compromised patients such as those receiving a bone marrow transplant (BMT) for a hematological malignancy. Resistance to acyclovir (ACV) is a growing major concern. Foscarnet is a non-thymidine kinase-dependent agent, but the emergence of ACV and foscarnet-resistant HSV requires a new therapeutic approach. We describe a girl treated with cidofovir for a life-threatening ACV-resistant HSV infection after an unrelated BMT for a relapse of an acute myeloblastic leukemia (AML).

Early evolution of cytochrome bc complexes.

Primary structures, functional characteristics and phylogenetic relationships of subunits of cytochrome bc complexes from phylogenetically diverse bacterial and archaeal species were analysed. A single case of lateral gene transfer, i.e. the import of an epsilon-proteobacterial cytochrome bc(1) complex into Aquificales, was identified. For the enzyme in the remainder of the species studied, the obtained phylogenies were globally in line with small subunit rRNA trees. The distribution of a few key phylogenetic markers, such as contiguousness of cytochrome b, nature of the c-type subunit or spacing between b-heme ligands, are discussed. A localised modification of previous tree topologies is proposed on the basis of the obtained data. The comparison of extant enzymes furthermore allowed us to define the minimal functional and evolutionary core of the enzyme. The data furthermore suggest that the ancestral enzyme was put together from subunits that previously had played a role in other electron transfer chains.

Redox components of cytochrome bc-type enzymes in acidophilic prokaryotes. I. Characterization of the cytochrome bc1-type complex of the acidophilic ferrous ion-oxidizing bacterium Thiobacillus ferrooxidans.

The redox components of the cytochrome bc1 complex from the acidophilic chemolithotrophic organism Thiobacillus ferrooxidans were investigated by potentiometric and spectroscopic techniques. Optical redox titrations demonstrated the presence of two b-type hemes with differing redox midpoint potentials at pH 7.4 (-169 and + 20 mV for bL and bH, respectively). At pH 3.5, by contrast, both hemes appeared to titrate at about +20 mV. Antimycin A, 2-heptyl-4-hydroxyquinoline N-oxide, and stigmatellin induced distinguishable shifts of the b hemes' alpha-bands, providing evidence for the binding of antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide near heme bH (located on the cytosolic side of the membrane) and of stigmatellin near heme bL (located on the periplasmic side of the membrane). The inhibitors stigmatellin, 5-(n-undecyl)-6-hydroxy-4,7-dioxobenzothiazole, and 2, 5-dibromo-3-methyl-6-isopropyl-p-benzoquinone affected the EPR spectrum of the Rieske iron-sulfur center in a way that differs from what has been observed for cytochrome bc1 or b6f complexes. The results obtained demonstrate that the T. ferrooxidans complex, although showing most of the features characteristic for bc1 complexes, contains unique properties that are most probably related to the chemolithotrophicity and/or acidophilicity of its parent organism. A speculative model for reverse electron transfer through the T. ferrooxidans complex is proposed.

[Eczema-like cutaneous graft versus host disease treated by UV-B therapy in a 2-year-old child]. / GVH cutanée eczématiforme traitée par UV-B thérapie chez un enfant de deux ans.

INTRODUCTION: Chronic graft versus host disease (GVHD) has rarely been reported in children. Optimal treatment should minimize infectious complications and preserve the child's growth. We report a case of cutaneous GVHD in a two year-old boy, who presented an eczema-like eruption and responded well to broad band UV-B therapy. CASE REPORT: A two year-old boy with acute myeloblastic leukemia had a heterologous bone marrow transplantation with a graft issued from an unrelated female donor. Three month later, he developed eczema-like lesions of the trunk, arms and legs associated with diffuse alopecia, despite oral corticosteroids and cyclosporine treatment. Histologic findings were consistent with GVHD. Topical corticosteroids and broad band UV-B therapy were initiated, while oral corticosteroids and cyclosporine doses were tappered off. GVHD lesions cleared, allowing withdrawal of oral corticosteroids and cyclosporine 3 and 12 months respectively after initiation of UV-B therapy. No relapse occurred 24 months after systemic treatment discontinuation and 12 months after broad band UV-B therapy was stopped. CONCLUSION: This observation suggests that broad band UV-B therapy is an effective treatment for eczema-like, cutaneous GVHD.

[Paraplegia due to medullary ischemia after repair of coarctation of the aorta in an infant]. / Paraplégie par ischémie médullaire après cure chirurgicale d'une coarctation de l'aorte.

UNLABELLED: Paraplegia after repair of coarctation of the aorta is uncommon. CASE REPORT: A 2-month-old boy underwent excision of the coarctation area and primary anastomosis because of persistent heart failure. Spastic paraplegia was noted some hours after surgery. Motor deficit partially improved, but bladder dysfunction appeared some months after. Medullary magnetic resonance imaging (MRI) revealed an ischemia-related narrowing of the medullary diameter. CONCLUSION: Paraplegia after repair of coarctation of the aorta, described in adults and infants, is also seen in neonates. Prevention by preoperative monitoring of somatosensory evoked potentials is effective in adults, but difficult to perform in very young children.

Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma. However, the prognostic factors and the longer term outcome of these patients remains unclear. Pattern of recurrences were analysed in three consecutive protocols of the Société Française d'Oncologie Pédiatrique (1985-91). A uniform surveillance programme including repeated lumbar puncture combined with computerized tomography (CT) or magnetic resonance imaging (MRI) scan was applied for all registered patients. Forty-six out of 116 patients had progressive or recurrent disease. The median time from diagnosis to recurrence was 10.5 months and 76% relapses occurred during the first 2 years. Seventeen patients had asymptomatic relapses that were detected by the surveillance protocol. Forty-one patients were treated at time of progression. Twenty-three responded to salvage therapy and 11 achieved a second complete remission. The median survival time after progression was 5 months (<1-41 months), and only two patients remained alive at time of follow-up. Length of survival is primarily related to some specific patterns of relapse (time from diagnosis to recurrence, circumstances of relapse, extent of relapse) and to the response to salvage therapy. No evidence of long-term benefit appeared from any form of treatment.

[Imerslund's disease. Clinical and biological aspects. Apropos of 6 cases]. / Maladie d'Imerslund. Aspects cliniques et biologiques. A propos de six cas.

BACKGROUND: Imerslund syndrome, a recessive autosomal disease, initially described by Imerslund and Grasbeck in 1960, associates megaloblastic anemia and proteinuria. CASE REPORT: We report on six cases, studied in five different families. All patients (mean age: 3.5 years) had clinical symptoms of anemia, three had malabsorption, proteinuria was present in five, at the time of diagnosis. Hemogram and decreased serum vitamin B12 levels were consistent with the diagnosis in all cases. Intra-muscular injections of cyanocobalamine was instituted on a life-time basis and the long term prognosis is good. CONCLUSION: The diagnosis should be evoked when the three typical features are present: macrocytic anemia, decreased serum B12 level and proteinuria. It will be confirmed by the bone marrow megaloblastic aspects and the Schilling test findings.

Therapy-related acute myeloid leukemia with t(8;21) in a child with previous Ewing's sarcoma.

Cases of secondary acute myeloid leukemia (AML) occurring after treatment for an Ewing's sarcoma are uncommon. Therapy-related AML with t(8;21) translocation is an entity which has been well characterized. A case of AML-2 with t(8;21) and t(3;15) occurring 4 years after treatment for an Ewing's sarcoma with cyclophosphamide, doxorubicin, vincristine, dactinomycin, and radiotherapy, is reported. Autologous bone marrow transplantation was performed during second remission, 23 months after diagnosis. Reverse transcriptase polymerase chain reaction of the AML1/ETO fusion gene product was performed in order to monitor the quality of the remission. The patient currently remains in remission 24 months after the bone marrow transplantation.

Prenatal ultrasound abnormalities in a patient with generalized neurofibromatosis type 1.

We describe a patient with an unusual neonatal disseminated form of neurofibromatosis (NF1). Prenatal ultrasound studies, at 35 weeks of gestation, revealed ambiguous external genitalia, an increased biparietal diameter and a decreased growth of long bones. Postnatal examination displayed generalized neurofibromatosis, with perineal, thoracic and spinal cord invasion by tumors. Spinal cord compression was responsible for paraparesis. The child died of a pulmonary infection at five years of age. No previous report of such prenatal abnormalities has been described. Genetic counselling is difficult because of the variable expression of the illness.

[Antineoplastic chemotherapy and Wernicke's encephalopathy]. / Chimiothérapie anticancéreuse et encéphalopathie de Gayet-Wernicke.

BACKGROUND: Wernicke's encephalopathy is usually seen in alcoholic adults. It is rare in childhood and usually discovered in a context of several pathological events. We report here a typical case of a teenager. CASE REPORT: A 15-year-old girl with acute leukemia was given chemotherapy that resulted in profound aplasia and serious infection. She exhibited abnormal eye movements, ataxia, lethargy, enuresis and amnesia. MR examination showed T2-weighted images with increased signal in the thalami (pulvinar) and periaqueducal region. The symptoms improved dramatically with thiamine therapy. Omission of the usual vitamin supplementation between the courses of chemotherapy was responsible for this encephalopathy. CONCLUSION: Thiamine deficiency can lead to death or amnesia. Rapid efficacy of vitamin supplementation helps diagnosis and prevents sequelae.

[Aniridia and Wilms tumor: 2 cases of fetal rhabdomyomatous nephroblastoma]. / Aniridie et tumeur de Wilms: deux cas de néphroblastome foetal rhabdomyomateux.

BACKGROUND: Wilms tumor is associated in 7 to 10% of patients with congenital abnormalities. Among those, aniridia is the most constant feature of the WAGR syndrome that includes, in one third of cases. Wilms tumor. We report two cases of aniridia associated with fetal rhabdomyomatous nephroblastoma. CASE REPORTS: Case 1. A one-year old girl with congenital aniridia was admitted for macroscopic hematuria. Abnormal ultrasonography and tomodensitometry revealed a large, bilateral, kidney tumor. The patient was given actinomycin and vincristine, without efficacy. Bilateral tumorectomy was performed 6 months later and the histological study showed a fetal rhabdomyomatous nephroblastoma. This patient is in remission at the age of 5. Case 2. A boy, also with congenital aniridia, presented with macroscopic hematuria at the age of 2 years revealing a nephroblastoma located on his right kidney. Preoperative chemotherapy remained uneffective and the nephrectomy performed 1 month later permitted the diagnosis of fetal rhabdomyomatous nephroblastoma. The patient is well 4 years later. CONCLUSION: Both cases of fetal rhabdomyomatous nephroblastoma, a histological variant of Wilms tumor, seem to be the first reported in the WAGR syndrome.

A study of long-term survival, functional outcome and quality of life in patients with polymyositis or dermatomyositis.

UNLABELLED: There have been few studies of long-term functional outcomes and quality of life in patients with polymyositis or dermatomyositis. PATIENTS: 28 patients, 16 female and 12 male, meeting Bohan's and Peter's criteria and admitted between 1970 and 1993, were studied retrospectively; nine had polymyositis and 19 dermatomyositis (with onset during childhood in five cases); mean age was 43.5 years. METHODS: we reevaluated 18 of the 28 patients, after a mean interval of eight years; among the ten remaining patients, eight had died, one could not be traced and one declined reevaluation. Survival, muscle function, joint function, respiratory function and quality of life (AIMS 1) were determined. Factors predicting the value of these parameters were looked for. RESULTS: significant excess mortality was observed as compared with the general population in the Seine Maritime region of France. Easy fatigability and decreased exercise tolerance were found in 50% of evaluated patients; Ritchie's index was 0 in 67% of patients and between 1 and 7 in 33%; 55% of patients had dyspnea and 50% had abnormal respiratory function parameters; quality of life items were usually rated "fairly good" or "very good", except for "physical activities", which were given "poor" or "very poor" ratings by one third of patients. We found no factors associated with survival or any of the above-mentioned functional parameters, except for male gender, which predicted better muscle function. DISCUSSION: polydermatomyositis is associated with excess mortality; alterations in muscle function persist in half the cases and the ability to carry out physical activities is often reduced. The retrospective design of our study, small sample size and heterogeneity of our population precluded identification of factors predictive of survival, loss of function, or poor quality of life.

[Hypoplasia of abdominal aorta, rare cause of hypertension in childhood]. / Hypoplasie de l'aorte abdominale, cause rare d'hypertension artérielle du grand enfant.

BACKGROUND: The majority of children with secondary hypertension have a renal abnormality or renovascular lesions. Coarctation of the aorta is also a classical cause, rarely located to the abdominal aorta. CASE REPORTS: Two girls, 11 and 12 years-old, were suspected of having recent sustained hypertension. Pulsed-wave doppler ultrasonography and angiography showed abdominal aortic hypoplasia associated with renal artery stenosis, unilateral in one patient and bilateral in the other. Both patients became normotensive 10 and 18 months, respectively, after corrective vascular surgery. CONCLUSION: Examination of the abdominal part of the aorta is mandatory in all patients with hypertension.

Preirradiation chemotherapy including "eight drugs in 1 day" regimen and high-dose methotrexate in childhood medulloblastoma: results of the M7 French Cooperative Study.

The aim of this study was to evaluate the feasibility and efficacy of a protocol that includes "sandwich" chemotherapy, that is, chemotherapy alternated with radiotherapy, and reduced doses of supratentorial irradiation in children with medulloblastoma. Between March 1985 and September 1988, 70 successive children with newly diagnosed medulloblastoma from eight centers were treated in this prospective nonrandomized study. Patients were assigned to two risk groups. Group A included patients with macroscopically complete or subtotal excision, no brainstem involvement, no atypical cells in the cerebrospinal fluid, normal myelography, and who were more than 2 years of age. Group B patients encompassed those who did not fit the criteria for Group A. Two children were excluded from analysis after histological review confirmed ependymoma. Thus, a population of 68 children was selected, with 31 in Group A and 37 in Group B. Treatment consisted of two courses of the "eight drugs in 1 day" ("8/1") regimen followed by two courses of high-dose methotrexate (12 g/m2). Radiotherapy was begun during the 7th week after surgery in Group A and during the 5th week in Group B. In patients older than 2 years, the median radiation dose to the posterior fossa, the spinal axis, and the brain was 54 Gy, 36 Gy, and 27 Gy, respectively. Group B patients received postirradiation chemotherapy with four 8/1 courses monthly. The median time from surgery to radiation therapy was 50 days (range 21 to 141 days). One fatality due to chicken pox on Day 102 and one World Health Organization Grade IV infection occurred. The estimated 5- and 7-year disease-free survival (DFS) rates were 62% and 59%, respectively. These were 74% and 62% in Group A and 57% and 57% in Group B. Patient age, extent of resection, and radiation dose to the whole brain had no prognostic value. Patients with metastasis had a nonsignificant trend for a worse prognosis than patients with nonmetastatic disease (7-year DFS 45% vs. 68%, p = 0.11). In Group B, the 7-year DFS rates for children who received more or less than 30 Gy to the brain were 69% and 52% respectively (p = 0.15). There were recurrences in the posterior fossa (37%), spine (20%), and brain (20%). After a review of radiotherapeutic treatments, only one supratentorial failure could be blamed on reduction of the supratentorial radiation dose. This "sandwich" chemotherapy appeared to be feasible and did not show adverse survival data when compared to other series.

Metastatic medulloblastoma: the experience of the French Cooperative M7 Group.

A retrospective analysis was performed to determine the outcome of children with metastatic medulloblastoma given a standardised treatment programme. Of 68 consecutive patients treated in the French M7 protocol for medulloblastoma, 23 presented with metastatic disease. They were uniformly treated with surgery, and the same protocol of chemotherapy and craniospinal radiotherapy. The 7-year relapse-free survival rate is 43% for metastatic patients compared to 68% for patients with localised disease. Survival did not correlate with age, sex, location of metastases, extent of initial surgery and the dose of radiation therapy on the posterior fossa. Survival did correlate with the dose to the cranial field with a threshold dose of 30 Gy. Patients with metastatic disease have a worse prognosis and require more aggressive therapies at initial presentation. The prognostic impact of the different sites of metastatic disease requires further evaluation in cooperative studies.

Carboplatin and VP 16 in medulloblastoma: a phase II Study of the French Society of Pediatric Oncology (SFOP).

The purpose of this study is to evaluate the antitumor activity of combination carboplatin and etoposide in measurable medulloblastoma. From January '89 to January '92, 26 patients with medulloblastoma were included in a multicentric phase II study of 2 courses of carboplatin 160 mg/m2/d day 1 to day 5 and VP16 100 mg/m2/d day 1 to day 5. Median age was 10 years (19 months-14.5 years). First treatment was surgery alone in 1 patient, surgery + radiotherapy in 4 patients, surgery + chemotherapy in 2 patients less than 3 years old, surgery + radiotherapy + chemotherapy in 19 patients ("8 drugs in 1 day" based:17, SIOP I:1, SIOP II:1). Previous treatment included cisplatin (20 cases), carboplatin (1 case), and VP16 (7 cases). Measurable disease was evaluated by CT scan, MRI or myelogram and CSF. Response rate (RR) was 72 +/- 10%:8 complete responses (CR), 10 partial responses (PR), 1 objective effect (OE), 6 progressive disease (PD), 1 non-evaluable. Thirty-six courses were evaluated for toxicity. Median duration of WHO grade 4 neutropenia was 8 days (0-23). One patient died at day 18 after the first course because of diffuse haemorrhage during septic aplasia. Five other non-life-threatening septicemias were recorded. Median number of platelet transfusions was 1 (0-4). One child who had achieved a PR after two courses died from CNS bleeding after the third course. This drug combination achieves a high response rate in childhood medulloblastoma. Severe toxicity has been mainly encountered in previously heavily treated patients. Tolerance may be acceptable in newly diagnosed children, but careful hematological follow-up and platelet transfusional support are definitely mandatory.