Severe hypoplasia of the abdominal aorta and its branches in a patient and his daughter.

We report the history of a patient and his daughter, both affected with hypoplasia of the abdominal aorta and its branches, leading to early and dramatic complications. In the index patient, renal ischaemia as a result of severe hypoplasia of the abdominal aorta and the origin of renal arteries led to progressive renal failure and end-stage renal disease at the age of 32 years. Other vascular abnormalities included hypoplasia of the celiac trunk (CT) and superior mesenteric artery (SMA). After a successful kidney transplantation at the age of 40 years, he eventually deceased following an episode of possibly ischaemic acute pancreatitis at 47 years. The patient's daughter suffered from an haemorrhagic stroke at the age of 7 years, which led to the discovery of severe hypertension caused by bilateral narrowing of renal arteries, as well as hypoplasia of CT, SMA, subclavian and pulmonary arteries. Biopsy of the narrowed renal artery of the daughter showed a particular form of fibrodysplasia characterized by an unusual fibrosis of the inner part of the media, just beneath the internal elastic lamina. To our knowledge, this is the first report of familial hypoplasia of the abdominal aorta. It might be the cardinal manifestation of a familial form of fibromuscular dysplasia (FMD). Interestingly, the histological lesions described in the daughter's renal artery differ from the classical form of medial FMD.

Unusual evolution of an Epstein-Barr virus-associated leiomyosarcoma occurring after liver transplantation.

We report the case of a child who developed, 2 yr after orthotopic liver transplantation (OLTx) for biliary atresia, a multi-focal hepatic tumor with lymphonodular metastases, identified as an Epstein-Barr virus (EBV)-associated leiomyosarcoma. Chemotherapy was given without tumor response. Subsequently, slow growth of the tumor was observed. Immunosuppression was tapered and stopped 9 yr after transplantation. At the present time, 12 yr after the discovery of the first hepatic lesions, the patient is alive and completely symptom-free, the abdominal masses are stable, and liver function tests are completely normal. Smooth muscle tumors are increasingly recognized in children with various immunodeficiencies occurring after organ transplantation. This unusual evolution of a clinically aggressive tumor into a stable disease after restoration of immunity confirms that the immune status of the patient is a crucial factor.

[Bone marrow transplantation in Fanconi's anemia: report of seven cases]. / Greffe de moelle dans l'anémie de Fanconi: à propos de sept cas.

OBJECTS: Follow-up of patients with Fanconi's anemia treated in our unit and review of the literature concerning bone marrow transplantation in Fanconi's anemia. PATIENTS AND METHODS: Ten patients were followed in our unit for 20 years. We summarize their clinical features, treatment and clinical course. RESULTS: Among the ten patients, seven received allogeneic marrow transplantation. Only two patients are still alive. Two transplanted patients died from complications shortly after the transplantation. Three other patients died later after the transplantation, two of them from oropharyngeal carcinomas. DISCUSSION: The 5-year survival is about 70% in the transplantation with an HLA-identical sibling donor; it is only about 30% if the donor is an HLA-matched unrelated or mismatched related patient. Furthermore, retrospective studies have shown that the long-term outcome of carcinoma is a major complication after the transplantation. CONCLUSION: Our series of patients with Fanconi's anemia reflects fairly faithfully the complications encountered in this disease. Although the improvement of the graft technique may decrease the rate of death due to transplantation, the long-term development of solid tumors remains a problem for which no solution has been suggested up to now.

[Fanconi's anemia and molecular biology research]. / L'anémie de Fanconi à l'heure de la biologie moléculaire.

Fanconi's anemia is a rare autosomal recessive disease characterized by congenital abnormalities, a progressive pancytopenia and a predisposition to cancer. The diagnosis is based on an abnormal increase of spontaneous chromosome breakage, more specifically on a clear-cut increase of chromosome breakage in the presence of bifunctional alkylating agents. Eight complementation groups (A to H) have been defined, and the genes corresponding to four of these groups have been cloned (FANCA, FANCC, FANCF and FANCG). The function of the proteins encoded by the genes of Fanconi's anemia remains unknown. Numerous studies indicate that different cellular processes are probably involved, including DNA repair pathways, apoptosis, cell cycle regulation and oxygen metabolism. Nevertheless, the exact cellular and molecular mechanisms implicated in Fanconi's anemia remain a challenge for fundamental research. The treatment of Fanconi's anemia is also the subject of intense research, bearing principally upon bone marrow transplantation, which is successful in the case of HLA-identical sibling donors, and gene therapy, which is still at a preliminary stage on the clinical level.

Intracellular cytokine profile of cord and adult blood monocytes.

Cord blood (CB) transplantations are associated with low graft-versus-host disease (GVHD). The pathophysiology of GVHD involves interaction and activation of different cell types, as lymphocytes and monocytes, and results in a cascade of cytokine production. After antigen or mitogen stimulation, CB monocytes release lower levels of cytokines than adult blood (AB) monocytes. In this study, the detection of intracellular IL-1 beta and TNF-alpha produced by monocytes was evaluated in response to tuberculin PPD to investigate whether the reduced capacity of CB monocytes to secrete cytokines could be related to an impaired functional activity and to a particular phenotypic profile. Results showed that the percentage of CD64(+)monocytes producing intracellular IL-1 beta and TNF-alpha was significantly lower in CB and that the phenotypic profile of CB monocytes producing these cytokine (CD64(+)CD14(+)) was different to that of AB monocytes (CD64(+)CD14(+), CD64(+)CD33(+) and CD64(+) CD45RO(+)). These results suggest that the lower capacity of CB monocyte populations to produce IL-1 beta and TNF-alpha might be due to a functional immaturity of CB monocytes at the cellular level as reflected by the different phenotypic profile of CB monocytes.

Smooth muscle tumor developing in an immunocompromised child after therapy for leukemia.

We report a 5.5-year-old boy who underwent autologous peripheral blood stem cell transplantation for high-risk acute lymphoblastic leukemia and who had two abdominal masses develop 6 months later. Macroscopically complete resection of the abdominal tumors was performed and revealed a well-differentiated leiomyosarcoma. Smooth muscle tumors, benign or malignant, are increasingly recognized in children with various immunodeficiencies; the association with acute lymphoblastic leukemia is rarely described.

Expression of HLA-DR, CAM and co-stimulatory molecules on cord blood monocytes.

Umbilical cord blood (CB) transplantations are associated with a lower risk of severe graft-versus-host disease (GVHD) compared to BMT. GVHD is an immune reaction that involves interaction between cell surface molecules resulting in cell activation and release of many cytokines. Monocytes are known to be an important source of cell adhesion (CAM) and co-stimulatory molecules which play a crucial role in the efficient activation of T and B cells. We analyzed the phenotype of CB monocytes in the presence or absence of an inflammatory signal (rIFN-gamma) and compared them to adult blood (AB); the expression of HLA-DR and 17 different markers (CD11a, CD11b, CD11c, CD18, CD29, CD40, CD44, CD49a, CD49d, CD49e, CD49f, CD54, CD58, CD62L, CD80, CD86 and CD102) was measured by flow cytometry. Statistical analysis showed that, compared to AB, CB monocytes did not express CD11b, CD11c, CD49d and after stimulation with rIFNgamma, they lost the expression of CD58 and CD102, whereas CD80 and CD86 expression was induced. The analysis of fluorescence intensity (MFI) revealed that CB monocytes expressed some CAM (CD29, CD54, CD102) with a lower intensity than AB monocytes except CD44. In conclusion, absence and reduced expression of some markers argue for a different phenotypic profile of CB monocytes compared to AB monocytes, which might partly contribute to their impaired immune response and to the low incidence of GVHD observed after CB transplantations. However, CB monocytes expressed CD80 and CD86 co-stimulatory molecules, but this expression did not prove a normal co-stimulatory function.

Prognostic study of continuous variables (white blood cell count, peripheral blast cell count, haemoglobin level, platelet count and age) in childhood acute lymphoblastic leukaemia. Analysis Of a population of 1545 children treated by the French Acute Lymphoblastic Leukaemia Group (FRALLE).

Many cutpoints have been proposed to categorize continuous variables in childhood acute lymphoblastic leukaemia (white blood cell count, peripheral blast cell count, haemoglobin level, platelet count and age), and have been used to define therapeutic subgroups. This variation in the choice of cutpoints leads to a bias called the 'Will Rogers phenomenon'. The aim of this study was to analyse variations in the relative risk of relapse or death as a function of continuous prognostic variables in childhood ALL and to discuss the choice of cutpoints. We studied a population of 1545 children with ALL enrolled in three consecutive protocols named FRALLE 83, FRALLE 87 and FRALLE 89. We estimated the risk of relapse or death associated with different values of each continuous prognostic variable by dividing the sample into quintiles of the distribution of the variables. As regards age, a category of children under 1 year of age was distinguished and the rest of the population was divided into quintiles. The floated variance method was used to calculate the confidence interval of each relative risk, including the reference category. The relation between the quantitative prognostic factors and the risk was monotonic for each variable, except for age. For the white blood cell count (WBC), the relation is log linear. The risk associated with WBC values in the upper quintile was 1.9 times higher than that in the lower quintile. The peripheral blast cell count correlated strongly with WBC (correlation coefficient: 0.99). The risk increased with the haemoglobin level, and the risk in the upper quintile was 1.3 times higher than that in the lower quintile. The risk decreased as the platelet count increased: the risk in the lower quintile was 1.2 times higher than that in the upper quintile. The risk increased gradually with increasing age above one year. The small subgroup of patients (2.5% of the population) under 1 year of age at diagnosis had a risk 2.6 times higher than the reference category of patients between 3 and 4.3 years of age. When the risk associated with a quantitative prognostic factor varies monotonously, the selection of a cutpoint is arbitrary and represents a loss of information. Despite this loss of information, such arbitrary categorization may be necessary to define therapeutic stratification. In that case, consensus cutpoints must be defined if one wants to avoid the Will Rogers phenomenon. The cutpoints proposed by the Rome workshop and the NCI are arbitrary, but may represent an acceptable convention.

Clonal monosomy 7 and 5q--in a child with myelodysplastic syndrome.

The authors report the case of a 5-year-old boy referred for thrombocytopenia and neutropenia. Bone marrow examination showed a myelodysplasia with clonal monosomy 7. The acceleration of the disease was marked by the appearance of an additional cytogenetic abnormality, i.e., the deletion of the long arm of chromosome 5 in the clonal cells. RAS gene mutation was not detected. Chemotherapy was started to achieve complete remission before a bone marrow transplantation. This treatment was complicated by a prolonged aplasia and the patient died of systemic mycotic infection.

The value of interphase fluorescence in situ hybridization for the detection of translocation t(12;21) in childhood acute lymphoblastic leukemia.

Translocation t(12;21)(p13;q22) is the most frequent cytogenetic abnormality in childhood acute lymphoblastic leukemia (ALL) and is generally associated with favorable prognosis. In this report, we assessed the value of dual-color interphase fluorescence in situ hybridization (FISH) for the detection of t(12;21). Fifty-three patients were screened for ETV6/CBFA2 fusion by means of FISH, using two cosmid probes mapped on ETV6 and on CBFA2, respectively. The cut-off value (mean + three standard deviations) for positivity established on control patients was 9.3%. A comparison between FISH and molecular methods [reverse-transcriptase polymerase chain reaction/Southern blot (RT-PCR/SB)] was possible in 52 patients: 34 of 52 (65.4%) showed negative results with both approaches, and 13 of 52 (25%) were positive; 5 of 52 (9.6%) showed discrepancies: four patients who were positive using RT-PCR/SB were negative using FISH. Conversely, one patient negative when using RT-PCR/SB was positive with FISH. Further investigations on this patients, cytogenetically characterized by add(12p), showed an atypical breakpoint on ETV6, located 5' to the common breakpoint. Compared with RT-PCR and SB, dual-color interphase FISH with the cosmid probe set proved to be highly specific but showed limited sensitivity.

Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation.

Severe congenital neutropenia (CN) (Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia leading to absolute neutrophil counts (ANC) below 0.2 x 10(9)/L associated with severe bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) beginning in 1994 indicate that more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (r-HuG-CSF) treatment with an ANC greater than 1. 0 x 10(9)/L. For patients who are refractory to r-HuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation is the only currently available treatment. We report on a total of 11 patients with CN reported to the SCNIR who underwent transplantation for reasons other than malignant transformation between 1976 and 1998. Of these patients, 8 were nonresponders or showed only partial response to r-HuG-CSF treatment with ongoing infections. Results from these patients suggest that transplantation of stem cells from an HLA-identical sibling is beneficial for patients refractory to r-HuG-CSF. (Blood. 2000;95:1195-1198)

Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation.

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.

Identification of new prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan anemia patients. DBA group of Société d'Hématologie et d'Immunologie Pédiatrique (SHIP), Gesellshaft für Pädiatrische Onkologie und Hämatologie (GPOH), and the European Society for Pediatric Hematology and Immunology (ESPHI).

Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.

Ferritin-associated iron induces neutrophil dysfunction in hemosiderosis.

Neutrophils (PMNs) from patients with secondary iron overload have an increased iron and ferritin content as well as a phagocytosis defect. Several serum components might be incriminated in the cellular iron accumulation. We therefore compared the effects on the PMN phagocytosis of total serum as well as the ferritin and transferrin fractions of serum derived from patients with thalassemia major and healthy control subjects. An incubation system of PMNs was developed. PMN phagocytosis was measured before and after incubation. Total serum from patients with thalassemia induced a defect that was prevented by co-incubation with deferoxamine (DFO). Gel-filtration chromatography was performed to separate the serum fraction containing transferrin and albumin from that containing ferritin. The transferrin-albumin fraction had no effect on PMN phagocytosis. On the contrary, the ferritin fraction of normal serum was deleterious to PMN phagocytosis, and the same fraction from thalassemic serum decreased PMN phagocytosis even more. Co-incubation with DFO or catalase improved this defect. Moreover, a cellular increase in the L-type subunit of ferritin was observed after the incubation of PMNs with the ferritin-containing fraction from thalassemic serum. In conclusion, serum from patients with thalassemia is toxic to PMNs, and this toxicity is due to ferritin-associated iron.

Circadian and seasonal variations of hematopoiesis in cord blood.

Cord blood hematopoietic progenitors undergo circadian and seasonal variations. The lowest values are obtained between 4:00 and 12:00, as well as between May and August. This represents the first observation of such rhythms before birth.

Related cord blood transplants: the Eurocord experience from 78 transplants. Eurocord Transplant group.

Eurocord Transplant has established a registry for studying results of cord blood transplant. We have analyzed 78 patients who have received a related CBT between October 1988 and December 1996. The median follow-up time was 29 months (1-99). The median age was 5 years (0.2-20), median weight 19 kg (5-50). Forty-six patients had a malignant disease: 32 acute leukemia (AL), six chronic myeloid leukemia (CML), four myelodysplastic syndrome, two neuroblastoma and two non-Hodgkin lymphoma. Thirty-two patients were transplanted for non-malignant diseases including 17 bone marrow failure syndromes (BMFS), three sickle cell anemia, five thalassemia and seven inborn errors. The donor was an HLA-identical sibling in 60 cases and an HLA-mismatched donor in 18 cases. As conditioning, 36 patients received irradiation and 40 patients received associated busulfan-containing regimens. GVHD prophylaxis consisted of CsA alone in 36 cases, CsA associated with prednisone in eight cases, CsA, methotrexate (Mtx) with or without prednisone in 28 cases and CsA with monoclonal antibody or ATG in four cases. The median number of nucleated cells (NC) infused/kg was 3.9 x 10(7) (0.7-15). One-year survival was 63 +/- 6%. Age, weight, HLA identity and negative cytomegalovirus (CMV) serology in the recipient were significant favorable prognostic factors. Among these 78 patients, the incidence of grade > or = II GVHD was 9% in HLA-matched CBT and 50% in mismatched CBT (P < 0.001). Neutrophil engraftment was associated with age <6 years (P = 0.02) and weight <20 kg (P = 0.02). It was 73% in patients receiving <3.7 x 10(7) nucleated cells (NC) infused/kg and 85% in patients receiving more (P = 0.06). Favorable factors for platelets engraftment were age <6 years (P = 0.03), weight <20 kg (P = 0.002) and HLA identity (P < 0.0001). Related cord blood transplantation offers a good alternative to BMT. Theses results are in favor of freezing cord blood in families in whom a transplant might be indicated.

Total body irradiation-high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study.

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean +/- SE) of disease-free survival (DFS) at 7 years was 59.5 +/- 9% (95% confidence interval). The estimated chance of relapse was 22.5 +/- 15% with a median follow-up of 88.5 months (range 51-132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD. site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 +/- 12.6%, 37.5 +/- 19.8% and 774 +/- 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3-4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.

Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle group. French Acute Lymphoblastic Leukaemia study group.

We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54.8% (SD 1.9), 43.1%) (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 x 10(9)/l), circulating blastosis. haemoglobin >12 g/dl, platelet count <100 x 10(9)/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.