Lipid trafficking in plant cells.
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Biological Transport↗
Biomedical subjects
P Moreau
Publications and source records attributed to P Moreau.
Specific binding of nuclear factors to the HLA-G gene promoter correlates with a lack of HLA-G transcripts in first trimester human fetal liver.
The nonclassical MHC class I HLA-G antigen is expressed in cytotrophoblasts during pregnancy and may play a role in inhibiting lysis by maternal natural killer cells. HLA-G gene transcription was analyzed in human fetal liver of 6-8 wk of gestation, a development stage where classical HLA class I expression is very reduced. We demonstrated that HLA-G transcription is undetectable in these cells and we investigated the molecular mechanisms that control the lack of HLA-G gene transcription. We compared protein interactions of nuclear extracts from first trimester fetal livers, YT2C2-PR (HLA-G negative) and JEG-3 (HLA-G positive) cell lines to a 244-bp EcoR I/Hind III DNA region located 1.2 kb from the HLA-G gene, previously shown to direct HLA-G expression in transgenic mouse placenta. A strong specific C7-factor was specifically detected in first trimester fetal liver that could account for the inhibition of HLA-G transcription. Interaction of C7-factor and cell-specific factors previously detected in YT2C2 cell line (C5, C6) with two distinct regulatory regions identify this 244-bp EcoR I/Hind III fragment as a putative target for inhibition of HLA-G transcription.
Animals↗
Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin.
The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3-6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.
Aminoglycosides↗
Early intensive therapy with autologous stem cell transplantation in advanced Hodgkin's disease: retrospective analysis of 158 cases from the French registry.
This retrospective study was undertaken to evaluate cure rates, toxicity and late effects of early intensive therapy followed by autologous stem cell transplantation (ASCT) in patients with advanced Hodgkin's disease (HD). One hundred and fifty-eight cases of ASCT registered in the French database (SFGM) were retrospectively analyzed. Disease status at the time of ASCT was first partial response (PR) in 85, first complete remission (CR1) in 45 or primary refractory in 28 cases. The median time interval between diagnosis and ASCT was 7 months (range 4-13). At the time of analysis in December 1995, 121/158 patients (76.6%) were alive, including 111 (70.2%) in continuous CR with a median follow-up for surviving patients of 46 months (range 8-123). Peri-ASCT toxic death rate was 3%, and the actuarial risk of new malignancies was 4.9% at 5 years. The cumulative probability of 5-year overall survival (OS) was 75.2% for the entire group of patients, 80.6% for the chemosensitive ones, and 33.9% for the primary refractory (chemosensitive vs refractory, P < 0.0001). The cumulative probability of 5-year event-free survival (EFS) was 66.1% for the entire group of patients, 73.7% for the chemosensitive ones, and 26.1% for the primary refractory (chemosensitive vs refractory, P < 0.0001). The only significant prognostic factor for both OS and EFS was disease status at the time of ASCT. Early ASCT in advanced HD is feasible, with a low risk of toxicity and without a higher rate of late effects compared with conventional treatment. Results achieved in chemosensitive patients at the time of transplantation lay the basis of future prospective randomized trials comparing ACST as front-line treatment to conventional treatment in high-risk cases.
Adolescent↗
Peripheral blood stem cell transplantation as front-line therapy in patients aged 61 to 65 years: a pilot study.
The aim of the present trial was to investigate the feasibility of high-dose therapy followed by autologous peripheral blood stem cell transplantation (PBSCT) as a component of front-line treatment in patients with disseminated intermediate- and high-grade non-Hodgkin's lymphoma (NHL) aged 61-65 years. From October 1993 to June 1996, 14 consecutive patients entered this single-center prospective pilot trial. Patients were five males and nine females, median age 63 (range 61-65). The first-line treatment consisted of three courses of CHOP therapy. Patients achieving either a partial response (PR) or a complete response (CR) after initial therapy were eligible for PBSCT, while those with refractory or progressive disease were not autografted but included in the feasibility study in an intent-to-treat analysis. Of the 14 patients, 11 achieved either a CR (one) or a PR (10) after three courses of CHOP while the three patients with no response were not autografted and subsequently died of progressive disease. PBSC collection was feasible in responding patients after G-CSF priming (10 microg/kg/day for 6 days). Conditioning therapy was the BEAM protocol. All patients engrafted after PBSCT. The median time to granulocyte (>0.5 x 10(9)/l) and platelet recovery (>25 x 10(9)/l) was 12 (range 9-18) and 13 days (range 7-22), respectively. No toxic deaths VOD or IP were observed. Four of the 11 responding patients relapsed 2, 7, 9 and 12 months after PBSCT, respectively, and all died from progressive disease. Overall, 7/14 patients are alive and free from disease, 16-43 months after initial diagnosis (median 28). The actuarial overall survival is 45.7 %, and the actuarial event-free survival is 50% at 3.5 years. This study shows the feasibility of high-dose therapy and PBSCT in patients with intermediate- or high-grade disseminated NHL aged 61-65 years. Such patients should not be excluded from trials evaluating the role of ASCT as part of initial treatment for disseminated and histologically aggressive NHL.
Aged↗
High-dose therapy with stem cell transplantation for mantle cell lymphoma: results and prognostic factors, a single center experience.
From 1991 to 1997 18 consecutive patients with well-defined mantle cell lymphoma (MCL) underwent high-dose therapy with unpurged autologous (17 patients) or allogeneic (one patient) stem cell transplantation. Tissue sections were reviewed for morphology, immunophenotype, cyclin D1 and P53 expression as well as proliferation index (PI). Median age of patients was 47 years (range 40-60). Sixteen had stage IV disease with bone marrow involvement in 12 and performance status was > or =1 in 12 patients. At the time of high-dose therapy 10 patients were in first partial response (PR), one was in second complete remission (CR), four were in second PR and three were refractory to conventional anthracycline-containing chemotherapy. The conditioning regimen consisted of TBI plus chemotherapy in 13 patients and chemotherapy only (BEAM) in five patients. No treatment-related deaths were observed. With a median follow-up of 36 months (range 13-80) after transplant, disease-free survival (DFS) and overall survival (OS) are estimated to be 48 and 80% at 4 years, respectively. Significantly better results are achieved for patients transplanted after a TBI containing regimen with a 4 year OS and DFS estimated at 89 and 71%, respectively compared to 60 and 0% respectively for patients who were conditioned without TBI (P = 0.07 for OS and P < 0.0001 for DFS). There is a trend towards better DFS when the transplant is performed in PR1 (4 year DFS: 80% with eight patients out of 10 in continuous CR 13 to 80 months, median 36 months after transplant) compared to more advanced stages (4 year DFS: 18% with only three patients out of eight in continuous CR 16, 17 and 58 months after transplant). Blastic histology and P53 overexpression are also associated with a trend towards a worst prognosis.
Adult↗
Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients.
We retrospectively investigated the feasibility and the toxicity of autologous stem cell transplantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (+/-10.8) and 29.9% (+/-14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance < 30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.
Adult↗
Sympathetic functions in NG-nitro-L-arginine-methyl-ester-induced hypertension: modulation by the renin-angiotensin system.
BACKGROUND: Nitric oxide and angiotensin II have been shown to attenuate cardiac beta-adrenergic inotropism. OBJECTIVE: To study sympathetic presynaptic and post-synaptic functions after chronic nitric oxide synthesis blockade with NG-nitro-L-arginine-methyl-ester (L-NAME, for 40 days) in association with renin-angiotensin system blockade (during the last 12 days) in order to evaluate the possible physiological interactions between these systems. METHODS: Haemodynamic parameters in conscious rats were assessed. Release of noradrenaline from isolated atria and cardiac beta-adrenergic-adenylyl cyclase pathway in rats of sham-treated and L-NAME-treated groups, with or without losartan or enalaprilat treatment, were assessed. RESULTS: L-NAME-treated rats developed a time-dependent increase in blood pressure associated with increased plasma adrenaline levels whereas plasma noradrenaline and cardiac catecholamine levels were similar to those in sham-treated rats. Field-stimulated release of noradrenaline, cardiac beta-adrenoceptor density and affinity and isoproterenol-stimulated formation of cyclic AMP were similar in sham and L-NAME-treated rats. However, Gpp(NH)p, NaF and forskolin-stimulated adenylyl cyclase activity were greater in L-NAME rats although Gs and Gi protein levels were similar in sham-treated and L-NAME-treated rats. Losartan and enalaprilat treatments exerted equipotent angiotensin-pressor response blockade and hypotensive effects whereas catecholamine levels were not altered. Interestingly, only losartan treatment acted to reduce the increased Gs-adenylyl cyclase activity in L-NAME rats, without alteration of G protein levels. CONCLUSIONS: The nitric oxide synthase blockade-induced hypertension seems to be associated with increased adrenal-medullary system and renin-angiotensin system activities. The increased Gs-adenylyl cyclase activity after chronic inhibition of formation of nitric oxide suggests that nitric oxide plays a modulatory role in formation of cyclic AMP, to which angiotensin II seems to contribute through an angiotensin II type 1 receptor-mediated mechanism.
Adenylyl Cyclases↗
Alterations to the nitric oxide pathway in the spontaneously hypertensive rat.
OBJECTIVES: To examine the role of nitric oxide in the cardiovascular system in spontaneous hypertension. In particular, we wanted to know whether the production of nitric oxide in the cardiovascular system of the spontaneously hypertensive rat is different from that of the normotensive Wistar-Kyoto rat and whether nitric oxide is biologically effective in this system. DESIGN: We studied various aspects of the L-arginine-nitric oxide pathway in the cardiovascular system of spontaneously hypertensive rats and Wistar-Kyoto rats. METHODS: To address the first objective we analysed the expression of endothelial nitric oxide synthase in the heart by Western blotting and the activity of constitutive nitric oxide synthase in resistance microvessels obtained from the mesenterium, both from spontaneously hypertensive rats and Wistar-Kyoto rats aged 14-18 weeks. We also analysed the concentration of the oxidative product of nitric oxide, nitrate, in plasma from these rats. To address the second objective, that is, to assess the bioactivity of nitric oxide, we studied the accumulation in tissue of cyclic guanosine 3',5'-monophosphate (GMP), as well as the acute and chronic effects of withdrawing the nitric oxide vasodilatory tone with the inhibitor of nitric oxide synthesis NG-nitro-L-arginine methyl ester on Wistar-Kyoto rats and spontaneously hypertensive rats. RESULTS: We found that the expression of endothelial nitric oxide synthase in the heart, the activity of constitutive nitric oxide synthase in resistance microvessels and the concentration of nitrate in plasma were all significantly higher in the spontaneously hypertensive rats. In contrast, neither cyclic GMP levels nor the effects of NG-nitro-L-arginine methyl ester were greater in the spontaneously hypertensive rat than they were in the Wistar-Kyoto rat. CONCLUSIONS: The nitric oxide pathway is upregulated in the resistance circulation and the heart of the spontaneously hypertensive rat by a mechanism involving induction of the constitutive nitric oxide synthase and overproduction of nitric oxide. However, nitric oxide is not sufficiently bioactive to stimulate the formation of cyclic GMP and to maintain an adequate nitric oxide-dependent vasodilatory tone.
Animals↗
Differential modulation of the renal and myocardial endothelin system by angiotensin II in Vivo. Effects of chronic selective ETA receptor blockade.
Angiotensin II (Ang II) stimulates endothelin-1 (ET-1) production in glomerular endothelial and mesangial cells and in cardiac fibroblasts in vitro. We investigated the effects of Ang II in vivo (200 ng/kg/min for 2 weeks) with or without the ETA receptor antagonist LU135252 (50 mg/kg/day) on blood pressure, renal and myocardial ET-1 protein expression, and [125I]ET-1 uptake in male Wistar-Kyoto (WKY) rats. ET-1 was extracted from whole kidneys and ventricular myocardium and was measured by radioimmunoassay (pg ET-1/g tissue). Organ tissue uptake was calculated as percentage of total DPM recovered after i.v. administration of radiolabeled [125I]ET-1. Ang II treatment increased blood pressure by 35 +/- 3 mm Hg, which was partly reduced by LU135252 (15 +/- 2 mm Hg, p < 0.05). LU135252 in part prevented the impaired weight gain induced by Ang II (p < 0.05). Ang II induced a threefold increase in expression of ET-1 (pg/g tissue) in kidneys (from 19 +/- 2 to 58 +/- 10, p < 0.05), which was normalized by LU135252 (20 +/- 9, p < 0.05). In myocardial tissue, Ang II had only minor effects (5 +/- 1 vs. 3.6 +/- 1, n.s.). However, concomitant LU135252 treatment reduced myocardial ET-1 levels (1.4 +/- 0.4, p < 0.05 vs. Ang II and control). Ang II increased uptake of [125I]ET-1 in kidneys (from 6.9 +/- 0.1% to 10.9 +/- 0.9% of total DPM, p < 0.05) but not in myocardium (1.45 +/- 0.26% vs. 1.59 +/- 0.18% of total DPM), which was unaffected by LU135252 treatment. These data suggest that the kidney, but not the ventricular myocardium, is a target for Ang II-mediated activation of the ET system in vivo, leading to expression and uptake of ET-1. ETA antagonists may provide a new approach to inhibit production and effects of ET-1 in diseases associated with increased activity of the renin-angiotensin system.
Angiotensin II↗
18FDG-PET for the assessment of primary head and neck tumors: clinical, computed tomography, and histopathological correlation in 38 patients.
OBJECTIVES: To evaluate the clinical usefulness of FDG-PET (fluoro-2-deoxy-glucose-positron emission tomography) in the detection of lymph node involvement and recurrences in patients with head and neck cancer. STUDY DESIGN: Retrospective review of 38 patients with biopsy-proven head and neck cancers who underwent clinical, computed tomography (CT), and FDG-PET examinations. Twenty-five patients were studied prior to therapy and 13 patients were evaluated for disease recurrence. METHODS: All patients were operated and clinical data, CT, and FDG-PET results were correlated with histopathological findings. RESULTS: All primary tumors in 25 patients were detected, with the exception of one small superficial localization of the epiglottis. Histopathological examination showed lymph node involvement in 10 patients; PET detected lymph node involvement in five. FDG-PET found one case of nodal disease not identified by clinical and CT examination. With so few cases, this could be anecdotal. Five false-negative results (microscopic lymph node involvement) and two false positives were noted. Twelve of 13 patients with recurrent disease were correctly identified with FDG-PET. FDG-PET was the only imaging technique to identify local recurrence in two patients and lymph node involvement in two others. One false-positive result occurred in a patient with a foreign body granuloma. CONCLUSIONS: FDG-PET is a useful diagnostic modality for the detection of recurrent tumors and, in selected cases, precise lymph node involvement. The best way to further investigate the utility of clinical FDG-PET is in the follow-up of treated patients.
Adult↗
Transport of sterols to the plasma membrane of leek seedlings
To investigate the intracellular transport of sterols in etiolated leek (Allium porrum L.) seedlings, in vivo pulse-chase experiments with [1-14C]acetate were performed. Then, endoplasmic reticulum-, Golgi-, and plasma membrane (PM)-enriched fractions were prepared and analyzed for the radioactivity incorporated into free sterols. In leek seedlings sterols are present as a mixture in which (24R)-24-ethylcholest-5-en-3beta-ol is by far the major compound (around 60%). The other sterols are represented by cholest-5-en-3beta-ol, 24-methyl-cholest-5-en-3beta-ol, (24S)-24-ethylcholesta-5,22E-dien-3beta-ol, and stigmasta-5, 24(24(1))Z-dien-3beta-ol. These compounds are shown to reside mainly in the PM. Our results clearly indicate that free sterols are actively transported from the endoplasmic reticulum to the PM during the first 60 min of chase, with kinetics very similar to that of phosphatidylserine. Such a transport was found to be decreased at low temperature (12 degreesC) and following treatment with monensin and brefeldin A. These data are consistent with a membrane-mediated process for the intracellular transport of sterols to the PM, which likely involves the Golgi apparatus.
Journal Article↗
Molecular and immunologic aspects of the nonclassical HLA class I antigen HLA-G: evidence for an important role in the maternal tolerance of the fetal allograft.
PROBLEM: Human leukocyte antigen (HLA)-G is a major histocompatibility complex class I antigen, which is referred to as nonclassical because it displays a tissue-restricted distribution in the placenta, a reduced cytoplasmic domain, a limited polymorphism, and several isoforms. The HLA-G antigen is thought to play an essential role during pregnancy by protecting the semi-allogeneic fetus from recognition and destruction by maternal immune cells. METHOD OF STUDY: Alternative splicing of HLA-G mRNA was analyzed by Southern blot of reverse transcriptase-polymerase chain reaction products from trophoblasts of the first trimester of gestation and term placenta. The regulation of HLA-G gene expression was investigated by electrophoretic mobility shift assays using nuclear extracts from cells expressing different levels of HLA-G gene activity. Using polymerase chain reaction-single strand conformational polymorphism and sequencing, we studied HLA-G gene polymorphism in families from the Centre d'Etude du Polymorphisme Humain in Paris. To understand the function of the HLA-G molecule, cytotoxicity assays were carried out with peripheral blood mononuclear cells or polyclonal natural killer effectors cells from 30 different donors against HLA-G1 and HLA-G2 transfectants. RESULTS: Four main aspects have been elucidated: 1) The primary transcript of the HLA-G gene is alternatively spliced into five main mRNA forms: HLA-G1 (full length), HLA-G2 (minus exon 3), which encodes a membrane-bound isoform associated with beta-2 microglobulin, HLA-G3 (minus exons 3 and 4), HLA-G4 (minus exon 4), and HLA-G5 (plus intron 4), which encodes a soluble form of the HLA-G antigen; 2) specific nuclear factors bind to an important regulatory element located more than 1.2 kb from the HLA-G gene. Three specific complexes are observed in cells that show HLA-G transcriptional activity and an additional factor that could correlate with the repression of HLA-G gene expression that is detected in natural killer cells; 3) we observed an important genomic polymorphism in exon 3 but a very low polymorphism at the protein level; 4) HLA-G1 and HLA-G2 transfectants clearly demonstrated that both HLA-G isoforms are capable of inhibiting natural killer lytic activity. CONCLUSION: These results suggest that HLA-G acts as the public ligand for natural killer inhibitory receptors, thus protecting the fetus against maternal rejection.
Alternative Splicing↗
ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension.
Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190+/-4 versus 152+/-2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49+/-4% versus 81+/-4%, P<.0001) and contractions to ET-1 (92+/-7 versus 136+/-8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168+/-3 versus 190+/-4 mm Hg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET(A) receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
Acetylcholine↗
Effect of chronic nitric oxide deficiency on angiotensin II-induced hypertrophy of rat basilar artery.
BACKGROUND AND PURPOSE: Although in vitro studies suggest that nitric oxide has an inhibitory effect on cellular proliferation and migration, in vivo experiments failed to support this conclusion. The present study was designed to determine the effect of endogenous nitric oxide on angiotensin II-induced hypertrophy of small arteries in vivo. METHODS: Angiotensin II (200 ng/kg per minute), alone or in combination with N(omega)-nitro-L-arginine methyl ester (L-NAME) (60 mg/kg per day), was administered for 2 weeks in normotensive rats. Basilar arteries were harvested, and their geometry was determined in perfused and pressurized conditions. RESULTS: Angiotensin II increased media thickness, media-lumen ratio, and cross-sectional area of the arteries, confirming the presence of hypertrophic remodeling. The concomitant administration of L-NAME, an inhibitor of nitric oxide synthesis, prevented vascular hypertrophy. The remodeling of the basilar artery geometry in the combined treatment was of eutrophic nature, similar to that observed with the administration of L-NAME alone. CONCLUSIONS: Our results suggest that endogenous nitric oxide does not inhibit angiotensin II-induced vascular hypertrophy in vivo. Nitric oxide may even be a necessary factor for hypertrophy to develop.
Analysis of Variance↗
Early intensive therapy with autologous stem cell transplantation in high-risk Hodgkin's disease: long-term follow-up in 35 cases.
Thirty-five adult patients with high-risk HD (HD) defined by (1) Ann Arbor stage IV or bulky nodal disease (tumor/thorax ratio > 0.45) and (2) no or partial response (PR) (< 75%) to the initial 3 courses of ABVD, received an early intensive therapy with autologous stem cell transplantation (ASCT). Thirty patients were considered as partial responders and 5 as refractory to initial chemotherapy. Conditioning regimen consisted of chemotherapy alone (CBV in 11 patients before 1993, BEAM in 13 patients since 1993) followed by adjuvant radiotherapy: 40 Gy) on the initial sites of bulky disease, or 12 Gy total body irradiation plus 120 mg/kg cyclophosphamide in 11 patients with disseminated extra-nodal disease. All 30 patients in PR at the time of ASCT experienced prolonged complete remission (CR). One patient died in CR from an acute myocardial infarction 48 months after ASCT. Four out of the 5 patients with refractory disease at the time of ASCT experienced rapid progression of HD leading to death in 3 cases. After 6 years of CR post-ASCT, the last refractory patient died of myelodysplastic syndrome diagnosed 2 years after intensive therapy. With a median follow-up for surviving patients of 51 months (range: 11-111), the cumulative probability of 8-year overall survival is 75.6% for the entire group of patients, 94.1% for the chemosensitive ones, and 0% for the primary refractory (P < .0001). The cumulative probability of 8-year event-free survival is 79.9% for the entire group of patients, 94.1% for the chemosensitive ones, and 0% for the primary refractory (P < .0001). We conclude that early intensive therapy with ASCT is feasible in patients with high-risk HD and induces a high cure rate in chemosensitive patients. In primary refractory patients, new therapeutic approaches are warranted.
Adolescent↗
An unusual complication of panendoscopy of the upper aero-digestive tract: esophageal perforation. A report of 3 cases.
Three cases of iatrogenic esophageal perforation are presented from a series of 1275 panendoscopies of the upper aero-digestive tract utilising rigid esophoscopy (0.24%). In all cases, the diagnosis was made during the endoscopy permitting immediate surgical treatment under the same anesthesia, via thoracoscopy or laparoscopy in two cases and by means of thoracotomy in the remaining case. The perforation was localised at the level of the inferior third of the esophagus in all three cases. In spite of the early intervention, there was one mortality in a patient whose pre-existing fibrothorax created a hazardous terrain.
Adult↗
French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance.
Fifty French previously untreated patients with severe hemophilia A (factor VIII < 1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (> or = 10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.
Child↗