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Resume Introduction Le lymphome a grandes cellules B intravasculaire est une proliferation de cellules tumorales aboutissant a l’occlusion de la lumiere des petits vaisseaux. Il s’agit d’une hemopathie maligne rare et de diagnostic difficile en raison d’une presentation clinique polymorphe. Observation Nous rapportons ici l’observation d’un patient atteint d’un lymphome intravasculaire revele par un syndrome d’activation macrophagique. Cette association est tres souvent marquee par une plus grande severite clinique et impose une prise en charge therapeutique precoce et adaptee. Conclusion En raison du caractere polymorphe et de la presentation systemique du lymphome a grandes cellules B intravasculaire, l’interniste peut etre confronte a cette pathologie, plus grave encore lorsqu’elle s’associe a un syndrome d’activation macrophagique. Il faut donc savoir l’evoquer d’autant que le pronostic depend de la rapidite de la prise en charge avec notamment la mise en route precoce d’une polychimiotherapie associee au rituximab.

Resume La survie des patients ayant un lymphome de Hodgkin s’est nettement amelioree ces dernieres annees, avec cependant une augmentation des complications tardives, en particulier neoplasiques. Nous rapportons l’observation d’un patient ayant presente une rechute d’un lymphome de Hodgkin classique concomitante a la decouverte d’un adenocarcinome bronchique, 20 ans apres la prise en charge initiale par chimiotherapie de type Mopp et radiotherapie en mantelet. Les mecanismes physiopathologiques de ces complications sont discutes. Une surveillance prolongee est necessaire chez tous les patients ayant un lymphome de Hodgkin.

Lead is known to induce hematological disturbances resulting from abnormalities in cell differentiation and hemoglobin synthesis during hematopoiesis. The aim of the present work was to study human erythropoiesis in vitro in the presence of lead. Human erythroblastic progenitors, burst-forming units-erythroid (BFU-E), were exposed to lead acetate at increasing concentrations during 14 days of culture. Hematotoxicity was evaluated in vitro according to proliferation and differentiation of cell colonies arising from BFU-E development. The ability of cells to synthesize proteins, porphyrins, and hemoglobin was measured by spectrophotometric tests and by high-pressure liquid chromatography (HPLC). Results showed that in the presence of 10(-3) mol/L lead acetate, no hemoglobinized cells were observed in culture and no fluorescent porphyrins were detected in cells. Up to 10(-3) mol/L, lead acetate is not cytotoxic, i.e., it does not induce cell destruction. The present work demonstrates that lead acetate interferes with the porphyrin synthesis of human erythroblastic progenitors in vitro. The decrease of porphyrin content with 10(-5) mol/L lead acetate suggest that delta-aminolevulinic acid dehydratase can be inhibited by lead acetate during in vitro erythropoiesis. In vivo erythropoiesis occurs in the bone marrow. As about 95% of the body burden of lead in adults is located in the bones with a biological half-life of some years, the concentration of lead acetate found to block porphyrin synthesis in vitro has to be compared with in situ bone marrow lead concentrations.

The rapid rate of blood cell renewal makes the hematopoietic system a susceptible target for xenobiotic toxicity, and xenobiotics could interfere with cell proliferation and differentiation. Hematotoxic molecules can affect one or more hematopoietic lineages, leading to blood disorders (neutropenia, agranulocytosis, thrombopenia, anemia, and pancytopenia). Erythropoiesis is the part of hematopoiesis responsible for red blood cell production by proliferation and differentiation of specific erythroblastic progenitors, the BFU-E/ CFU-E (Burst and Colony-Forming Unit-Erythroid). Some drugs and chemicals (antituberculosis drugs, chloramphenicol, penicillamines, ethanol, and lead) are able to cause dysfunction in heme biosynthesis and are responsible for hematological diseases such as porphyrias. The aim of this work was to obtain a useful tool to predict the toxic effect of xenobiotics in the proliferation or erythroblastic progenitors and on their differentiation. Optimal growth conditions for erythroblastic ...

T-2 toxin is a trichothecene mycotoxin produced by vari ous species of fungi. Trichothecenes are known as major contaminants of cereals and their derivatives. In man as well as in animals, T-2 toxin has been shown to induce ali mentary intoxication and, among others, haematological symptoms. Granulo-monocytic progenitors from human umbilical cord blood on the one hand and granulo-mono cytic progenitors from rat bone marrow on the other, were cultured in the presence of T-2 toxin (from 10-7to 10-10M) for 14 days. A study of concentration and effect relation ships showed a strong and rapid effect of T-2 toxin on rat colony forming unit-granulocyte and macrophage (CFU-GM) between 5.10-9M and 10-9M. On the other hand, human CFU-GM were able to grow in the presence of the same T-2 toxin concentrations. IC50were determined on day 7, 10 and 14. They were, respectively, 1.6.10-9 M; 3.6.10-9M; 1.4.10-9M for human cells, and 2.2.10-9M; 3.3.10-9M; 2.6.10-9M for rat cells. The present study was prompted by the need to define precisely the cytotoxic and inhibitory T-2 toxin concentrations for rat and human CFU-GM. It is particularly relevant for the investigation of cellular T-2 toxin targets and in order to elucidate the mechanism of trichothecene haematotoxicity.

Phloem necrosis of rubber tree (Hevea brasiliensis) is characterized by cell wall degradation, alteration of the middle lamella, the vesiculation of endomembranes, the formation of tylosoids and the internal coagulation of rubber

In patients with hematological malignancy (HM) developing acute respiratory failure (ARF) bronchoalveolar lavage (BAL) is considered as a major diagnostic tool. However, the benefit/risk ratio of this invasive procedure is probably lower in the subset of patients with acute myeloid leukemia (AML). The study was to analyze the yield of BAL performed in HM patients (n=175) with AML or lymphoid malignancies (LM) admitted in intensive care unit (ICU) for ARF and pulmonary infiltrates. BAL was performed in 121 patients (53/73 AML patients (73%) and 68/102 LM patients (67%)) without a definite diagnosis at admission or contraindication for fiberoptic bronchoscopy. Life-threatening complications were noticed in 12/121 patients (10%). The overall diagnostic yield of BAL was 47% (25/53) in AML patients and 50% (34/68) in LM patients. A microorganism was recovered from BAL in 23% (12/53) of AML patients and 41% (28/68) of LM patients (P

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

Summary Background Some patients treated by transplantation of haemopoietic stem cells (peripheral blood or bone marrow) become permanently infertile, but others retain or recover fertility. We assessed the outcome of conception in women, and partners of men previously treated by autologous or allogeneic stem cell transplantation (SCT). Method We sent questionnaires to 229 centres of the European Group for Blood and Marrow Transplantation. We sought details about the original disease, transplant procedure, and outcome of conception for both male and female patients. Findings 199 centres gave information relating to 19 412 allogeneic and 17 950 autologous transplant patients. 232 (0·6%) patients conceived after SCT. Crude annual birth rate for 4-month survivors of SCT was lower than the national average for England and Wales at 1·7 per 1000 patients. 312 conceptions were reported in 113 patients (74 allograft) and partners of 119 patients (93 allograft). Most pregnancies were uncomplicated and resulted in 271 livebirths. 28 (42%) of 67 allograft recipients had caesarean section compared with 16% in the normal population (difference=26% [95% CI 15–38]), 12 (20%) of 59 had preterm delivery compared with a normal rate of 6% (14% [4–24]), and 12 (23%) of 52 had low birthweight singleton offspring compared with a normal rate of 6% (17% [6–29]). Interpretation Pregnancy after SCT is likely to have a successful outcome. Pregnancies in allograft patients who have received total body irradiation should be treated as high risk for maternal and fetal complications.

Aim In order to assess the influence of total-body irradiation (TBI) on the outcome and incidence of complication after bone marrow transplantation (BMT), we retrospectively analyzed our patients treated for acute leukemia and conditioned with TBI prior to BMT. Patients and Methods Between 1980 and 1993, 326 patients referred to our department with acute non-lymphoblastic leukemia (ANLL, n=182) and acute lymphoblastic leukemia (ALL, n=144) in complete remission underwent TBI either in single dose (190 patients: 10 Gy administered to the midplane, and 8 Gy to the lungs [STBI]) or in 6 fractions (136 patients: 12 Gy on 3 consecutive days, and 9 Gy to the lungs [FTBI]) before BMT. The male-to-female ratio was 204/122 (1.67), and the median age was 30 years (mean: 30 ± 11, range: 3 to 63). The patients were analyzed according to 3 instantaneous dose rate groups: 118 patients in the LOW group (≤0.048 Gy/min), 188 in the MEDIUM group (> 0.048 and ≤ 0.09 Gy/min), and 20 in the HIGH group (> 0.09 cGy/min). Conditioning chemotherapy consisted of cyclophosphamide (CY) alone in 250 patients, CY and other drugs in 54, and 22 patients were conditioned using combinations without CY. Following TBI, allogeneic and autologous BMT were realized respectively in 118 and 208 patients. Median follow-up period was 68 months (mean: 67 ± 29, range: 24 to 130 months). Results Five-year survival, LFS, RI and TRM rates were 42%, 40%, 47%, and 24%, respectively. Five-year LFS was 36% in the STBI and 45% in the FTBI group (p = 0.17). It was 36% in the LOW group, 42% in the MEDIUM group, and 30% in the HIGH group (p > 0.05). Five-year RI was 50% in STBI, 43% in FTBI, 55% in LOW, 41% in MEDIUM, and 44% in HIGH groups (STBI vs. FTBI, p = 0.48; LOW vs. MEDIUM, p = 0.03: MEDIUM vs. HIGH, p = 0.68). TRM was not influenced significantly by the different TBI techniques. When analyzing separately the influence of fractionation and the instantaneous dose rate either in ANLL or ALL patients, no difference in terms of survival and LFS was observed. Fractionation did not influence the 5-year RI both in ANLL and ALL patients. However, among the patients with ANLL, 5-year RI was significantly higher (58%) in the LOW group than the MEDIUM group (31%, p = 0.001), whereas instantaneous dose rate did not significantly influence the RI in ALL patients. The 5-year TRM rate was significantly higher in allogeneic BMT group both in ANLL (37%) and ALL (37%) patients than those treated by autologous BMT (ANLL: 15%, ALL: 18%: p = 0.002 and 0.02, respectively). The 5-year estimated interstitial pneumonitis (IP) and cataract incidence rates were 22% and 19%, respectively, in all patients. IP incidence seemed to be higher in the HIGH group (46%) than the MEDIUM (19%, p = 0.05) or LOW (25%, p = 0.15) groups. Furthermore, cataract incidence was significantly influenced by fractionation (STBI vs. FTBI, 29% vs. 9%; p = 0.003) and instantaneous dose rate (LOW vs. MEDIUM vs. HIGH, 0% vs. 27% vs. 33%; p < 0.0001). Multivariate analyses revealed that the best factors influencing the survival were 1st CR (p = 0.0007), age ≤ 40 years (p = 0.003), and BMT after 1985 (p = 0.008). The RI was influenced independently only by the remission status (p = 0.0002). On the other hand, the TRM rate was lower in patients who did not experience graft-vs.-host disease (GvHD, p < 0.0001), and in those treated after 1985 (p = 0.0005). GvHD was the only independent factor involved in the development of IP (p = 0.01). When considering the cataract incidence, the only independent factor was the instantaneous dose rate (p = 0.0008). Conclusion The outcome of BMT patients conditioned with TBI for acute leukemia was not significantly influenced by the TBI technique, and TRM seemed to be lower in patients treated after 1985. On the other hand, cataract incidence was significantly influenced by the instantaneous dose rate.

Trichothecenes are mycotoxins produced by various species of fungi which can occur on various agricultural products. Among these compounds, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) are the most naturally encountered and potent trichothe cenes. Consumption of trichothecene contaminated foods by farm animals and humans leads to mycotoxicoses. Trichothecenes are known to induce haematologic dis orders such as neutropenia, thrombopenia, and aplastic anemia in human and animals. The aim of our investigations is to explore the effects of trichothecenes on the haematopoietic progenitors. The four trichothecenes previously demonstrated to be strongly cytotoxic for human CFU-GM have been tested on human BFU-E. For this purpose, a culture model of human erythroblastic progenitors (BFU-E) optimized for toxicological studies was used to determine the effects of T-2, HT-2, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) on red blood cell precursor proliferation and differentiation. Results showed that human BFU-E are as sensitive to trichothecenes as human CFU-GM, except for DON, in the range of concentrations tested. Differentiation of erythroblastic progenitors could be perturbed by these mycotoxins. Human erythroblastic progenitors are also a target of trichothecenes.

Two successive studies comparing tazocilline (12 g piperacillin + 1.5 g tazobactam/ day) + aminoside (15 mg/k/day amikacin in the first trial, 3 mg/kg/d tobramycin in the second) to ceftazidime (3 g/day) + aminoside included 466 febrile episodes in profoundly neutropenic patients after chemotherapy (or chemo-radiotherapy) for hematological malignancies. Patients were treated for acute leukemia (72%), or autografted for non-Hodgkin lymphoma or myeloma (25%), few patients for solid tumors. The mean duration of neutropenia was 21 days ± 11 (92% > 7 days); 466 febrile episodes were analysed for intention-to-treat, and were attributed to bacteremia in 119 cases, to local infection in 178 cases, and were of unknown origin (FUO) in 169 cases. A majority of Gram positive strains (55.5%) was isolated at day 0. The 72 h apyrexia was obtained more often (51.6% of the cases) with Tazocillin + aminoside than with ceftazidime + aminoside (33.6%, p < 0.0001). This results was due to a better control of bacteremia (p = 0.03) and local infection (p = 0.006) with tazocillin + aminoside, but not FUO (p = 0.19). Identical results of both antibiotic associations were observed during the first course of antitumoral chemotherapy, but tazocillin was significantly superior for 72 h apyrexia when fever occurred during consolidation therapy (p < 0.0001) or relapse treatment (p = 0.006). Superinfections due to Gram positive strains and major infectious events (infectious deaths and retardations of underlying disease treatment due to infection) were less frequent when patients received tazocillin + aminoside (respectively p = 0.002 and p = 0.02). The initial empirical antibiotic association remained unchanged and lead to a persisting apyrexia in only 20.3% of the cases treated with tazocillin + aminoside, but this was significantly better than with the other association (9.5%, p = 0.02).

Thirteen patients (pts) with highly refractory acute myeloid leukemia (AML) 10 pts with de novo AML and 3 with blast crisis of chronic myeloid leukemia were treated with carboplatin (CP) 150 mg/m2/day through continuous IV infusion for 7 consecutive days. Seven of them received CP at least as third or more line therapy after a median duration of the disease of 26 weeks. None achieved a complete remission but a good hematologic response, with disappearance of circulating blast cells along with correction of bone marrow failure, persisting for 3 months was obtained in one patient and correction of hyperbasophilemia was observed in another with blast crisis of chronic myelogenous. Myelosuppression was the most consistent toxic effect. Two deaths occurred, one from renal acute failure and the other from sepsis. Median survival after CP was 8 weeks (range 4 days-11 months) and the majority of patients were able to return home. When used as a single agent and with the dose-schedule used in this study, CP does not appear effective in refractory AML. Other studies are necessary to assess its role at an higher dose or in combination with other agents in earlier phases of the disease.

Blood dyscrasias such as aplastic anaemia and leukopenia are described following the use of lindane for agricultural purposes or against ectoparasites in animal and human health. In order to determine the involvement of lindane in these effects, an in vitro model of haematotoxicity evaluation has been used.Culture of haematopoietic progenitors, Colony Forming Unit-Granulocyte and Macrophage (CFU-GM), have been performed in the presence of lindane with increasing concentrations.Results showed that lindane was cytotoxic for human progenitors. They were one thousand times more sensitive to the lindane than rat CFU-GM.This cytotoxicity was observed with lindane concentrations similar to those measured in human blood in cases of acute intoxication and in fat tissues of exposed populations.

On rubber plantations Hevea brasiliensis is attacked mainly by Rigidoporus lignosus and Phellinus noxius, two Basidiomycete causing white rots (they degrade lignin) of tree roots. Some infected trees were shown to survive to the fungal aggression, both in field and greenhouse conditions, pointing out that rubber trees are able to develop successful reactions. Therefore host reactions were extensively investigated both at cellular and molecular levels.

Three phenol oxidases, of which two are excreted byRigidoporus lignosus and one byPhellinus noxius, have been isolated and purified from culture filtrates. Based on their substrate specificities and spectral characteristics, these enzymes arep-diphenol : oxygen oxidoreductases (laccases; EC 1.10.3.2). A number of their physicochemical properties have been determined. The fact that the two parasites excrete laccases indicates that they belong to the group of lignin degrading (white rot) fungi. Laccase L1 fromR. lignosus was purified to homogeneity.

The acitivty and spatial distribution of eight enzymes in adult tap root tissues colonized by R. lignosus and P. noxius are investigated. Their physiological significance in the pathogenic process is discussed.

In the present study, we report the results of our evaluation of the use of the continuous-flow cell separator Cobe 2997 to isolate from human bone marrow (BM) aspirates the mononuclear cell (MNC) fraction containing hematopoietic stem cells. This MNC concentrate is isolated in 15% of the original BM volume and contains 23% of the initial nucleated cells. It is enriched as concerns the BM MNC fraction (lymphocytes + monocytes recovery; 80%), whereas the contamination with granulocytes, red blood cells and platelets is reduced to 7.2, 1.5% and 41%, respectively, of the cells initially present in the BM suspensions. Furthermore, it is demonstrated that this MNC concentrate is highly enriched in granulocyte-macrophage-colony-forming cells (CFU-GM; recovery 83%). The method is simple, inexpensive, efficient and reproducible. It allows rapid processing of a large volume of BM without substantial loss of hematopoietic progenitor cells. It represents a valuable method of BM MNC concentration prior to further in vitro manipulations such as T cell or tumor cell depletion or cryopreservation.

Pathogenicity and physiological characteristics were studied for the two populations of isolates. Exidence of variations has been demonstratcd for each fungus but no correlations could be established between the in vivo and in vitro parameters.

A study on biochemical mechanisms of the rubber tree aggression by two root rotting fungi Rigidoporus lignosus and Phellinus noxius was carried out. The activity of eight enzymes and their spatial distribution in adult tap root tissues were measured. Finally their origin, host or parasite, and physiological signification in the pathogenic process were discussed.

A patient with aplastic anaemia, successively treated with caspofungin then liposomal amphotericin, developed a disseminated infection due to Acremonium, further confirmed as resistant in vitro to these drugs. Successful treatment was achieved with voriconazole. Multiple antifungal treatments may expose to the risk of breakthrough of multi-resistant pathogens in haematology patients.

On estates, the rubber-tree, Hevea brasiliensis , is subject to a variety of diseases. Among them, root rots caused by Rigidoporus lignosus and Phellinus noxius are responsible for severe losses. When these parasites infect the roots they induce an increase in the peroxidase activity in the host tissues. Similar increases are shown in reaction zone tissues developed in response to Sphaerostilbe repens injury and in similar zones sometimes developed in R. lignosus infection, but then always devoid of any parasite. Comparative biochemical studies of the peroxidases from different types of tissue, including chromatographic separation into different peroxidase fractions, purification of one of the isoperoxidases and determination of some of its physico-chemical characteristics, lead to the following conclusions: (a) one isoperoxidase is mainly responsible for the increase in enzyme activity; (b) this isoenzyme is synthesized, probably de nova , by the host, not by the parasites, and thus represents a host reaction to parasite infection; (c) the presence of the parasite causes the tissue to produce this particular isoenzyme in excess of the amount normally found in healthy tissue; (d) this isoperoxidase polymerizes coniferyl alcohol, therefore it may contribute to the lignification reaction which was previously shown to occur. Thus, the peroxidase reaction may be involved, among others, in the host defence mechanisms.

In vitro wood slats degradation assays reveal that both the white root rot fungus R. ligitosus and the brown root rot fungus P. noxius cause a white rot of wood. In vivo (infected tap roots) they cause the same type of decay. Nevertheless lignin determination show the rubber-tree ability to react against the parasite aggression by increased lignification of tissues.

A method for the selective removal of red blood cells (RBC) from bone marrow cell suspension is described. The technique is based on the use of a dense (D = 1.090) Ficoll gradient, and a low speed centrifugation. Results show that more than 90% of the nucleated cells (NC) could be collected by this technique. RBC contamination in the NC fraction was less than 1 RBC per 8 NC. 1 NC per 1300 or more RBC was found in the pellet. This method may provide a useful step in the standardization of the bone marrow cell suspension for in vitro studies on colony forming cells as well as for any other experiment requiring purified red cell or nucleated cell populations.