Methods: All patients with DLBCL and renal extranodal involvement diagnosed from January 1, 1982 to August 1, 2007 at the British Columbia Cancer Agency were retrospectively identified in the Lymphoid Cancer Database. Patients were included if they were >16 years old, had advanced stage (stage III /IV, or stage I /II with B symptoms or bulky (>10cm)) disease, were treated with curative intent and free of CNS involvement at diagnosis.

Les limitations à l’exercice des patients atteints de bronchopneumopathie chronique obstructive (BPCO) représentent un handicap important. Elles sont multifactorielles mais le poids des perturbations spirométriques, cardiovasculaires ou musculaires périphériques qui pourraient être impliquées est imparfaitement connu. L’importance du taux de précurseurs endothéliaux circulants chez les patients BPCO a été notée dans plusieurs travaux, mais les mécanismes de stimulation aboutissant à leur mise en circulation restent imprécis. Pour répondre à ces questions, nous avons étudié de façon prospective 26 patients BPCO. Nous avons réalisé une étude de l’hémodynamique de repos par cathétérisme cardiaque droit, des épreuves fonctionnelles respiratoires avec gazométrie artérielle et capacité de transfert du CO, un test de marche de 6 minutes, une épreuve d’effort maximale à charge incrémentielle sur bicyclette avec mesure des principaux paramètres cardiorespiratoires. Les précurseurs endothéliaux circulants ont été mesurés au repos et des dosages successifs ont été réalisés après l’arrêt de l’exercice (n = 5 patients). Les variables corrélées à la VO2 maximale sont reproduites dans ce tableau:variablesrpspirométrie et DLCOVEMS0,4< 0,05DLCO0,620,002hyperinflation dynamiquevolume minute maximale0,7< 0,0001Vd/Vt à l’exercice0,84< 0,0001variables cardiovasculairesévolution du pouls entre repos et exercice0,69< 0,0001pression artérielle systolique de repos0,420,03pression artérielle diastolique de repos0,460,02 Nous ne retrouvons pas de lien avec l’hématose de repos ou d’effort, l’hémodynamique ou les taux de précurseurs endothéliaux. Ce dernier n’est pas plus élevé à l’arrêt immédiat de l’exercice (0,089 + 0,1 vs. 0,08 + 0,089 p = NS) qu’au repos mais augmente dans l’heure suivant l’arrêt de l’effort. Ces données préliminaires confirment l’importance de l’hyperinflation dynamique dans la limitation à l’effort dans la BPCO. La réserve chronotrope semble déterminante dans la limitation à l’exercice. La chronologie d’évolution des précurseurs endothéliaux à l’exercice oriente vers certains mécanismes de stimulation.

The characteristics of severe neutropenia with delayed onset following administration of rituximab were evaluated in 293 consecutively patients treated for B-cell malignancies between Oct. 1996 and Feb. 2004. Eighteen episodes of severe neutropenia were identified between 2 to 36 weeks after rituximab, delivered alone in 4 cases or combined to chemotherapy in 14 other cases. At the time of occurrence of neutropenia, 10 patients had completed treatment and were in complete remission and 8 were still on therapy. All patients had a normal neutrophil count before rituximab treatment. In 4 cases, neutropenia was complicated by fever requiring hospitalisation. Among the18 patients [diffuse large B-cell lymphoma: 12, follicular lymphoma: 3, mantle cell lymphoma: 1, post transplant lymphoproliferative disorder: 1, chronic lymphocytic leukemia (CLL): 1], 8 had previouly been treated with high-dose therapy followed by autologous stem-cell transplantation. None of the known causes of neutropenia were found. Neutropenia was associated with selective marrow depletion of neutrophil precursors in all episodes. The peripheral blood lymphocyte subset repartition was documented in 16 cases; a severe B lymphopenia was observed in all except one - patient with CLL - and CD4+ lymphopenia was seen in 13. T-cell clonality was studied in 8 cases and was positive in 5. Parvovirus B19 DNA was not detected in the 11 tested cases. Tests for antineutrophil antibodies were positive in 5 cases; no hemolytic anemia, autoimmune thrombocytopenia or large granular natural killer lymphocytosis were observed. Filgrastim was given to 4 patients only. The median time of neutrophil recovery for the entire group was 14 days (range: 2–180).

Myelodysplastic syndromes (MDSs) are heterogeneous diseases of bone marrow (BM) cell precursors for which immunophenotypic characterization is still considered irrelevant despite the accuracy and sensitivity of flow cytometry techniques. The aim of this study was to determine whether immunophenotypic abnormalities could be defined in MDSs and could correlate with the French-American-British classification and cytogenetics. Analysis was performed on 275 BM samples (207 MDS patients, 68 controls) and 25 control blood samples. Immunophenotyping was based on a primary gating of blast cells, monocytes, and granulocytes according to CD45 antigen expression and side scatter light diffraction. Immunophenotypic hierarchical clustering was performed to analyze the results. The data obtained show that (1) immunophenotypic clustering partly discriminates patients with refractory anemia with excess blasts/refractory anemia with excess blasts in transformation (RAEB/RAEB-T), chronic myelomonocytic leukemia (CMML), and refractory anemia/refractory anemia with ring sideroblasts (RA/RARS) for CD45(lo) blast cells and patients with RA/CMML, RARS, and RAEB/RAEB-T for CD45(hi)/side scatter(hi) (SS(hi)) granulocytes; (2) the most discriminating markers were CD16, CD34, CD36, CD38, CD71, and HLA-DR for blast cells and CD11b, CD13, CD33, CD36, CD38, CD71, and HLA-DR for CD45(hi)/SS(hi) granulocytes; (3) clusters related to CD34 expression were associated with high levels of blast cells on BM smear; (4) clusters related to high levels of CD36 expression on CD45(lo) blast cells and CD45(hi)/SS(hi) granulocytes were associated with a poor International Prognosis Scoring System score; and (5) high levels of CD71 expression on CD45(hi)/SS(hi) granulocytes were associated with the RARS category. These results show a close relationship between immunophenotypic abnormalities and BM dysplasia and suggest that flow cytometry could be a future tool for the characterization of MDSs.

The reciprocal t(4;11)(q21;q23) is often described in acute lymphoblastic leukemia (ALL). In some cases, variant or complex t(4;11) has been detected in ALL by cytogenetic analysis, but to our knowledge no molecular study has been reported in these variant translocations. We describe a 27-year-old woman suffering from pre-B-cell ALL with an unusual rearrangement between chromosomes 4 and 11. Because this complex rearrangement involved the 11q23 chromosome band known to be associated with poor prognosis, we performed fluorescence in situ hybridization, Southern blot, and reverse transcription polymerase chain reaction analyses. This confirmed myeloid lymphoid leukemia gene rearrangement and showed the presence of MLL/AF4 fusion transcript. These results showed the importance of molecular analysis that allowed minimal residual disease monitoring in this patient.

The tal-1 gene encodes a basic helix-loop-helix (bHLH) transcription factor required for primitive and definitive hematopoiesis. Additionally, ectopic activation of the tal-1 gene during T lymphopoiesis occurs in numerous cases of human T-cell acute lymphoblastic leukemia. With the use of transgenic mice, we show that, in adult hematopoiesis, constitutive expression of TAL-1 protein causes disorders in the hematopoietic lineages that normally switch off tal-1 gene expression during their differentiation process. Myelopoiesis was characterized by a moderate increase of myeloid precursors and by Sca-1 antigen persistence. Although no lymphoid leukemia was observed, T lymphopoiesis and B lymphopoiesis were severely impaired. Transgenic mice showed reduced thymic cellularity together with a decrease in double-positive cells and a concurrent increase in the single-positive population. B cells exhibited a differentiation defect characterized by a reduction of the B-cell compartment most likely because of a differentiation block upstream of the intermediate pro-B progenitor. B cells escaping this defect developed normally, but transgenic splenocytes presented a defect in immunoglobulin class switch recombination. Altogether, these results enlighten the fine-tuning of TAL-1 expression during adult hematopoiesis and indicate why TAL-1 expression has to be switched off in the lymphoid lineages.

Among six synthetic retinoids tested, the retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) was highly efficient in inducing growth inhibition of 8MG-BA and GL-15 human glioblastoma cell lines, with growth arrest at the S phase of the cell cycle. CD 437 also induced apoptosis in these cells, with 8MG-BA being the most sensitive. In these cells, induction of apoptosis by CD437 has been related to the downregulation of Bcl-2 expression and to CPP32 activation, but not to p53 expression. The remaining non-apoptotic cells presented a morphological pattern of astroglial differentiation with overexpression of glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). The mechanism of action of CD437, originally developed as a RARγ agonist, is not yet elucidated. However, our results suggest that it acts through an increase of the expression of retinoid-inducible genes, such as RARβ2 and/or RARα2.

Background Chimerism analysis is essential in understanding the etiology of graft failure occurring after allogeneic stem cell transplantation. The detection of marrow and/or blood host cells suggests graft rejection, relapse of the underlying disease, or a state of stable mixed chimerism, However, complete donor chimerism may be observed in some cases. Our objective was to characterize, by a sensitive process of chimerism analysis, six cases of graft failure occurring after transplant.Methods. Six cases of secondary graft failure, in which previous analysis had shown complete donor chimerism by standard polymerase chain reaction amplification of variable number of tandem repeats, were studied. In order to detect a minority population of recipient cells, we increased the sensitivity of the process by using fluorescent polymerase chain reaction and analyzing the origin of T, B, and natural killer lymphocytes at the time of graft failure.Results, The complete donor origin of mononuclear cells and lymphocytic populations was confirmed with this method in five of six patients, In the remaining patient, diagnosis of graft failure was clarified by the detection of a previously undetected mixed chimerism, compatible with graft rejection. in the other five patients, graft rejection was thereby excluded and graft failure could be related to viral infection or to graft-versus-host disease.Conclusion. Our sensitive process of fluorescent lineage-specific chimerism analysis may help in distinguishing between graft rejection and other mechanisms of graft failure, which is essential for deciding appropriate therapy.

To address the value of ex vivo expanded haematopoietic cells for shortening cytopenia in autologous haematopoietic transplantation, we designed an ex vivo expansion protocol based on a cocktail of early acting cytokines and short‐term culture and tested it in a baboon model. Expansion involved enriched CD34 + peripheral blood haematopoietic cells cultured for 6 d with a combination of FLT3‐L, stem cell factor (SCF), thrombopoietin (TPO) and interleukin (IL)‐3 (50 ng/ml each); CD34 + cells, granulocyte–macrophage colony‐forming units (GM‐CFU) and megakaryocytic colony‐forming units (MK‐CFU) were amplified, respectively, 10·5‐, 20·5‐ and 17·9‐fold. Baboons were submitted to a myeloablative regimen consisting of cyclophosphamide plus total body irradiation (TBI; 6 Gy) and were then grafted with either 2 × 10 6 /kg unmanipulated CD34 + cells (control group, n = 4) or cells cultured from 2 × 10 6 /kg CD34 + cells (expansion group, n = 4). No cytokines were administered after transplantation. All the animals engrafted. The mean times to white blood cell (WBC), granulocyte and platelet recovery were significantly shorter in the expansion group than in the control group: WBC (> 1 × 10 9 /l) and neutrophil (> 0·5 × 10 9 /l) recovery occurred on days 8 (range 6–9) and 9 (range 6–11), respectively, compared with days 12 (range 10–15) and 14 (range 11–16); platelets recovered (> 20 × 10 9 /l) on day 9 (range 7–12) compared with day 13 (range 11–15) in the control group ( P < 0·05). No toxicity was observed after reinfusion. No secondary hypoplasia was observed during more than 12 months of follow‐up. Functions of both neutrophils and platelets produced from expanded cells were normal in terms of oxidative metabolism, chemotaxis and the bleeding time. This study shows that in comparison with unmanipulated cells peripheral blood haematopoietic cells expanded from similar doses of CD34 + cells, under the conditions defined here, accelerated both neutrophil and platelet recovery without impairing long‐term haematopoiesis.

Positive selection of CD34+ cells in autologous grafts, designed to deplete tumour cells, also results in T‐cell depletion. To assess the reconstitution of the different lymphocyte subsets and of the T‐cell repertoire diversity following autologous transplantation of selected CD34+ peripheral blood stem cells (PBSC), we analysed sequential blood samples in eight patients autografted for advanced B‐cell non‐Hodgkin's lymphoma in a phase I–II pilot study. Although natural killer cell recovery was rapid, T‐ and B‐cell recovery was delayed with a median of 110/μl CD4+, 175/μl CD8+ T cells and 45/μl B cells at 12 months post‐transplant. The naive CD45RA+ T‐cell compartment was profoundly deficient up to 12 months for both CD4+ and CD8+ subsets. A transient expansion of memory CD8+CD45RO+ T cells consisting of an increased percentage of CD57+CD28− cells occurred within the first 3 months post‐transplant, but the memory CD4+CD45RO+ T cells remained far below the normal value. The CD8+CD28+ T‐cell subset did not recover. Using multiplex PCR analysis of the T‐cell receptor γ locus, we found that the repertoire diversity improved at 12 months after being poor and oligoclonal during the first 3 months post‐transplant. As shown by monoplex PCRγ analysis of every VJ combination, despite T‐cell depletion of the graft, mature T cells were carried over with the selected CD34+ PBSC and contributed to the T‐cell recovery after transplantation.

Introduction. - Hemolysis and red cell fragmentation accompanying vitamine B12 deficiency may misdirect the diagnosis. Signs of malabsorption and abnormalities related to folic acid metabolism characterized by discrepancies between folic acid normal serum levels and erythrocytic folic acid levels may also exist. Exegesis. - We report the occurrence of hemolysis and red cell fragmentation mimicking microangiopathic hemolytic anemia, malabsorption and folic acid deficiency in the course of vitamine Bit deficiency. Appropriate replacement therapy corrected all abnormalities. Conclusion, - An association between hemolysis, malabsorption and folic acid deficiency should lead physicians to search for signs of vitamine B12 deficiency. (C) 1998 Elsevier, Paris.