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Erythroblastic synartesis is a rare cause of acquired dyserythropoiesis. Only 9 cases have been previously reported. We hereby report 3 cases of patients diagnosed with erythroblastic synartesis associated with monoclonal immunoglobulin and an overt malignant lymphoid disorder. A different B-cell clone may produce the monoclonal immunoglobulin, forming a biclonal disorder. In light of these data and literature review, treatment targeting the paraprotein seems to be efficient to control synartesis and correct anemia. In the case of monoclonal gammapathy associated with chronic lymphocytic leukemia, therapeutics should be adapted to control both chronic lymphocytic leukemia and monitored monoclonal immunoglobulin titer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Serine/threonine phosphatases are responsible for modulating the activities of the protein kinases implicated in the development of several pathologies. Here we identified by a PEP-scan approach a peptide of LRRK2, a Parkinson's disease associated protein, interacting with the phosphatase PP1. In order to study its biological activity, the peptide was fused via its N-terminal to an optimized cell penetrating peptide. We synthesized from the original peptide five interfering peptides and identified two (Mut3DPT-LRRK2-Short and Mut3DPT-LRRK2-Long) able to disrupt the LRRK2/PP1 interaction by competition in anti-LRRK2 immunoprecipitates. Using FITC-labelled peptides, we confirmed their internalization into cell lines as well as into primary cells obtained from healthy or ill human donors. We confirmed by ELISA test the association of Mut3DPT-LRRK2-Long peptide to purified PP1 protein. The peptides Mut3DPT-LRRK2-5 to 8 with either N or C-terminal deletions were not able to disrupt the association LRRK2/PP1 nor to associate with purified PP1 protein. The interfering sequences blocking the PP1/LRRK2 interaction were also fused to a shuttle peptide able to cross the blood brain barrier and showed that the newly generated peptides BBB-LRRK2-Short and BBB-LRRK2-Long were highly resistant to protease degradation. Furthermore, they blocked PP1/LRRK2 interaction and they penetrated into cells. Hence, these newly generated peptides can be employed as new tools in the investigation of the role of the LRRK2/PP1 interaction in normal and pathological conditions., Competing Interests: The authors have declared that no competing interests exist.

Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W and H499C strongly drive dimerization of TpoR. Activation by tryptophan substitution is exquisitely specific for position 498. Using structure-guided mutagenesis, we identified upstream amino acid W491 as a key residue required for activation by L498W or canonical activating mutations such as S505N and W515K, as well as by eltrombopag. Structural data point to a common dimerization and activation path for TpoR via its TM domain that is shared between the small-molecule agonist eltrombopag and canonical and novel activating TpoR mutations that all depend on W491, a potentially accessible extracellular residue that could become a target for therapeutic intervention., (© 2020 by The American Society of Hematology.)

Cell penetrating peptides (CPP) are able cross the membrane and to transport cargos, presenting a great potential in drug delivery and diagnosis. In this paper, we have identified novel natural or synthetic CPPs. We have validated their rapid and efficient time and dose-dependent penetration, the absence of toxicity, the intracellular localization and the stability to proteases degradation, one of the main bottlenecks of peptides. Moreover, we have associate a cargo (an interfering peptide blocking the association of the serine/threonine phosphatase PP2A to its inhibitor, the oncogene SET) to the new generated shuttles and showed that they new bi-functional peptides keep the original properties of the shuttle and, in addition, are able to induce apoptosis due to the properties of the cargo. The CPPs identified in this study have promising perspectives for future anti-cancer drug delivery., Competing Interests: CONFLICTS OF INTEREST None.

Histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare and poorly reported complication of Waldenström macroglobulinaemia (WM). We performed a retrospective study of 77 WM patients with biopsy-proven transformation to DLBCL. The median time from WM diagnosis to HT was 4·6 years and 16 patients (21%) had never been treated for WM. At HT, extranodal sites were observed in 91% of patients with a rather high incidence of central nervous system, cutaneous or testicular involvement. Fluorodeoxyglucose-positron emission tomography was performed in half of the patients and the median maximum standardized uptake value was 15 for transformed disease. More than 80% of cases with available data for assessment by the Hans' algorithm harboured a non-germinal centre B-cell phenotype. First-line treatment for transformation consisted of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-like regimen in 85% of patients. The overall response rate after first-line treatment was 61% and the median overall survival was only 16 months for the entire cohort. Time to transformation above 5 years (P = 0·0004) and elevated LDH (P = 0·02) were associated with worse outcome. Based on these findings, HT should be considered and lead to a biopsy in WM patients presenting with extranodal involvement, elevated LDH and constitutional symptoms. The optimal therapeutic approaches remain to be defined., (© 2017 John Wiley & Sons Ltd.)

Background: Disruption of alternative splicing in apoptotic factors has been associated to chronic lymphocytic leukemia among other cancers and hematological malignancies. The proapoptotic proteins Caspase-9 and PP2Acα are functionally related in a direct interaction, which constitutes a promising target for cancer therapy. Both proteins present aberrant mRNA splicing variants that are antiapoptotic (Caspase-9b) and catalytically inactive (PP2Acα2), respectively., Results: In this work we have analyzed the relative abundance of the aberrant spliced forms Caspase-9b and PP2Acα2 in several cell lines and chronic lymphocytic leukemia patients and correlated it with several parameters of the disease. Despite 40 % of the patients presented Caspase-9b dysregulation, there was no direct association between alterations in Caspase-9b relative abundance and the parameters analyzed in medical records. More importantly, PP2Acα2 dysregulation was observed in 88 % of CLL patients and was related with advanced stages of the malignancy., Conclusions: Caspase-9b dysregulation seemed to be associated with the disease, although the differences between healthy donors and CLL patients were not statistically significant. However, PP2Acα2 dysregulation was significantly different between healthy donors and CLL patients and correlated with Binet B and C stages; therefore, we propose the use of PP2Acα2 dysregulation as a potential biomarker for advanced stages of chronic lymphocytic leukemia.

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second-line options after fludarabine-cyclophosphamide-rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non-randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second-line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second-line regimen, followed by alemtuzumab-based regimens, R-CHOP, and FCR. Median progression-free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression-free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months., (© 2015 Wiley Periodicals, Inc.)

PP2A is a serine/threonine phosphatase critical to a number of physiological and developmental processes. In this manuscript, we show that a peptide, specifically blocking the caspase- 9/PP2A interaction, DPT-C9h, induces apoptosis in primary tumour B cells isolated from peripheral blood mononuclear cells or bone marrow of chronic lymphocytic leukemia (CLL) patients, but not on B cells obtained from healthy donors (HD). Moreover, in both CLL patients and HD, DPT-C9h does not induce apoptosis on T- and NKcells and monocytes. Our results strongly suggest that DPT-C9h peptide has tumour specificity and that caspase-9/PP2Ac interaction constitutes a novel therapeutic approach for the treatment in CLL patients.

Background: Urticarial vasculitis (UV) is a rare form of leukocytoclastic vasculitis in which skin lesions resemble urticaria. UV comprises hypocomplementemic and normocomplementemic subtypes. To date, only 4 cases of UV associated with myeloproliferative disorders have been described, including 3 cases with essential thrombocythaemia (ET) and one case with polycythaemia vera., Patients and Methods: We describe the case of a 59-year-old male patient with JAK2-positive TE and secondary myelofibrosis and who developed multiple urticarial papules persisting for more than 24hours. Skin biopsy showed perivascular neutrophilic infiltrate with margination of neutrophils in the lumen of vessels and some leukocytoclastic patterns, and with red cell extravasation consistent with UV. Treatment with ruxolitinib (a JAK2 inhibitor) induced transient and partial control of the haematological symptoms but did not prevent UV flare. Prednisolone 20mg once daily was added, with good clinical response., Discussion and Conclusion: To our knowledge, this is the fourth reported case of UV associated with ET and the first case associated with MF., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain (IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice.

The sickle cell trait-asymptomatic carriage is frequent in people originating from sub-Saharan Africa. Several host factors (including sickle cell anemia) have been previously reported to act upon the course of HIV disease. We studied the progression of infection in a cohort of African patients heterozygous for the sickle hemoglobin gene and harboring normal hemoglobin genes. No significant difference was evidenced between the two groups from this preliminary study.

Background: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome., Patients and Methods: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV., Results: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed., Conclusion: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.

Purpose: The prognosis of relapsing primary CNS lymphoma (PCNSL) is poor. We report the results of a prospective multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem-cell rescue (IC + HCR) in immunocompetent adult patients with PCNSL or intraocular lymphoma (IOL) after failure of high-dose methotrexate-based treatment., Patients and Methods: Salvage treatment consisted of two cycles of high-dose cytarabine and etoposide (CYVE). Intensive chemotherapy combined thiotepa, busulfan, and cyclophosphamide. Forty-three patients (median age, 52 years; range, 23 to 65 years) were included, with relapse (n = 22), refractory disease (n = 17), or a partial response to first-line treatment (n = 4). The response to CYVE was not assessable in three cases because of treatment-related death. Twenty patients (47%) were chemosensitive to CYVE: 15 of them proceeded to IC + HCR. IC + HCR was also administered to 12 patients who did not respond to CYVE. All but one of the 27 patients who underwent IC + HCR entered complete remission., Results: With a median follow-up of 36 months, the median overall survival was 18.3 months in the overall population, and 58.6 months among patients who completed IC + HCR. The respective median progression-free survival (PFS) times after IC + HCR were 11.6 and 41.1 months. The 2-year overall survival probability was 45% in the whole population and 69% among the 27 patients who received IC + HCR. The 2-year PFS probability was 43% among all the patients and 58% in the IC + HCR subpopulation., Conclusion: IC + HCR is an effective treatment for refractory and recurrent PCNSL.

Angiogenesis plays an important role in the progression of tumors. This relationship has been described in several hematologic malignancies. Vascular endothelial growth factor and basic fibroblast growth factor are predictors of poor prognosis in leukemia and non Hodgkin's lymphoma. Bone marrow microvessels were found increased in multiple myeloma, but also in lymphoma and in acute lymphoblastic leukemia. Microvessel density is correlated with decreased survival in myeloma patients and relapse or resistance to chemotherapy in lymphoma. New drugs with antiangiogenic activity such as bevacizumab (binding and inactivation of VEGF) or VEGF-tyrosine kinase inhibitors have shown promising results in phase 1 trials. It will therefore be a future challenge to integrate anti-angiogenesis agents in currently existing treatment protocols to improve the outcome of therapy.

Background: Reactivation of occult hepatitis B virus (HBV) infection is a well-known complication of cytotoxic chemotherapy. Lamivudine prophylaxis is recommended to reduce the incidence and severity of hepatitis in this context., Case Report: An HIV-infected patient positive for HBs antigen became positive for HBc antibody alone under lamivudine given as part of antiretroviral therapy. He was treated with chemotherapy for non-Hodgkin's lymphoma while under lamivudine. Then, he developed HBV-related hepatitis that led to delay chemotherapy. He received adefovir that induced a dramatic decline in HBV DNA load and a normalisation of hepatic enzyme levels. However, the patient died of a relapse of lymphoma. Retrospective analysis of stored plasma samples showed evidence of lamivudine-resistant occult hepatitis before the onset of chemotherapy and reactivation of the HBV mutant., Conclusion: To our knowledge, this is the first report of occult hepatitis reactivation due to lamivudine-resistant mutant selected under lamivudine therapy in an HIV-infected patient. Our study underlines the need to carefully investigate lamivudine resistance in HIV-infected patients with occult infection under lamivudine therapy. Those patients should be monitored with the addition of anti-viral agents effective against the mutant strain.

We described the ex vivo production of mature and functional human smooth muscle cells (SMCs) derived from skeletal myoblasts. Initially, myoblasts expressed all myogenic cell-related markers such as Myf5, MyoD and Myogenin and differentiate into myotubes. After culture in a medium containing vascular endothelial growth factor (VEGF), these cells were shown to have adopted a differentiated SMC identity as demonstrated by alphaSMA, SM22alpha, calponin and smooth muscle-myosin heavy chain expression. Moreover, the cells cultured in the presence of VEGF did not express MyoD anymore and were unable to fuse in multinucleated myotubes. We demonstrated that myoblasts-derived SMCs (MDSMCs) interacted with endothelial cells to form, in vitro, a capillary-like network in three-dimensional collagen culture and, in vivo, a functional vascular structure in a Matrigel implant in nonobese diabetic-severe combined immunodeficient mice. Based on the easily available tissue source and their differentiation into functional SMCs, these data argue that skeletal myoblasts might represent an important tool for SMCs-based cell therapy.

Acute hemorragic and thrombotic complications in cancer are often life threatening. Hemorragic disease are frequent (10%) and sometimes revealed the cancer. In more than 50% thrombocytopenia is involved. Bleeding is related to a vessel wound in 30% of the hemorragic complications either by a tumoral diffusion or by the tumor itself. In less than 10%, the bleeding is linked to disseminated intravascular coagulation. Very rarely coagulation factor deficit is found. Thrombotic manifestations are also frequent (15% of cancer patients). Venous system are usually involved. Clinicians must be aware of these complications to favor the best treatment early as possible to prevent fatal complications.

The case of an 80-year-old woman displaying myelodysplastic syndrome evolving into a myeloproliferative disorder with myelofibrosis and pulmonary fibrosis, is reported. This case is characterized by an initial presentation of a myelodysplastic syndrome with normal karyotype and moderate fibrosis, its evolution towards a myeloproliferative disorder with myelofibrosis and the worsening of pulmonary fibrosis in parallel to the acceleration of the myeloproliferative disorder and myelofibrosis. These features and the high concentration of plasma platelet factor-4 suggest a role of megakaryocyte/platelet degranulation in the development of fibrosis., (Copyright 2003 S. Karger AG, Basel)

Background: Treatment of adults with autoimmune thrombocytopenic purpura (AITP) is based more on individual experience than on results of controlled studies. We compared intravenous immunoglobulin with high-dose methylprednisolone in untreated adults with severe AITP and assessed efficacy of subsequent oral steroids compared with placebo. Primary outcome was number of days with platelet count greater than 50 x 10(9)/L within the first 21 days., Methods: We did a randomised multicentre trial based on a 232 design. 122 adults with severe AITP (platelet count < or =20 x 10(9)/L) were randomly assigned to receive either intravenous immunoglobulin or high-dose methylprednisolone on days 1-3 (randomisation A), and then to receive either oral prednisone or placebo (randomisation B) on days 4-21. Analysis was by intention to treat., Findings: Six patients were excluded from the analysis. The number of days on which platelet counts were above 50 x 10(9)/L was 18 in 56 patients receiving intravenous immunoglobulin and 14 in 60 receiving high-dose methylprednisolone (p=0.02). Percentage of patients who had platelet counts over 50 x 10(9)/L on days 2 and 5 was 7% and 79%, respectively, in the intravenous immunoglobulin group compared with 2% and 60%, respectively, in the high-dose methylprednisolone group (p=0.04). During the second treatment period, prednisone was more effective than placebo for all short-term endpoints. Patients who received intravenous immunoglobulin and prednisone had platelet count greater than 50 x 10(9)/L for 18.5 days (p=0.005), and those treated with high-dose methylprednisolone and prednisone had this count for 17.5 days., Interpretation: Intravenous immunoglobulin and oral prednisone seems to be more effective than high-dose methylprednisolone and oral prednisone in adults with severe AITP, although the latter treatment is effective and well tolerated.

Fibrinogen plays a complex role in hemostasis, thrombosis, and vascular disease. Hyperfibrinogenemia is an independent vascular risk factor and dysfibrinogenemia can provoke thrombosis. Afibrinogenemia is usually responsible for hemorrhagic diathesis, and unexpected ischemic lesions are intriguing. We report the case of an afibrinogenemic patient, who at the age of 30 developed ischemic lesions of the feet related to severe stenosis of the iliac and hypogastric arteries. The biopsy of the iliac artery lesion showed an intense myointimal hyperplasia. We performed standard hemostatic analysis and analyzed the activation markers of platelets and coagulation factors and the kinetics of thrombin generation in the patient and in normal control plasmas treated or not with reptilase. Occlusive arterial lesions were attributed to a disruptive hematoma penetrating the vascular lumen. Thrombin concentration after calcium addition increase markedly in the afibrinogenemic patient and in defibrinated normal plasma, as compared to untreated normal plasma. Thrombin-antithrombin complexes (T-AT) were markedly enhanced while F1+2 prothrombin fragments stayed in the normal range. These results suggested activation of coagulation and in vivo circulating thrombin. Thrombin activates the platelets that secrete growth factors for smooth muscle cells and generate the intimal hyperplasia. Recurrent hemorrhage within the vessel wall might induce injury and local thrombin generation. Thrombin not trapped by the clot is available for platelet activation and smooth muscle cell migration and proliferation. The absence of a protective fibrin cap on the intima might account for intima vulnerability and embolization. Afibrinogenemia appears in this paradoxical situation as a vascular risk factor.

Erythroblastic synartesis is a rare form of acquired dyserythropoiesis, first described by Breton-Gorius et al in 1973. This syndrome is characterized by the presence of septate-like membrane junctions and "glove finger" invaginations between erythroblasts, which are very tightly linked together. This phenomenon, responsible for ineffective erythropoiesis, leads to an isolated severe anemia with reticulocytopenia. In the following report, we describe 3 new cases of erythroblastic synartesis associated with dysimmunity and monoclonal gammapathy. In all cases, the diagnosis was suggested by characteristic morphological appearance of bone marrow smears, and further confirmed by electron microscopy. Ultrastructural examination of abnormal erythroblast clusters showed that these cells were closely approximated with characteristic intercellular membrane junctions. The pathogenesis of the dyserythropoiesis was modeled in vitro using crossed erythroblast cultures and immunoelectron microscopy: when cultured in the presence of autologous serum, the erythroblasts from the patients displayed synartesis, whereas these disappeared when cultured in normal serum. Moreover, synartesis of normal erythroblasts were induced by the patient IgG fraction. Immunogold labeling showed that the monoclonal IgG were detected in, and restricted to, the synartesis. A discrete monoclonal plasmacytosis was also found in the patient bone marrow. The adhesion receptor CD36 appeared to be concentrated in the junctions, suggesting that it might be involved in the synartesis. These experiments indicated that a monoclonal serum immunoglobulin (IgG in the present cases) directed at erythroblast membrane antigen was responsible for the erythroblast abnormalities. Specific therapy of the underlying lymphoproliferation was followed by complete remission of the anemia in these cases.

We have conducted a phase II outpatient trial testing weekly oral administration of idarubicin (ZAVEDOS-ZVD) alone to determine the rate of objective response and toxicity in poor risk acute myeloid leukemia (AML) patients over 60 years of age. The treatment consisted of three phases: induction, with 20 mg/m2 of ZVD on days 1, 8, 15 and 22; consolidation with 20 mg/m2 of ZVD for 4 weeks; and maintenance with six cycles lasting 3 months and consisting of oral 6 mercapto-purine 2 mg/kg/day, 4 days a week for 2 months; subcutaneous cytarabine 1 mg/kg, once a week for 2 months; and oral ZVD 20 mg/m2 on day 1 and day 8 of the third month. In case of failure after induction course, patients received salvage treatment with 4 weekly oral doses of 40 mg/m2 ZVD. Fifty-one patients with a median age of 76 years were enrolled and could receive induction course. Of these 51 patients, 37 could receive subsequent courses, which consisted either of consolidation, or salvage. Only 11 patients underwent maintenance treatment. Sixty-three percent of patients had to be hospitalized during induction, for a median duration of 14.5 days, and 87% required hospitalization during salvage for a median duration of 17.5 days. Only five patients (38%) required hospitalization during consolidation. There were three toxic deaths (6%), two from hemorrhage and one from pulmonary embolism. The overall response rate was 29%, with 12 patients in complete response (25%) and two in partial response (4%). The median overall survival rate is 4 months for the whole population, and the median DFS is 9.6 months among the 14 responding patients. The results of this trial show that this new weekly schedule of oral ZVD chemotherapy is feasible and effective in poor risk elderly patients with AML. This regimen may be helpful for patients unable to tolerate intensive intravenous regimens, and is a real alternative to palliative treatments.

We analyzed 33 patients with AILD T-NHL in a retrospective multicentric study. The median age was 62 yr (35-84 yr) (19 patients over 60 yr). Advanced disease (n = 31) and B-symptoms were consistently found (n = 29) and 20 patients had bone marrow involvement. The main laboratory abnormalities were: anemia (n = 13), hypereosinophilia (n = 13), lymphopenia (n = 14), hypergammaglobulinemia (n = 17), elevated lactate dehydrogenase (LDH) level (n = 24). First-line therapy was chemotherapy (ChT) alone (n = 25) or ChT after steroids (n = 8). Most patients received a CHOP-like regimen for a median number of 6 cycles and 3 patients received interferon alpha (IFN alpha) as consolidation after chemotherapy. With a median follow-up of 46 mo, 60% achieved a complete response but the outcome was poor with a relapse rate at 56%, a median survival referring to the total population was of 36 mo (2-108+ mo) and an overall survival at 5 yr of 36%. Two patients received high-dose chemotherapy (with total body irradiation) and autologous progenitor-cell transplantation for chemosensitive relapse and were free of disease at, respectively, 76 and 24 mo+. In conclusion AILD T-NHL still has a poor prognosis compared to other NHL. The role of intensive therapy and IFN alpha still remains to be evaluated.

Interactions between endothelial cell adhesion molecules and their beta2 integrin adhesive receptors on leukocytes are thought to play a role in the pathogenesis of inflammatory diseases and probably vasculitis. We describe a case in whom leukocytoclastic vasculitis was associated to a monoclonal immunoglobulin G2 kappa (IgG2K). During the vasculitic crisis, the patient's serum and the isolated IgG from this serum induced the expression of E-selectin, VCAM-1 and ICAM-1 at the HUVEC surface, but not tissue factor activity, whereas normal, control serum and patient serum at remission were without any effect. A close relationship between the vasculitis and the serum level of the monoclonal IgG was observed. We suggest that the monoclonal IgG might induce the vasculitis by increasing the expression of E-selectin, VCAM-1 and ICAM-1 which facilitate the interaction of leukocytes with vascular endothelium.

The observation of pulmonary mucormycosis occurring in a patient presenting with aplasia induced therapeutically during treatment for acute myeloblastic leukaemia, has led to a review of the characteristics of this rare opportunistic fungal infection: it occurs in a particular condition; the clinical manifestations are characterised by the thrombotic character and the rapidly necrosing nature of the histological lesions; the diagnosis is usually very difficult to make and is linked to the rarity of the pathology and the frequently negative mycological specimens apart from tissue biopsies; the value of a medicosurgical therapeutic strategy on which the prognosis of the infection depends.

CD16 antibodies recognize Fcgamma receptors III of a and b types. In a patient with severe idiopathic aplastic anaemia (AA), polymorphonuclear cells, which in normal subjects express FcgammaRIIIb, were found to be CD16 negative. The FcgammaRIIIb gene configuration was analysed by PCR on peripheral blood mononuclear cells. Bi-allelic deletion encompassing at least part of the coding exon 5 was found in the patient and his brother, suggesting a hereditary defect. The patient underwent successful bone marrow transplantation from his HLA-matched brother despite a similar phenotype and genotype. This observation suggests that FcgammaRIIIb hereditary deficiency in donor and/or recipient does not impair engraftment and justifies the use of other monoclonal antibodies in addition to CD16 in the study of GPI-anchored antigen expression.

Aim of the Study: To evaluate in a prospective trial three courses of an ABVD-like chemotherapy (CT) regimen given before radiation therapy (RT) (subtotal nodal irradiation (STNI) in favorable stage Hodgkin's disease (HD). The efficacy, risk factors and medium-term toxicities are reported., Patient Characteristics: Stage I or II with at least one of the following factors, mediastinal involvement, histological type 3, age > 40 years, ESR rate > 50 mm, or stage IIIA. 189 patients with newly diagnosed HD were treated between 01/89 and 01/94 (stage I, n = 33; stage II, n = 129, stage IIIA, n = 27). Three courses of an ABVD-like regimen (adriamycin 25 mg/m2, bleomycin 10 mg, vindesine 2 mg/m2 and dacarbazine 250 mg/m2 day 1 and 8) were given before STNI at 36/40 grays. At diagnosis, prognostic factors were distributed as follows: B symptoms (n = 54), bulky mediastinum (n = 41), hemoglobin < 12 g/dl (n = 37), ESR > 50 (n = 65), age > 45 (n = 24)., Results: After chemotherapy, 90% had an objective response (partial response > 75%) and 98% were in complete remission (CR) at the end of RT. Three patients had primary refractory disease and 13 patients (7%) relapsed, 3 at the initial site, 4 at previously uninvolved sites and 6 at both. With a median follow-up of 60 months, 170 patients are in 1st CR, 5 in 2nd or greater CR and 11/14 patients have died from HD. Bulky mediastinum (p = 0.009), age > 45 years (p = 0.03) and EST > 50 mm (p = 0.05) were adverse prognostic factors for survival. Bulky mediastinum (p = 0.009) was the only prognostic factor for freedom from progression. TOXICITIES: Two patients died from treatment related toxicity and one patient died with an osteogenic sarcoma. No secondary leukemia has so far been detected. 24 pregnancies were reported. Cardiopulmonary toxicity was always < grade 1 (WHO) in 95 patients evaluated. Two patients over 45 years old had a myocardial infarction., Conclusion: With an acceptable medium-term toxicity, this treatment achieved 85% survival at 5 years.

Background: Mucosal erosions can be a presenting feature of the hypereosinophilic syndrome. The aim of this study was to analyze in situ the presence of eosinophil proteins and the state of eosinophil activation. Biopsy specimens of mucosal lesions and normal skin were taken from two men with oral and genital erosions typical of hypereosinophilic syndrome. Tissue sections were immunohistochemically labeled with anti-major basic protein, anti-eosinophil-derived neurotoxin, and anti-eosinophil peroxidase antibodies. The same specimens were also subjected to electron microscope examination., Observations: Eroded specimens displayed areas of eosinophil spongiosis within which extracellular deposits of eosinophil peroxidase, major basic protein, and eosinophil-derived neurotoxin were present. In normal skin, only a few eosinophils were present within the capillary lumen, and no extracellular deposits of these proteins were seen. Under the electron microscope, the cytoplasmic membranes of eosinophils located around the erosion were disrupted. Remnants of necrotic keratinocytes were found near these lysed eosinophils., Conclusion: As with other involved organs in hypereosinophilic syndrome, mucosal erosions seem to be the consequence of eosinophil protein release.

We report a patient with congenital factor VII deficiency who developed severe arterial thrombosis. A 63-year-old-woman presented low factor VII clotting activity, amidolytic activity and antigen level < 4%. Activated factor VII plasmatic level was < 0.03 ng/ml compared to 4 ng/ml for the control value. She developed severe aorto-iliac thrombosis. 7 d before the thrombotic event, factor VII replacement therapy had been infused. Successful low molecular weight heparin therapy led to total disappearance of the aorto-iliac thrombus without bleeding complications. This suggests that factor VII infusion might have a thrombogenic effect in vivo and might be responsible for thrombosis.

Somatostatin receptor imaging (SRI) was carried out as part of the initial staging of 26 patients with histologically proven Hodgkin's (3) and non-Hodgkin's (23) lymphoma, and in the assessment of the first treatment's efficacy in seven of these patients. Static acquisitions over the whole body were performed 4 and 24 h after intravenous administration of 150 MBq of indium-111 pentetreotide. SRI data were compared with the results of conventional methods (clinical data, abdominal and thoracic computed tomography, bone marrow biopsy). Only 50 of the 86 (58%) confirmed extra-medullary tumour sites were detected by SRI. Twelve previously unknown localizations were visualized in seven patients. The Ann Arbor clinical stage was modified in only one of them. When tumoral tracer uptake was present, a tumour uptake index (TUI) was calculated using two regions of interest (one over the tumoral hot spot and one over the shoulder) on 24-h planar images. The patients were classified into three groups: high tumour uptake (TUI > 2.5 in all tumour sites, group A, six patients), low tumour uptake (1.5 < TUI < 2.5 in all tumour sites, group B, 18 patients), and no tumour uptake (group C, two patients). The sensitivity of SRI detection was higher in group A (90%) than in group B (52%) (P < 0.001). Six weeks after the fourth chemotherapy cycle, conventional methods and SRI were concordant in five of seven investigated cases (four complete remissions and one residual active thoracic mass showing tracer uptake), and discordant in two. SRI demonstrated residual tumoral tracer uptake in these two patients, who had previously been considered to be in complete remission. In conclusion, SRI does not seem to be reliable for the initial staging of lymphomas because of the highly variable and usually low tumoral tracer uptake. It may be more useful in the diagnosis of residual masses after treatment. However, further studies are needed to assess its specificity.

Eight patients with severe chronic autoimmune thrombocytopenic purpura (AITP) refractory to high-dose intravenous immunoglobulin (IVIgG) and/or oral prednisone were treated with one to three infusions of high-dose methylprednisolone (HDMP) (15 mg/kg/day). The mean platelet count before treatment was 12 +/- 10 x 10(9)/L. HDMP therapy led to a safe platelet count (> 50 x 10(9)/L) after 2-5 days in five patients, and a minimal platelet increase (34 x 10(9)/L) able to stop bleeding in a sixth patient. The effect of HDMP was, however, transient in four of five responders. No side effects were observed, even in the four patients older than 70 years. HDMP thus appears to be a good alternative in emergency situations or prior to surgery for patients with AITP refractory to conventional therapy.

Binding of 125I-thrombin to human umbilical vein endothelial cells (HUVECs) was specifically displaced by the synthetic tetradecapeptide SFLLRNPNDKYEPF, named thrombin receptor agonist peptide (TRAP), which has recently been described as a peptide mimicking the new N-terminus created by cleavage of the thrombin receptor, and F-14, a tetradecapeptide representing residues 365-378 of the human alpha-thrombin B chain. Binding of 125I-TRAP to HUVECs was time-dependent, reversible and saturable, showing high affinity (KD = 1.5 +/- 0.4 microM) and high binding capacity (Bmax. = 7.1 +/- 0.6 x 10(6) sites/cell) (n = 3). Unlabelled thrombin and TRAP competitively and selectively inhibited the specific binding of 125I-TRAP with IC50 values of 5.8 +/- 0.7 nM and 2.8 +/- 0.4 microM respectively, whereas F-14 remained ineffective at displacing 125I-TRAP from its binding sites, suggesting the presence of at least two different types of thrombin-binding sites on HUVECs. TRAP was a potent mitogen for HUVECs in culture. Both TRAP and alpha-thrombin stimulated the proliferation of HUVECs with half-maximum mitogenic responses between 1 and 10 nM. F-14 also promoted HUVEC growth. The mitogenic effects of F-14 and TRAP were additive. N alpha-(2-Naphthylsulphonylglycyl)-DL-p-amidinophenylalanylpiper idine (NAPAP) and hirudin (two specific inhibitors of the enzyme activity of thrombin) specifically inhibited thrombin-induced HUVEC growth (IC50 values 400 +/- 60 and 52 +/- 8 nM respectively) but remained without effect on the mitogenic effect of TRAP or F-14. This demonstrated that the mitogenic effect of alpha-thrombin for HUVECs was intimately linked to its esterolytic activity but also showed that thrombin can stimulate HUVEC growth via another non-enzymic pathway. This hypothesis was further reinforced by the fact that F-14-induced proliferation of HUVECs remained unaltered by two antibodies directed against TRAP or the cleavage site on the extracellular portion of the thrombin receptor, which both strongly reduced thrombin-induced proliferation of HUVECs. Thrombin-, TRAP- or F-14-induced HUVEC proliferation was strongly inhibited by a neutralizing monoclonal antibody directed against basic fibroblast growth factor (bFGF), suggesting that thrombin regulates the autocrine release of bFGF in HUVECs.

Immunologic thrombopenic purpura refers to several diseases including the most frequent, autoimmune thrombopenic purpura (AITP). Immunologic thrombopenia is related to anti-platelet autoantibodies, usually IgGs. In 15 to 20% of the cases, no auto-antibody can be detected. The severity of the cutaneomucosal manifestations is not always correlated with the degree of thrombopenia but only occurs for platelet counts less than 50 x 10(9)/L. The clinical course includes acute episodes of AITP and complete remissions in 80% of the cases in the episodes of AITP and complete remissions in 80% of the cases in the very young child. Inversely, in the adult, treatment of AITP has been highly debated because chronicity is frequent. Two therapeutic approaches, corticotherapy and splenectomy, have been widely used. Corticoids given at a dose of 0.5 to 1 mg/kg/day leads to remission in 15 to 30% of the cases. Splenectomy, a second intention therapy, leads to platelet counts above 100 x 10(9)/L in 60 to 70% of the patients. In 1981, intravenous polyvalent immunoglobulins were first employed for 13 children in a study reported by Imbach et al. The results have been confirmed in children and in adults. There are few side effects with this method and the dose of 1 g/kg over 2 days is effective. Response is rapid (platelet counts above 50 x 10(9)/L in 1 to 5 days) but often temporary (relapse to former levels in 5 to 45 days). The high cost of this intravenous polyvalent immunoglobulins has led to much debate over their use.(ABSTRACT TRUNCATED AT 250 WORDS)

The bleeding diathesis in patients with acute promyelocytic leukemia (APL) is generally attributed to disseminated intravascular coagulation (DIC), initiated by the release of procoagulant activity from leukemic cells. Primary fibrinogenolysis, mediated by the release of leukocyte proteases, may also contribute to this disorder. We analyzed coagulation parameters in 15 non-septic APL patients. Before treatment, there was evidence of thrombin activation with DIC: increased levels of circulating thrombin-antithrombin III complexes, prothrombin fragments 1 + 2 and D-Dimer complexes. This DIC syndrome was probably limited, since no prothrombin time decrease, no significant factor V consumption, and normal levels of coagulation inhibitors (antithrombin III and protein C) were observed in APL patients when compared to normal controls. In this context, marked hypofibrinogenemia suggested primary fibrinogenolysis as the predominant etiology. Despite normal or high tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) antigen levels, the plasma PAI-1 activity and the formation of tPA/PAI-1 complexes were lower in APL patients than in normal controls, suggesting a proteolytic degradation of PAI-1, not able to complex tPA. Two other fibrinolytic inhibitor molecules (alpha-2 plasmin inhibitor antigen and histidine-rich glycoprotein antigen) were also significantly reduced, as well as the two subunits of fibrin stability factor XIII, although only subunit A is known to be susceptible to thrombin action. Evidence of degraded forms of von Willebrand factor in the plasma suggested an extended proteolytic activity. Four patients treated with all-trans-retinoic acid (ATRA) as a single differentiating agent were studied serially. A dissociation between these two syndromes--DIC and fibrinogenolysis/proteolysis--was observed. The rapid correction of the lysis markers contrasted with a more prolonged persistence of the procoagulant activity. We observed persistently high elastase/alpha 1-proteinase inhibitor complex levels during ATRA therapy, despite progressive correction of all lysis markers. Thus, the release of elastase from promyelocytic leukemic cells is probably not the only determinant of the fibrinogenolytic/proteolytic syndrome. In summary, the present findings provide new arguments for the association of DIC and proteolysis syndromes in APL-associated coagulation disorders. Further prospective studies are needed in order to confirm the persistence of thrombin activation in course of ATRA therapy.

Ability of response in proliferation and cytotoxicity of lymphocytes, after in vitro allogeneic reaction was tested in three independent series of experiments, before and after seven days of ticlopidine treatment (500 mg daily) taken by normal adult individuals. In the third experiment, blood samples were taken twice before treatment and twice during the treatment. In two of the three series of experiments the ability of proliferation of responding cells in a mixed lymphocyte reaction was decreased (P less than 0.01). Cytotoxicity was reduced in the three series of experiments when the combination effector/target cells after treatment was compared with the combination before treatment (P less than 0.01 - 0.001), at various effector to target cells ratios for one target (50:1 and 100:1).