Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

Bing and neel syndrome.

Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenström's macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen (rituximab, fludarabine, and cyclophosphamide). In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM.

Caspase-activated ROCK-1 allows erythroblast terminal maturation independently of cytokine-induced Rho signaling.

Stem cell factor (SCF) and erythropoietin are strictly required for preventing apoptosis and stimulating proliferation, allowing the differentiation of erythroid precursors from colony-forming unit-E to the polychromatophilic stage. In contrast, terminal maturation to generate reticulocytes occurs independently of cytokine signaling by a mechanism not fully understood. Terminal differentiation is characterized by a sequence of morphological changes including a progressive decrease in cell size, chromatin condensation in the nucleus and disappearance of organelles, which requires transient caspase activation. These events are followed by nucleus extrusion as a consequence of plasma membrane and cytoskeleton reorganization. Here, we show that in early step, SCF stimulates the Rho/ROCK pathway until the basophilic stage. Thereafter, ROCK-1 is activated independently of Rho signaling by caspase-3-mediated cleavage, allowing terminal maturation at least in part through phosphorylation of the light chain of myosin II. Therefore, in this differentiation system, final maturation occurs independently of SCF signaling through caspase-induced ROCK-1 kinase activation.

[High risk of cardiac dysfunction after treatment of secondary acute myeloid leukemia following chemotherapy and radiotherapy for breast cancer]. / Risque élevé de dysfonction cardiaque des leucémies aiguës myéloïdes secondaires à un cancer du sein.

Secondary acute myeloid leukaemia (AML) occurring after breast cancer is a rare long-term complication of the chemo- and/or radiation therapy required to treat breast cancer. The usually recognized curative option of these secondary AML includes courses of anthracycline-based chemotherapy followed by haematopoietic stem cell transplantation (HSCT). Cardiac dysfunction during AML treatment of these patients previously treated with anthracyclines for breast cancer has not been reported to date. We evaluated the evolution of cardiac function in seven patients treated with anthracyclines and/or autologous or allogeneic bone marrow transplantation for secondary AML occurring after breast cancer. All of the patients who received a cumulative anthracycline dose above the cardiac toxicity threshold developed cardiac symptoms during AML chemotherapy courses. Moreover, four of the five transplanted patients developed severe heart failure among which two were fatal. Thus, the risk of severe cardiac dysfunction after treatment of secondary AML following breast cancer must be taken in account as part of the therapeutic strategy of those patients. As discussed here, an accurate evaluation of risk factors, the use of sensitive detection tests and of cardioprotective drugs as well as that of non-cardiotoxic chemotherapy might decrease the occurrence and severity of this life-threatening complication.

[Long-term efficacy of autologous stem cell transplantation for stage IV mycosis fungoides]. / Efficacité a long terme d'une autogreffe de cellules souches au cours d'un mycosis fongoïde de stade IV.

BACKGROUND: Mycosis fungoides during large cell transformation to lymphoma has a poor prognosis with mean survival of 36 months. Autologous stem cell transplantation is rarely proposed in this indication. We report the case of a young man still in complete remission for transformed mycosis fungoides 14 years after autologous stem cell transplantation. CASE REPORT: A 25-year-old man presenting eczema-like patches since childhood was treated by chemotherapy for multiple lymphadenopathies considered as Hodgkin's lymphoma. He was referred with diffuse skin tumours and infiltrated patches. Histology of tumour samples revealed atypical T-cell infiltrate with epidermotropism and presence of more than 25% of large CD30-positive cells. Non-infiltrated patches showed small T-cell lymphoma with epidermotropism. Histological verification of a previous lymphadenopathy confirmed the diagnosis of transformed mycosis fungoides. Despite multiple courses of chemotherapy, the disease progressed, with neurological involvement in particular. Because of tumour aggressiveness, autologous stem cell transplantation was performed and resulted in rapid regression of the tumours, lymphadenopathy and neurological symptoms. Non-transformed mycosis fungoides patches persisted but were controlled with topical mechlorethamine. This patient is still in complete remission for tumour and extracutaneous lesions 14 years after the autograft. DISCUSSION: This was probably a case of juvenile mycosis fungoides diagnosed and transformed in adult age. Neurological involvement by mycosis fungoides is rare and usually carries a drastic prognosis. To our knowledge, this is the longest remission of transformed mycosis fungoides seen after autograft. It highlights the value of this method in aggressive transformed mycosis fungoides, especially in patients ineligible for allograft.

Detection of circulating Aspergillus fumigatus DNA by real-time PCR assay of large serum volumes improves early diagnosis of invasive aspergillosis in high-risk adult patients under hematologic surveillance.

Detection of galactomannan antigen (GMA) in serum is the standard assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematological disorders. Detection of Aspergillus DNA in serum has been proposed, but its sensitivity is lower than that of GMA when small serum volumes (SSV) are used. In this study, we investigated whether extraction of DNA from large serum volumes (LSV) improves diagnostic yield. In a 13-month prospective study, we compared the performances of twice-weekly screening of serum for GMA by an enzyme immunoassay and weekly screening for Aspergillus fumigatus DNA by a real-time PCR (RT-PCR) assay of 1.0 ml (LSV) or 100 mul (SSV) of serum. We included 124 patients (138 treatment episodes), with 17 episodes of EORTC (European Organization for Research and Treatment of Cancer)/MSG (Mycoses Study Group)-documented IA. In all, 1,870 samples were screened for GMA. The sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV and NPV, respectively) of GMA for IA were 88.2%, 95.8%, 75%, and 98.3%, respectively. We screened 938 samples for Aspergillus DNA by using LSV; 404 of these samples were also tested with SSV. The Se, Sp, PPV, and NPV of RT-PCR were 100%, 96.7%, 81%, and 100%, respectively, with LSV and 76.5%, 96.7%, 81.3%, and 95.6%, respectively, with SSV. DNA detection gave a positive result when performed on LSV in two cases of IA where the GMA assay result remained negative. Furthermore, in four IA cases, DNA was detected earlier than GMA. The use of LSV for extraction improved the performance of the RT-PCR, which appears highly sensitive and specific for the early diagnosis of IA in high-risk patients with hematological disorders.

High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group.

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.

Autoimmune manifestations in acquired idiopathic splenic atrophy: A puzzling association.

Splenic atrophy is an uncommon diagnosis associated with celiac sprue or other well-characterized connective tissue diseases, drepanocytosis, or amyloidosis. We report two patients with splenic atrophy revealed by thrombocytosis. Both patients had anti-nuclear antibodies. Patient 1 also had a grade III Chisholm lymphocytic sialadenitis with a rheumatoid factor, anti-extractable nuclear antibodies, and a polyclonal hypergammaglobulinemia consistent with the diagnosis of Sjögren's syndrome. Patient 2 displayed a previous history of idiopathic pericarditis. An anti-pneumococcal vaccination was given to both patients and neither experienced infectious complications. Splenic atrophy should be suspected in patients with thrombocytosis of unexplained origin and a blood smear consistent with asplenia. Such patients must be checked for clinical and biological symptoms of autoimmune disorders.

The VAD chemotherapy regimen plus a G-CSF dose of 10 microg/kg is as effective and less toxic than high-dose cyclophosphamide plus a G-CSF dose of 5 microg/kg for progenitor cell mobilization: results from a monocentric study of 82 patients.

A study was conducted to compare the efficiency and toxicity of two peripheral blood stem cell (PBSC) mobilization procedures for newly diagnosed patients with multiple myeloma. Patients from group 1 (n=51) were treated by high-dose cyclophosphamide (HD-CY) plus G-CSF (5 microg/kg/day), and the second group (n=31) by VAD regimen plus G-CSF administration (10 microg/kg/day). Successful mobilization, defined by a minimal count of 2.5 x 10(6) CD34(+) cells/kg collected, was achieved in 96 and 90% of patients in groups 1 and 2, respectively (P=0.15). The mean peripheral blood CD34(+) cells concentration and the mean CD34(+) cells/kg collected were higher in group 2 than in the group 1 (P=0.05). The mean number of leukaphereses necessary to collect a count of 2.5 x 10(6) CD34(+) cells/kg was reduced in group 2 compared to group 1. Adverse events, blood products consumption and time spent in the hospital were significantly greater after HD-CY. In conclusion, VAD plus a G-CSF dose of 10 microg/kg administration seems preferential to HD-CY plus a G-CSF dose of 5 microg/kg for PBSC collection because of equivalent or better efficiency in stem cell mobilization, strong favorable toxicity profile and reduced cost.

Prediction of relapse by day 100 BCR-ABL quantification after allogeneic stem cell transplantation for chronic myeloid leukemia.

Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (<10(-4)). Despite being comparable for all classical parameters, the incidence of relapse was significantly higher in the high MRD group (11/14 (79%)) compared to that of the low/negative MRD group (7/24 (29%)) (P = 0.009), with d100 MRD values representing an independent risk factor of relapse and disease-free survival, but not of overall survival, in multivariate analysis. These data should facilitate risk-adapted post-transplant immunosuppression and/or tyrosine kinase inhibitor therapy based on an early evaluation of MRD.

[EBV-associated cutaneous plasmocytoma in a renal transplant patient]. / Plasmocytome cutané EBV+ isolé chez une malade transplantée rénale: efficacité d'un traitement par rituximab.

INTRODUCTION: Postransplant lymphoproliferative disorders are well known complications of solid organ transplant, usually associated with Epstein-Barr virus (EBV). OBSERVATION: A 25 year old renal transplant patient presented with two subcutaneous nodules on the lower limb that appeared 3 years after a second renal transplantation. Biopsy of one nodule showed an EBV associated plasmocytoma located in the subcutaneous tissue. A complete systemic evaluation showed no evidence of extracutaneous involvement. The patient was treated with anti CD20 therapy (rituximab), and complete remission was achieved. DISCUSSION: Extranodular localisations of postransplant lymphoproliferative disorders are usually reported, but cutaneous localizations are rarely described. Histological presentation are various, but plasmocytoma-type is infrequent. Initial therapy of cutaneous EBV-associated postransplant lymphoproliferative disorders without extracutaneous involvement consists in reduction of the immunosuppression therapy and/or an antiviral treatment and prolonged surveillance. Treatment with monoclonal anti-CD20 antibodies (rituximab) is proposed.

T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.

Primary follicular lymphoma of the gastrointestinal tract: a study of 25 cases and a literature review.

BACKGROUND: To describe better the clinical, biological, endoscopic and pathological presentations, as well as the outcome, of primary follicular lymphoma (FL) of the gastrointestinal (GI) tract. PATIENTS AND METHODS: From November 1983 to February 2001, 25 eligible patients with primary FL of the GI tract were retrieved from several French Departments of Pathology departments based on histological diagnosis and immunophenotype. Median age was 56 years (range 44-71) with a sex ratio female/male of 2 (17/8). RESULTS: Abdominal pain was the main presenting symptom followed by intestinal obstruction. The small intestine was the most common site of involvement. Lesions were unifocal in the majority of patients (15/25). A pattern similar to lymphomatous polyposis was observed in 50% (7/14) of patients. Twelve patients had stage I, 10 patients stage II and three patients stage IV disease, and there was minimal extra intestinal involvement. Lymphoma tissues were composed of neoplastic follicles, most of which were grade 1 according to the World Health Organization (WHO) classification. The immunophenotype of the lymphoma cells was CD20+, CD10+, bcl2+ and CD5-. In tissue samples, IgH/bcl2 rearrangement at the MBR locus was present in 11 of 14 patients tested. Seven patients did not receive any treatment; four of them progressed after a median follow-up of 37.5 months. Treatment was otherwise heterogeneous, and complete remission was obtained in 15 patients which lasted for a median of 31 months. Relapses were either in the GI tract (n = 3) or outside the GI tract (n = 3). After a median follow-up of 34 months (range 5-203), 22 patients were still alive (complete remission, 11; partial remission, three; stable disease, six; progressive disease, two). CONCLUSIONS: Primary FL of the GI tract is a predominantly female lymphoma that most frequently involves the small intestine. Since the endoscopic and clinical presentation may not be different from lymphomatous polyposis, which is often associated with mantle cell origin of tumor cells, it is mandatory to perform an immunohistological and, if possible, a molecular analysis of GI lymphoma. The course of the disease is indolent and does not differ from nodal FL. Thus, therapy may not be required unless significant clinical symptoms are present or until disease progression.