121 research outputs found
Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy â usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed â the terminal complement inhibitor eculizumab â which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients
Detection of non-Hodgkin's lymphoma liver disease in cirrhotic patients
Computer tomography (CT) scan and ultrasound scan (US) are the preferred methods for staging subdiaphragmatic non-Hodgkinâs lymphoma (NHL),1 but their sensitivity in detecting focal lesions in the liver may be reduced if fibrosis is present. We investigated 6 NHL patients who also had a viral liver disease (chronic active hepatitis or cirrhosis) by US and CT liver scans and liver biopsy. US was performed using a Spazio-Hitachi instrument with a 3.5 MHz probe. With the exception of two patients, who underwent laparotomy as a diagnostic procedure, liver biopsy was performed under US guidance using a Menghini fine needle with automatic aspiration (1.2 mm in diameter x 150 mm in length), or a Chiba fine needle (0.7 mm x 150 mm)
Clinical relevance of intrahepatic hepatitis B virus DNA in HBsAg-negative HBcAb-positive patients undergoing hematopoietic stem cell transplantation for hematological malignancies.
Hepatitis flare-up due to hepatitis
B virus (HBV) is a well-recognized complication
associated with chemotherapy. Data on the clinical impact of HBV DNA in liver tissue of HB-surface antigen
(sAg)-negative patients undergoing
immunosuppression are scanty
CD34+ enriched donor lymphocyte infusions in a case of pure red cell aplasia and late graft failure after major ABO-incompatible bone marrow transplantation
A variety of immunohematological complications may occur after ABO-incompatible BMT. We report a CML patient (blood group O) who received a BMT from an HLA-identical sibling (blood group AB). The transplant was followed by normal myeloid and megakaryocytic engraftment, but erythroblastopenia persisted for more than 200 days after BMT. By bone marrow culture studies, a complement-dependent serum inhibitor of hemopoiesis was detected, suggesting immunological inhibition of erythropoiesis. The patient was resistant to a number of treatments such as intravenous gamma-globulins, prednisolone and high-dose erythropoietin. Full engraftment with normal blood counts and marrow cellularity was achieved after two dose-escalating CD34+-enriched donor lymphocyte infusions (DLI). This experience suggests that CD34+-enriched DLI may be an effective treatment for patients with delayed engraftment or late graft failure due to major ABO-incompatibility
Von Hippel-Lindauâdependent polycythemia is endemic on the island of Ischia: identification of a novel cluster
AbstractChuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1α activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1α activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world
An NMR Study of the Bortezomib Degradation under Clinical Use Conditions
The (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. Commercial BTZ samples, reconstituted according to the reported commercial instructions and stored at 4°C, were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material), the N-(1-(1-hydroxy-3-methylbutylamino)-1-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration) and the (S)-N-(1-(3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration), identified on the basis of their chemical and spectroscopic properties. The BTZ1 and BTZ2 finding suggests that, under the common condition of use and at 4°C, commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process
Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60Â years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dellâAdulto (GIMEMA) Leukemia Cooperative Groups
The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60Â years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5Â years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (Pâ=â0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (Pâ=â0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (Pâ<â0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60Â years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group
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