RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hemat-ocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.
The incidence of HBV reactivation was low in RA patients in whom HBV infection had been resolved. Screening for HBV reactivation and prophylactic therapy with entecavir were effective means of preventing HBV-associated hepatic failure in patients with HBsAg, as well as in those with only anti-HBc who received immunosuppressive therapy for RA.
Summary. Human parvovirus B19 infection has been shown to be transmissible by blood and blood products and to result in transient aplastic crisis in patients with rapid red cell turnover. We report three cases of iatrogenic parvovirus B19 infection resulting from the use of the same batch of ®brin sealant under operation. Fibrin sealant, which is a typical haemostatic agent produced from blood, has been used during surgery. Human parvovirus is resistant to existing virusinactivating techniques, suggesting that infection may occur from blood products contaminated with it. Use of recombinant products for these proteins may thus be necessary.Keywords: parvovirus B19, aplastic crisis, ®brin sealant, surgery.Infection with human parvovirus B19, which is the smallest DNA-containing virus, usually causes a minor, febrile illness or is asymptomatic (Cossart et al, 1975;Shneerson et al, 1980;Anderson, 1990). Blood group P antigen is the cellular receptor for this virus, which can only replicate in proliferating and differentiating erythroid precursor cells (Brown et al, 1993). Transient aplastic crisis as a result of maturation arrest within the erythroid lineage occurs in patients with chronic haemolytic anaemia. Aplastic crisis also occurs in patients who have rapid red cell turnover, such as those with acute blood loss. Transmission of this virus is by respiratory secretions, transplacentally and by transfusion of blood and blood products. We report here three cases of iatrogenic symptomatic human parvovirus B19 infection, resulting from the use of the same batch of ®brin sealant during surgery. CASE REPORTSBetween March 1998 and May 1998, three patients were infected with human parvovirus B19 during surgery in the gynaecology ward of our hospital. The clinical characteristics of the three patients are shown in Table I. One of the three cases has been described previously (Hino et al, 1999). All patients had blood group P2 phenotype (P1 antigen negative/P antigen positive). P antigen is the cellular receptor for parvovirus B19. In all three patients, fever and leucopenia were observed between days 6 and 11 after the operation. The lowest white blood cell counts were 1´11 0 9 /l to 1´4´10 9 /l. Bone marrow examination revealed severe erythroblastopenia (0´8%±1´8% of total nucleated cells) with giant proerythroblasts, suggesting recent human parvovirus B19 infection. Reticulocytopenia and anaemia developed subsequently. The lowest haemoglobin levels were 7´7±8´1 g/dl. Haematological ®ndings spontaneously improved within 10 days in all three patients. Anti-human parvovirus B19 IgM and IgG were detected in serum, and human parvovirus B19 DNA was detected by polymerase chain reaction (PCR) in all three patients (Sevall, 1990). Autologous bone marrow cultures revealed a high degree of inhibition of BFU-E-and CFU-E-derived colony growth by the patients' acute-phase serum, whereas CFU-GM-derived colony formation was normal. Human parvovirus B19-induced aplastic crisis was diagnosed in each of these three patients. Only one pa...
Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cellular IAP1 (cIAP1), cIAP2, and X-linked IAP. Among these members, cIAP2 expression was selectively up-regulated by stimulation with granulocyte colony-stimulating factor (G-CSF), but not with granulocytemacrophage CSF. The increased expression of cIAP2 mRNA was detected as early as 30 minutes after in vitro stimulation with G-CSF, and the elevated level of cIAP2 protein was detected at 1 hour. The elevated level of cIAP2 protein was also detected in peripheral blood neutrophils obtained from healthy donors receiving G-CSF administration. G-CSF-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the antiapoptotic effects were inhibited by pretreatment of cells with AG490, a specific inhibitor of Janus kinase 2 (JAK2). Mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable overexpression of cIAP2 mRNA and prolongation of survival, whereas cIAP2 mRNA expression and survival in mature neutrophils from patients with chronic myelogenous leukemia were essentially similar to those in normal neutrophils. These findings suggest that cIAP2 expression is upregulated by G-CSF through activation of the JAK2-STAT3 pathway, and increased expression of cIAP2 protein may contribute to G-CSF-mediated antiapoptosis. In addition, overexpression of cIAP2 may be partly responsible for sustained neutrophilia at least in some cases of chronic neutrophilic leukemia. (Blood.
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