Chest complications in immunocompromised patients without acquired immunodeficiency syndrome (AIDS): differentiation between infectious and non-infectious diseases using high-resolution CT findings.

AIM: To differentiate between infectious and non-infectious diseases occurring in immunocompromised patients without acquired immunodeficiency syndrome (AIDS) using high-resolution computed tomography (HRCT). MATERIALS AND METHODS: HRCT images of 555 patients with chest complications were reviewed retrospectively. Infectious diseases (n=341) included bacterial pneumonia (n=123), fungal infection (n=80), septic emboli (n=11), tuberculosis (n=15), pneumocystis pneumonia (n=101), and cytomegalovirus pneumonia (n=11), while non-infectious diseases (n=214) included drug toxicity (n=84), infiltration of underlying diseases (n=83), idiopathic pneumonia syndrome (n=34), diffuse alveolar haemorrhage (n=8), and pulmonary oedema (n=5). Lung parenchymal abnormalities were compared between the two groups using the χ2 test and multiple logistic regression analysis. RESULTS: The χ2 test results showed significant differences in many HRCT findings between the two groups. Multiple logistic regression analysis results indicated the presence of nodules with a halo and the absence of interlobular septal (ILS) thickening were the significant indicators that could differentiate infectious from non-infectious diseases. ILS thickening was generally less frequent among most infectious diseases and more frequent among most non-infectious diseases, with a good odds ratio (7.887, p<0.001). The sensitivity and accuracy for infectious diseases in the absence of ILS thickening were better (70% and 73%, respectively) than those of nodules with a halo (19% and 48%, respectively), while the specificity in the nodules with a halo was better (93%) than that of ILS thickening (78%). CONCLUSIONS: The presence of nodules with a halo or the absence of ILS thickening tends to suggest infectious disease. Specifically, ILS thickening seems to be a more reliable indicator.

High-resolution CT findings of idiopathic pneumonia syndrome after haematopoietic stem cell transplantation: based on the updated concept of idiopathic pneumonia syndrome by the American Thoracic Society in 2011.

Idiopathic pneumonia syndrome (IPS) is an acute lung dysfunction of non-infectious aetiology and a severe complication following haematopoietic stem cell transplantation (HSCT). Recently, the American Thoracic Society (ATS) updated the concept of IPS and extended the concept to a wider range; it defined IPS as "an idiopathic syndrome of pneumopathy after HSCT, with evidence of widespread alveolar injury and in which infectious aetiologies and cardiac dysfunction, acute renal failure, or iatrogenic fluid overload have been excluded." The ATS also categorised the presumed site of primary tissue injury into three patterns (pulmonary parenchyma, vascular endothelium, and airway epithelium), each of which has several entities. Since the therapeutic strategies for IPS are clearly different from those of infectious diseases, and therapeutic delay causes a poor prognosis, radiologists should be aware of some characteristic HRCT findings of IPS, which includes a wide spectrum of entities. In this article, the characteristic HRCT findings of these entities, including acute interstitial pneumonia/acute respiratory distress syndrome, eosinophilic pneumonia, non-cardiogenic capillary leak syndrome, diffuse alveolar haemorrhage, transfusion-related acute lung injury, organising pneumonia, and bronchiolitis obliterans syndrome, are shown.

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab.

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

Cytomegalovirus ventriculoencephalitis in a reduced- intensity conditioning cord blood transplant recipient.

Cytomegalovirus (CMV) encephalitis most commonly occurs in patients with advanced human immunodeficiency virus infection and profound CD4 cell depletion and is rare in transplant recipients. We describe a patient with pathologically proven CMV ventriculoencephalitis that occurred after human herpesvirus-6 limbic encephalitis, following reduced-intensity conditioning cord blood transplantation (CBT). At approximately day 150 after CBT, the patient became acutely confused after steroid therapy for grade III acute graft-versus-host disease. Fluid-attenuated inversion recovery magnetic resonance imaging of the brain revealed a communicating hydrocephalus with abnormal periventricular hyperintensity. Neuropathologic examination of the brain at autopsy revealed necrotizing CMV ventriculoencephalitis, limbic encephalitis, and multifocal necrotizing leukoencephalopathy. This case represents the first report of CMV encephalitis following CBT and serves to highlight the interrelationship between viruses in transplant recipients.

Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption.

Targeted disruption of the gene encoding MEK kinase 1 (MEKK1), a mitogen-activated protein kinase (MAPK) kinase kinase, defined its function in the regulation of MAPK pathways and cell survival. MEKK1(-/-) embryonic stem cells from mice had lost or altered responses of the c-Jun amino-terminal kinase (JNK) to microtubule disruption and cold stress but activated JNK normally in response to heat shock, anisomycin, and ultraviolet irradiation. Activation of JNK was lost and that of extracellular signal-regulated protein kinase (ERK) was diminished in response to hyperosmolarity and serum factors in MEKK1(-/-) cells. Loss of MEKK1 expression resulted in a greater apoptotic response of cells to hyperosmolarity and microtubule disruption. When activated by specific stresses that alter cell shape and the cytoskeleton, MEKK1 signals to protect cells from apoptosis.

A unique phenotype of acquired Glanzmann thrombasthenia due to non-function-blocking anti-αIIbß3 autoantibodies.

Essentials Acquired Glanzmann thrombasthenia (aGT) is generally caused by function-blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbß3 with anti-αIIbß3 Abs. The anti-αIIbß3 Abs of the patient did not inhibit platelet function but reduced surface αIIbß3. Internalization of αIIbß3 induced by the Abs binding may be responsible for the phenotype. SUMMARY: Background Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function-blocking anti-αIIbß3 autoantibodies. Aim We characterize an unusual case of aGT caused by marked reduction of surface αIIbß3 with non-function-blocking anti-αIIbß3 antibodies (Abs). Methods A 72-year-old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbß3 expression and genetic analysis were performed. We also analyzed effects of anti-αIIbß3 Abs of the patient on platelet function and αIIbß3 expression. Results Surface αIIbß3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbß3 to the amount of 40-50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbß3 expression caused a GT phenotype, and active internalization of αIIbß3 was suggested. Anti-αIIbß3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC-1 binding, indicating that the Abs were non-function-blocking. Surface αIIbß3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbß3 expression was recovered to 20% of normal with reduction of anti-αIIbß3 Abs. Conclusion We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbß3. Internalization induced by anti-αIIbß3 Abs may be responsible in part for the phenotype.

Significance of Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine, Cyclophosphamide, and Total Body Irradiation in Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignant Neoplasms.

Allogeneic hematopoietic cell transplant (HCT) is a curative procedure for myeloid malignant neoplasms, but relapse after HCT remains critical. A conditioning regimen involving granulocyte colony-stimulating factor-combined high-dose cytarabine, cyclophosphamide, and total body irradiation (G-CSF-combined high-dose cytarabine/cyclophosphamide/total-body irradiation [HDCA/CY/TBI]) was reported to improve outcomes after cord blood transplant (CBT) for myeloid malignant neoplasms, but this regimen was not previously evaluated among patients undergoing bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT). METHODS: We retrospectively analyzed 28 patients who underwent allogeneic HCT including BMT from a related (1 patient) or unrelated donor (9 patients), PBSCT from a related donor (7 patients), or single-unit CBT from an unrelated donor (11 patients) after a G-CSF-combined HDCA/CY/TBI regimen. RESULTS: All patients achieved neutrophil and platelet engraftment, which were significantly more rapid in the BMT/PBSCT group than in the CBT group. Eighteen patients were alive at a median follow-up of 54.3 months. The 3-year relapse and nonrelapse mortality rates were 28.6% and 7.1%, respectively, which were similar between the BMT/PBSCT and CBT groups. Overall survival and disease-free survival at 5 years after HCT were 62.6% and 64.3%, respectively, which were also similar between the BMT/PBSCT and CBT groups. Only disease status at HCT had a significant impact on overall survival and disease-free survival (86.7% with standard risk vs 38.5% with high risk and 86.7% with standard risk vs 38.5% with high risk, respectively). CONCLUSION: A G-CSF-combined HDCA/CY/TBI regimen is a promising conditioning in patients with myeloid malignant neoplasms who undergo not only CBT but also BMT or PBSCT.

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT.

To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(-)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(-) was significantly better than that in patients transplanted in MRD(+) (MRD(-): 67% vs MRD(+): 55% at 4 years; P=0.001). MRD(-) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(-) was significantly lower than that in patients transplanted in MRD(+) (MRD(-): 19% vs MRD(+): 29% at 4 years; P=0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P<0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.

Anti-apoptotic versus pro-apoptotic signal transduction: checkpoints and stop signs along the road to death.

The activation of caspases is a final commitment step for apoptosis. It is now evident that signal transduction pathways involving specific protein kinases modulate the apoptotic response. Both pro-apoptotic and anti-apoptotic pathways integrate environmental cues that control the decision to undergo apoptosis. Pro- and anti-apoptotic signal pathways regulate the activation of the caspases. In this review we describe our current understanding of apoptotic signal transduction.

The TAO of MEKK.

Cloning and characterization of MEKK1 in 1993 revealed that in addition to Raf there were other pathways activated by extracellular stimuli that were responsible for ERK activation. Since then, three additional MEKK family members have been cloned adding even further diversity to the regulation of MAPK pathways. The MEKK family members are regulated by a diverse array of extracellular stimuli ranging from growth factors to DNA damaging stimuli and so are important for the cell to sense exposure to various environmental stimuli. One important aspect of MEKK biology is that they can potentially serve in more than one pathway. Regulation of MEKK family members often involves LMWG proteins, phosphorylation and subcellular localization. With regard to at least MEKK1, serine/threonine kinases such as NIK, GLK and HPK1 appear also to be important for regulation. Of the MEKK family members, the biological role of MEKK1 is best characterized and studies have shown that MEKK1 is important in mediating survival vs. apoptosis, possibly via its ability to regulate transcription factors, the expression of death receptors and their ligands. The biological roles of MEKK2, 3 and 4 are under investigation and undoubtedly homologous deletion of these MEKK family members will be invaluable at determining the biological functions of these MEKKs. At present, the MEKK family members are characterized as localized sensors that control cell responses at the level of gene expression, metabolism and the cytoskeleton

[Bronchopulmonary lesions in cases of chronic graft-versus-host disease (cGVHD)].

We have studied bronchopulmonary lesions that developed in 3 allogeneic bone marrow recipients between days 120 and 250 post-transplant. Two cases had extensive chronic GVHD at the time of onset. All patients complained of low-grade fever, dry cough, and shortness of breath. The bronchopulmonary lesions were characterized by hypoxemia with increased AaDO2 and bilateral multiple noncircumscribed interstitial shadows on chest CT scan. Broncho-alveolar lavage (BAL) showed elevated numbers of lymphocytes in BAL fluid in all cases. BAL fluid was negative for CMV, pneumocystis carinii cysts, bacteria and fungi in all cases. The results of transbronchial lung biopsy (TBLB) showed interstitial infiltration of lymphocytes in all 3 cases. The bronchopulmonary lesions were improved by either starting or increasing the dose of immunosuppressants. These findings and clinical courses suggest that the bronchopulmonary lesions in these patients were related to chronic GVHD.

Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.

Reduced-intensity allogeneic stem cell transplantation for patients aged 50 years or older with B-cell ALL in remission: a retrospective study by the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

We retrospectively assessed the outcome and pretransplantation predictors of the outcome in 118 patients aged ≥ 50 years who received fludarabine-containing reduced-intensity allo-SCT (RIST) for B-cell ALL in the first or second CR. Eighty patients received transplants from unrelated donors. Seventy-eight patients were positive for the Ph chromosome. The median follow-up period was 18 months and the 2-year OS rate was 56%. The 2-year cumulative incidence of relapse and non-relapse mortality was 28% and 26%, respectively. The incidence of grades II-IV and III-IV acute GVHD was 46% and 24%, respectively. After 2 years, the incidence of chronic GVHD was 37%. Multivariate analysis of pretransplant factors showed that a higher white blood cell count (≥ 30 × 10(9)/L) at diagnosis (hazard ratio (HR)=2.19, P=0.007) and second CR (HR=2.02, P=0.036) were significantly associated with worse OS, whereas second CR (HR=3.83, P<0.001) and related donor (HR=2.34, P=0.039) were associated with a higher incidence of relapse. Fludarabine-containing RIST may be a promising strategy for older patients with B-cell ALL in their first remission.

Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR-ABL-positive ALL.

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49-76) and 58% (95% CI, 43-70), respectively. Prognostic factor analysis revealed that the major BCR-ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49-9.08); P=0.005 and HR, 6.25 (95% CI, 1.88-20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21-8.50); P=0.019 and HR, 6.92 (95% CI, 2.09-22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR-ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted.

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia.

A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.