Contemporary Outcomes and Factors Associated With Mortality After a Fetal or Postnatal Diagnosis of Common Arterial Trunk

Background

Common arterial trunk (CAT) is a rare anomaly with a spectrum of pathology. We sought to identify current trends and factors associated with postnatal outcomes.

Usefulness of docetaxel as first‐line chemotherapy for metastatic extramammary Paget's disease

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S‐1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first‐line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1‐year overall survival rate determined by the Kaplan–Meier method was 75.0%. All adverse effects were manageable and no treatment‐related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first‐line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.     

Diagnostic importance of CD179a/b as markers of precursor B-cell lymphoblastic lymphoma.

Surrogate light chains consisting of VpreB (CD179a) and lambda5 (CD179b) are expressed in precursor B cells lacking a complete form of immunoglobulin and are thought to act as substitutes for conventional light chains. Upon differentiation to immature and mature B cells, CD179a/b disappear and are replaced with conventional light chains. Thus, these molecules may be useful as essential markers of precursor B cells. To examine the expression of the surrogate light-chain components CD179a and CD179b in precursor B-cell lymphoblastic lymphoma, we analyzed tissue sections using immunohistochemistry techniques. Among a number of monoclonal antibodies for the surrogate light chains, VpreB8 and SL11 were found to detect CD179a and CD179b, respectively, in acetone-fixed fresh frozen sections. Moreover, we also observed VpreB8 staining in formalin-fixed, paraffin-embedded sections. Using these antibodies, we found that CD179a/b were specifically expressed in precursor B-cell lymphoblastic lymphomas, but not in mature B-cell lymphomas in childhood. Furthermore, other pediatric tumors that must be included in a differential diagnosis of precursor B-cell lymphoblastic lymphoma, including precursor T-cell lymphoblastic lymphoma, extramedullary myeloid tumors, and Ewing sarcoma, were also negative for both CD179a and CD179b. Our data indicate that CD179a and CD179b may be important markers for the immunophenotypic diagnosis of precursor B-cell lymphoblastic lymphomas.     

Regulation of autoimmune diabetes by non-islet-specific T cells - a role for the glucocorticoid-induced TNF receptor

Diabetogenic BDC2.5 CD4 T cells induce diabetes when injected into NOD.scid mice. However, when co-transferred with the OVA-specific DO11.10 CD4 T cells, BDC2.5 T cells failed to cause diabetes. This inhibition depended upon the stimulation of DO11.10 T cells only with soluble OVA, which skewed their differentiation to a Th2-type pattern of cytokine secretion in vivo. However, in vivo neutralization of IL-4, IL-10 or TGF-beta using monoclonal antibodies did not prevent the inhibition whereas treatment with an antibody against the glucocorticoid-induced TNF receptor abrogated the protection from disease. In the protected mice, the diabetogenic T cells could be isolated from their spleens and shown to transfer diabetes when injected into new NOD.scid recipients. Thus, the inhibition took place without the physical or functional elimination of the diabetogenic T cells.     

Impact of early expression of TCR alpha chain on thymocyte development

CD4(-)CD8(-) thymocytes expressing a transgenic T cell receptor (TCR) alpha chain have decreased capacity to give rise to CD4(+)CD8(+) thymocytes when compared with wild-type thymocytes. This inefficient CD4(-)CD8(-) to CD4(+)CD8(+) maturation is mediated by the transgenic TCR alpha chain pairing with endogenous TCR beta chain but not with endogenous TCR gamma chain. Comparison between TCR alpha chain-transgenic mice with or without a functional pre-TCR alpha (pT alpha ) chain reveals that the formation of transgenic alpha/endogenous beta TCR on CD4(-)CD8(-) thymocytes inhibits the formation of pre-TCR, but at the same time mediates CD4(-)CD8(-) to CD4(+)CD8(+) maturation in the absence of pre-TCR, albeit inefficiently. These results indicate that alpha beta TCR and pre-TCR provide different signals for thymocyte development. They also suggest that the precise regulation of the sequential rearrangements of TCR beta and alpha loci and the cellular expansion induced by the pre-TCR may both be evolved to ensure the efficient generation of mature alpha beta T cells.     

Apoptotic death of lymphocytes in murine acquired immunodeficiency syndrome: Involvement of Fas-Fas ligand interaction

Murine acquired immunodeficiency syndrome (MAIDS) is caused by a defective murine leukemia virus. The disease is characterized by abnormal lymphoproliferation, impaired T and B cell function and aberrant regulation of cytokines. Both T and B lymphocytes show activated phenotypes, but undergo apoptotic death with characteristic DNA fragmentation. These results indicate the presence of a continuous activation death pathway of the lymphocytes in MAIDS. Overexpression of the bcl-2 transgene in lymphocytes showed no effect on the apoptotic cell death or on the development of the disease. In contrast, mice carrying mutations in either Fas or Fas ligand exhibited accelerated progression of the disease upon infection with MAIDS virus. These results suggest the involvement of Fas-Fas ligand system in the pathogenesis of MAIDS.     

Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers

Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down‐slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low‐set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.