Yasushi Okoshi

Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation.

Immune responses are regulated by opposing positive and negative signals triggered by the interaction of activating and inhibitory cell surface receptors with their ligands. Here, we describe novel paired activating and inhibitory immunoglobulin-like receptors, designated myeloid-associated immunoglobulin-like receptor (MAIR) I and MAIR-II, whose extracellular domains are highly conserved by each other. MAIR-I, expressed on the majority of myeloid cells, including macrophages, granulocytes, mast cells, and dendritic cells, contains the tyrosine-based sorting motif and the immunoreceptor tyrosine-based inhibitory motif-like sequences in the cytoplasmic domain and mediates endocytosis of the receptor and inhibition of IgE-mediated degranulation from mast cells. On the other hand, MAIR-II, expressed on subsets of peritoneal macrophages and B cells, associates with the immunoreceptor tyrosine-based activation motif-bearing adaptor DAP12 and stimulates proinflammatory cytokines and chemokine secretions from macrophages. Thus, MAIR-I and MAIR-II play important regulatory roles in cell signaling and immune responses.

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

Background Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and Methods Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. Results Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. Conclusions We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor

After cecal ligation and puncture, mice lacking the phosphatidylserine receptor CD300a on mast cells show more neutrophil recruitment to the peritoneal cavity, improved bacterial clearance, and extended survival.

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—a systematic review and individual patient data meta-analysis

BACKGROUND To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Successful treatment of a patient with subcutaneous panniculitis-like T-cell lymphoma with high-dose chemotherapy and total body irradiation.

Abstract: A 24‐yr‐old man was referred for fever, right cheek swelling, subcutaneous tumor and liver dysfunction. Physical examination showed an elastic hard subcutaneous tumor on the right cheek, left axillary lymph node swelling and multiple small subcutaneous tumors in the trunk. Laboratory examinations showed elevated levels of transaminase, soluble interleukin‐2 receptor and ferritin. Biopsy of the subcutaneous tumor showed proliferation of medium‐sized cells with abundant clear cytoplasm and hyperchromatic nuclei among the subcutaneous fat tissues. These cells showed CD3+, CD4−, CD8+, CD56− and CD20− phenotype and possessed cytotoxic molecules such as granzyme B and T‐cell intracellular antigen‐1. Bone marrow aspiration showed proliferation of small numbers of abnormal lymphocytes with severe hemophagocytosis. He was thus diagnosed as having subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) and treated with dose‐escalated CHOP regimen. After three courses of the chemotherapy, he was further treated with high‐dose chemotherapy and total body irradiation (TBI) with autologous peripheral blood stem cell rescue. Thereafter, he has been in remission for more than 2 yr. We consider that SPTCL with hemophagocytosis is an extremely aggressive disease, and high‐dose chemotherapy and TBI should be included for the choice of the treatment.

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

We evaluated the efficacy of in vivo T‐cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)—Good Clinical Practice (ICH–GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2‐ or 3‐antigen‐mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II–IV acute graft‐versus‐host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation‐related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD4+ and CD8+ T‐cells and T‐cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2‐ or 3‐antigen‐mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT. Am. J. Hematol. 88:294–300, 2013.

Dual Assemblies of an Activating Immune Receptor, MAIR-II, with ITAM-Bearing Adapters DAP12 and FcRγ Chain on Peritoneal Macrophages

Certain activating immune receptors expressed on myeloid cells noncovalently associate with either DAP12 or FcεRIγ (FcRγ chain), the ITAM-bearing transmembrane adapter proteins. An activating receptor, myeloid-associated Ig-like receptor (MAIR) II, is expressed on a subset of B cells and macrophages in the spleen and peritoneal cavity of mice and associates with DAP12 in these cells. However, we demonstrate here that cross-linking MAIR-II with mAb induced secretion of a significant amount of the inflammatory cytokines TNF-α and IL-6 from DAP12−/− as well as wild-type (WT) peritoneal macrophages. We show that MAIR-II associates with not only DAP12 but also FcRγ chain homodimers in peritoneal macrophages. LPS enhanced the FcRγ chain expression and FcRγ chain-dependent cell surface expression of MAIR-II and had additive effects on MAIR-II-mediated inflammatory cytokine secretion from peritoneal macrophages. The lysine residue in the transmembrane region of MAIR-II was involved in the association with FcRγ chain as well as DAP12. Our findings present the first case of an activating receptor that uses either DAP12 or FcRγ chain as a signaling adapter. The FcRγ chain may provide cooperation with and/or compensation for DAP12 in MAIR-II-mediated inflammatory responses by peritoneal macrophages.

Detection of the STAT5B–RARA fusion transcript in acute promyelocytic leukemia with the normal chromosome 17 on G-banding

Acute promyelocytic leukemia (APL) is characterized by chromosomal rearrangements of 17q21, leading to fusion of the gene‐encoding retinoic acid receptor alpha (RARA) with a number of alternative partner genes. Signal transducer and activator of transcription 5 beta (STAT5B) is one of the alternative partners. We report a rare case of APL with STAT5B–RARA fusion transcript and the normal chromosome 17 on G‐banding. Administration of all trans‐retinoic acid improved disseminated intravascular coagulation without decrease of the leukemia cells in his peripheral blood and bone marrow. The molecular mechanism of fusion between STAT5B and RARA by chromosomal rearrangement is discussed based on the data from genome database. Clinical characteristics of APL with STAT5B–RARA are also discussed.

Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia

The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.48) nor a major molecular response (1,044 vs. 818 ng/ml, P = 0.17). Although this was significantly higher in patients with complete molecular response (CMR) than in those without (1,430 vs. 859 ng/ml, P = 0.04), the difference was not significant in the sub-population treated with a standard dose of IM (400 mg/day). Finally, multivariate analysis showed that the IM standard dose, but not Cmin, was predictive of the achievement of CMR. We thus suggest that, in practical clinics at least, adherence to the standard dose is the most important factor for the achievement of CMR.

Nodal CD8 Positive Cytotoxic T-Cell Lymphoma: A Distinct Clinicopathological Entity

We studied 11 cases of nodal cytotoxic T-cell lymphoma, which express the CD8+ phenotype and cytotoxic molecules (T-cell intracellular antigen-1, granzyme B and perforin), to characterize the clinicopathologic spectrum of these neoplasms. The 11 cases consisted of four men and seven women, aged 5 to 82 years (mean, 53 years). All cases were nodal, and eight of 11 had extranodal involvement, the most common being in bone marrow (eight cases) and liver (six cases). The expression of these cytotoxic molecules has been reported in some T/natural killer cell lymphomas mostly involved in extranodal sites of skin, nasopharyngeal region, or gastrointestinal tracts, but these types of extranodal involvement were rare in our cases. Morphologically these lymphomas could be divided into two groups. One group (n = 6) showed a diffuse large cell type and massive necrosis or apoptosis that was accompanied by disseminated intravascular coagulation (DIC) or hemophagocytic syndrome (HPS) on the initial. The prognosis of this group was generally poor (survival = 1–19 months, median = 5 mo), and four of these six cases were fulminant. The other group (n = 5) showed a diffuse medium or mixed cell type, and the prognosis was not so poor (median survival = 17 mo). Our results suggest that these nodal cytotoxic T-cell lymphomas originated from activated cytotoxic T-cells and were highly accompanied with DIC or HPS.