Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD.

Increased Soluble CD155 in the Serum of Cancer Patients.

Emerging evidence suggests that DNAM-1 (CD226) play an important role in the recognition of tumor cells and their lysis by cytotoxic T lymphocytes (CTL) and NK cells. Although the DNAM-1 ligand CD155 is ubiquitously expressed in various tissues, many human tumors significantly upregulate the expression of CD155; DNAM-1 on CTL and NK cells may be involved in tumor immunity. However, unlike those in mice, human tissues also express soluble isoforms of CD155 (sCD155) that lack the transmembrane region. Here, we show that sCD155 levels were significantly higher in the sera of 262 patients with lung, gastrointestinal, breast, and gynecologic cancers than in sera from healthy donors. In addition, the sCD155 levels were significantly higher in patients with early stage (stages 1 and 2) gastric cancer than in healthy donors, and were significantly higher in patients with advanced stage (stages 3 and 4) disease than in patients in those with early stage disease and healthy donors. Moreover, the sCD155 levels were significantly decreased after surgical resection of cancers. Thus, sCD155 level in serum may be potentially useful as a biomarker for cancer development and progression.

Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma.

AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.

Possibility of molecular targeting therapy for the treatment of cancer of unknown primary origin by analysis of intracellular signaling molecules.

Recently, antibody-mediated epidermal growth factor receptor (EGFR) blockade has become a major research focus, and a number of clinical studies on this new treatment have been started in the field of clinical oncology. This retrospective study investigated the role of KRAS gene mutations and clinical features for possibilities for new therapies in patients with cancer of unknown primary (CUP). We investigated the role of KRAS, PIK3CA and BRAF gene mutations and clinical features for possibilities for new therapies in patients with CUP. Nine patients with metastases from an unknown primary tumor were included in this retrospective study. The KRAS, BRAF and PI3KCA mutational analyses were carried out by means of PCR using genomic DNA for each PCR reaction. The mutation rate in CUP for codon 12 or 13 of the KRAS gene and for PIK3CA was lower than that in colorectal cancer, while the same mutation rate for BRAF was almost the same in the two; this means that the EGFR antibodies can possibly treat CUP.

Oxaliplatin-induced acute-onset thrombocytopenia and hemorrhage: Case report and review of the literature.

We report the case of a woman who developed acute thrombocytopenia with hemorrhagic diathesis during adjuvant treatment of colorectal adenocarcinoma with oxaliplatin, 5-fluorouracil and leucovorin. A 55-year-old woman started adjuvant chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6). Prior to starting the 12th course of chemotherapy, a complete blood cell count showed the following values: neutrophils 1800/mm(3), platelets 136,000/m(3) and hemoglobin 11.1 g/dl. A blood count revealed that the platelet levels had dropped to 35,000/mm(3), with no significant changes in hemoglobin levels following the course. The administration of corticosteroids was begun and the platelet number was recovered. Clinicians should be aware of the possibility of oxaliplatin-induced hematological emergencies during the treatment of colorectal cancer patients in order to optimize supportive treatment and avoid toxic mortality.

Requirement of the cytoplasmic portion for dimer formation of Fcalpha/micro receptor expressed on cell surface.

Fcalpha/mu receptor (Fcalpha/muR), an Fc receptor for IgA and IgM, is the only Fc receptor for IgM identified on hematopoietic cells in human and rodents and for IgA in rodents. Fcalpha/microR is a type 1 transmembrane protein containing one immunoglobulin-like domain in the extracellular portion. Both human and mouse Fcalpha/microR mediate endocytosis of the ligands IgA and IgM, for which the cytoplasmic portion of Fcalpha/microR is responsible. However, molecular characteristics of Fcalpha/muR involved in the function have been incompletely understood. Here, we show that both monomeric and dimeric Fcalpha/microR are expressed in a mouse B cell line BCL1-B20 and BW5147 or Ba/F3 transfectants stably expressing Fcalpha/microR. We also show that the dimeric, but not monomeric, Fcalpha/microR is preferentially localized to the cell surface of the transfectants. BW5147 transfectant expressing mutant Fcalpha/microR lacking the cytoplasmic portion expressed only the monomeric Fcalpha/microR. These results suggest that the cytoplasmic portion is required for the dimer formation and thus for efficient cell surface expression of Fcalpha/microR.