Clinical features and treatment outcome of very elderly patients over 80 years old with multiple myeloma:comparison with patients in different age groups in the era of novel agents

We retrospectively analyzed the outcomes of 175 consecutive patients admitted to our hospital between April 2004 and June 2014, and identified 42 (24%), 80 (46%), and 53 (30%) patients 80, 66-79, and 65 years old, respectively. The median progression-free survival (PFS) and overall survival (OS) of the 80, 66-79, and 65 years old groups were 19.1, 26.3, and 54.3 months, and 31.9, 54.8, and 83.8 months, respectively. Patients 80 but not 79 years old with ECOG performance score (PS) 3 and/or Charlson comorbidity index (CCI) 5 showed significantly shorter survival. ECOG PS and CCI predicted the treatment outcome of patients 80 but did not predict 79 years old.</p

Droplet digital polymerase chain reaction assay and peptide nucleic acid-locked nucleic acid clamp method for RHOA mutation detection in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T‐cell lymphoma (AITL) is a subtype of nodal peripheral T‐cell lymphoma (PTCL). Somatic RHOA mutations, most frequently found at the hotspot site c.50G > T, p.Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next‐generation sequencing (NGS), droplet digital PCR (ddPCR) and peptide nucleic acid‐locked nucleic acid (PNA‐LNA) clamp method for detecting the G17V RHOA mutation. G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA‐LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance (P T;50G > T], p.Gly17Leu in PTCL198; c.[50G > T;51A > C], p.Gly17Val in PTCL216; and c.50G > A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and the PNA‐LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had RHOA mutations at the p.Gly17 position. In conclusion, our results suggested that a combination of ddPCR/PNA‐LNA clamp methods and NGS are best method to assist the diagnosis of AITL by detecting RHOA mutations at the p.Gly17 position

Quantification of bone marrow plasma cell infiltration in multiple myeloma:Usefulness of bone marrow aspirate clot with CD138 immunohistochemistry

Accurate quantification of plasma cells (PCs) in bone marrow (BM) is critical for diagnosis and assessment of treatment response in patients with multiple myeloma (MM). We compared the % of BM PC quantified by 250 cell differential count on May–Giemsa-stained BM smears, by counting 500 – 2500 cells in 2 – 5 representative microscopy fields in CD138-immunostained BM clot and biopsy sections, and CD38/CD45/CD138 gated BM PCs on flow cytometry (FCM) in 150 sets of BM samples from 120 patients. Percentages of PC were significantly correlated between BM biopsy and clot, and between smear and FCM (r = 0.96, 0.93, respectively). However, quantification by smear and FCM significantly underestimated the PC compared to biopsy or clot, and the degree of underestimation increased with blood dilution. FCM consistently showed lower % of PC compared to aspirate smears. Fifty-nine of 103 patients with M-protein level < 3000 mg/dL in serum or 500 mg/24 h in urine and diagnosed with monoclonal gammopathy of undetermined significance (MGUS) based on smear alone were reclassified as smoldering MM when reassessed using CD138-stained biopsy/clot sections. Among the 72 patients with sMM diagnosed by BM biopsy and/clot, three patients (4.2%) had extensive BM infiltration of PC (≥ 60%) and required treatment. Our data clearly showed the necessity of CD138 immunostaining of BM biopsy/clot specimens for correct diagnosis of MM and related disorders

Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication.

International audienceDuplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis-1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin-1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome-based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication

Endogenous interleukin-22 prevents cardiac rupture after myocardial infarction in mice.

Myocardial infarction (MI) can result in fatal myocardial rupture or heart failure due to adverse remodeling and dysfunction of the left ventricle. Although recent studies have shown that exogenous interleukin (IL)-22 shows cardioprotective effect after MI, the pathophysiological significance of endogenous IL-22 is unknown. In this study, we investigated the role of endogenous IL-22 in a mouse model of MI. We produced MI model by permanent ligation of the left coronary artery in wild-type (WT) and IL-22 knock-out (KO) mice. The post-MI survival rate was significantly worse in IL-22KO mice than in WT mice due to a higher rate of cardiac rupture. Although IL-22KO mice exhibited a significantly greater infarct size than WT mice, there was no significant difference in left ventricular geometry or function between WT and IL-22KO mice. IL-22KO mice showed increase in infiltrating macrophages and myofibroblasts, and altered expression pattern of inflammation- and extracellular matrix (ECM)-related genes after MI. While IL-22KO mice showed no obvious changes in cardiac morphology or function before MI, expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were increased, whereas that of tissue inhibitor of MMPs (TIMP)-3 was decreased in cardiac tissue. Protein expression of IL-22 receptor complex, IL-22 receptor alpha 1 (IL-22R1) and IL-10 receptor beta (IL-10RB), were increased in cardiac tissue 3 days after MI, regardless of the genotype. We propose that endogenous IL-22 plays an important role in preventing cardiac rupture after MI, possibly by regulating inflammation and ECM metabolism