Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.
Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
To clarify the clinical features and outcome of Stenotrophomonas maltophilia infection among hematopoietic SCT (HCT) recipients, we retrospectively reviewed the records of 1085 consecutive HCT recipients and identified 42 episodes in 31 HCT recipients with S. maltophilia infection. We compared these recipients with 30 non-HCT patients with S. maltophilia infection. The mortality rate in HCT recipients was significantly higher than that in non-HCT patients (relative risk 5.7, P ¼ 0.04), and we identified seven patients with pulmonary hemorrhage due to S. maltophilia, exclusively in the HCT cohort. Six of these latter seven patients died within 1 day from the onset of hemorrhage and the isolate was identified after death in most cases; one patient, who received empiric therapy for S. maltophilia and granulocyte transfusion, survived for more than 2 weeks. The patients with pulmonary hemorrhage had a more severe and longer duration of neutropenia, persistent fever despite of the use of broad-spectrum antibiotics, complication by pneumonia and higher C-reactive protein levels than those without pulmonary hemorrhage. In conclusion, S. maltophilia was associated with fulminant and fatal pulmonary hemorrhage in HCT recipients. Empiric therapy with antibiotics before the onset of pulmonary hemorrhage may be effective in HCT recipients who carry the conditions identified.
Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/μl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet-albumin (PA) score low (platelet count ≥100,000/μl, albumin ≥3.5 g/dl, n = 243); intermediate (platelet count <100,000/μl, albumin ≥3.5 g/dl or platelet count ≥100,000/μl, albumin <3.5 g/dl, n = 125); and high (platelet count <100,000/μl, albumin <3.5 g/dl, n = 23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p < 0.001). Notably, most patients with a low platelet count (n = 30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n = 291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n = 171), intermediate (n = 101), and high (n = 19) groups were 77.6, 47.9, and 19.0 %, respectively (p < 0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.
We analyzed data from 64,539 consecutive patients in the Japanese national transplant registry, including 40,195 after allogeneic hematopoietic stem cell transplantation (HSCT), 24,215 after autologous HSCT and 129 after syngeneic HSCT, of whom 299 developed Epstein-Barr virus-positive post-transplant lymphoproliferative disorder (PTLD). The probability of developing PTLD at 2 years post-HSCT was .79% after allogeneic transplantation, .78% after syngeneic transplantation, and .11% after autologous transplantation. The following variables were identified as risk factors after allogeneic HSCT in multivariate analysis: antithymocyte globulin (ATG) use in a conditioning regimen, ATG use for acute graft-versus-host disease (GVHD) treatment, donor other than an HLA-matched related donor, aplastic anemia, second or subsequent allogeneic HSCT, the most recent year of transplantation, and acute GVHD. The probability at 2 years increased particularly after 2009 (1.24%) than before 2009 (.45%). To stratify the risk of PTLD before allogeneic HSCT, we developed a novel 5-point scoring system based on 3 pretransplant risk factors: ATG use in a conditioning regimen (high dose, 2 points; low dose, 1 point), donor type (HLA-mismatched related donor, 1 point; unrelated donor, 1 point; cord blood, 2 points), and aplastic anemia (1 point). Patients were classified into 4 risk groups according to the summed points: low risk (0 or 1 point), intermediate risk (2 points), high risk (3 points), and very high risk (4 or 5 points) groups, with probabilities at 2 years of .3%, 1.3%, 4.6%, and 11.5%, respectively. Our scoring system is useful for predicting patients at high risk for PTLD. Careful observation and close monitoring of Epstein-Barr virus reactivation are warranted for these high-risk patients.
BackgroundThe TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-κB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the detection of this in primary Hodgkin lymphoma (HL) specimens is hampered by the scarcity of Hodgkin Reed-Sternberg (HR-S) cells even after enrichment by micro-dissection.MethodsWe used anti-CD30 immunofluorescence with fluorescence in-situ hybridization (FISH) to evaluate the relative number of TNFAIP3/CEP6 double-positive signals in CD30-positive cells.ResultsFrom a total of 47 primary classical Hodgkin lymphoma (cHL) specimens, 44 were evaluable. We found that the relative numbers of TNFAIP3/CD30 cells were distributed among three groups, corresponding to those having homozygous (11%), heterozygous (32%), and no (57%) deletions in TNFAIP3. This shows that TNFAIP3 deletions could be sensitively detected using our chosen methods.ConclusionsComparing the results with mutation analysis, TNFAIP3 inactivation was shown to have escaped detection in many samples with homozygous deletions. This suggests that TNFAIP3 inactivation in primary cHL specimens might be more frequent than previously reported.
The IsK (minK or KCNE1) protein is known to co-assemble with the KvLQT1 (KCNQ1) protein to form a channel underlying the slowly activating delayed rectifier K+ current (IKs). Controversy remains as to whether the IsK protein assembles with ERG (the ether-a-go-go-related gene) products to form or modulate the channel-underlying the rapidly activating delayed rectifier K+ current (IKr). We investigated the effects of antisense oligodeoxynucleotides (AS-ODN) against IsK and its mutant D77N [which underlies a form of long QT syndrome (LQT5) in humans] on the delayed rectifier K+ current (IK) of neonatal mouse ventricular myocytes in primary culture. Patch-clamp experiments on these cells showed that IK consists of IKs and IKr. IK was not recorded from ventricular cells transfected with AS-ODN, while it was recorded from cells transfected with the corresponding sense oligodeoxynucleotides (S-ODN). IK was not recorded from cells transfected with the D77N mutant, and the action potential duration was much longer than in cells transfected with wild-type IsK. Furthermore, HERG could not induce currents in COS-1 cells co-expressed with the D77N mutant and HERG (the human form of ERG). These results indicate that the IsK protein associates with both KvLQT1 and ERG products to modulate IKr and IKs in cardiac myocytes.
Post-transplant lymphoproliferative disorder (PTLD) following hematopoietic stem cell transplantation (HSCT) is a rare, but life-threatening complication. PTLD typically develops within 6-12 months of HSCT, which is before the reconstitution of EBV-specific cytotoxic T-cell immunity. Several risk factors for developing PTLD have been reported in the literature, including the use of antithymocyte globulin (ATG) and ex vivo T-cell depletion (TCD). However, only a few large-scale retrospective studies have been conducted and risk scores have not yet been well defined. Therefore, to further evaluate the probability of and risk factors for PTLD and establish a risk scoring system, we conducted a retrospective multicenter analysis using data from a Japanese nationwide transplant outcome registry database. A total of 71,904 patients aged 16 years or older who received HSCT between January 1990 and December 2016 were included in this study. We excluded patients for whom information regarding the transplantation type or PTLD development was unavailable, resulting in 64,539 patients ultimately being analyzed. The probability of developing PTLD was estimated using the Kaplan-Meier method, and differences between groups were evaluated using the log-rank test. To identify risk factors for PTLD, univariate and multivariate analyses were performed using the Cox's proportional hazard regression model for patients who received allogeneic HSCT. Among the 64,539 patients analyzed, 40,195 received allogeneic HSCT, 24,215 received autologous HSCT, and 129 received syngeneic HSCT. A total of 299 patients developed PTLD, including 267 who had received allogeneic HSCT, 31 who had received autologous HSCT, and one who had received syngeneic HSCT. The median age of patients with PTLD after allogeneic HSCT was 44 years (range, 16-76), and males accounted for approximately 60%. The underlying disease was acute myeloid leukemia and myelodysplastic syndrome in 20,474 patients (51%), acute lymphoblastic leukemia in 6,808 (17%), chronic myeloid leukemia and myeloproliferative disorder in 2,827 (7%), malignant lymphoma in 7,824 (19%), aplastic anemia (AA) in 1,327 (3%) and others in 932 (2%). ATG was used in 4,026 patients (10%) who underwent allogeneic HSCT. In contrast, ex vivo TCD was used only in 296 (0.7%). The donor type was human leukocyte antigen (HLA)-matched-related donor (MRD) in 13,058 patients (33%), HLA-mismatched-related donor (MMRD) in 4,095 (10%), HLA-matched-unrelated donor (MURD) in 10,216 (25%), HLA-mismatched-unrelated donor (MMURD) in 1,993 (5%) and unrelated cord blood (CB) in 10,118 (25%), but was unknown for the remaining 715 patients (2%).The probability of PTLD at 2 years after HSCT was 0.79% with a median onset of 131 (range, 15-6,356) days in patients after allogeneic HSCT. In contrast, the probability of PTLD was 0.11% with a median onset of 198 (range, 21-4,759) days in those after autologous HSCT. Only one patient developed PTLD at 29 days in those after syngeneic HSCT (0.78%). In multivariate analyses performed for patients after allogeneic HSCT, the following variables were identified as risk factors for PTLD: the use of ATG, donor type (MMRD, MURD, MMURD and CB), disease (AA), the number of HSCT, year of HSCT, and acute graft-versus-host disease (grade II-IV). To predict the risk of developing PTLD before HSCT, we established a novel scoring system using three pre-transplant risk factors that correlated with the development of PTLD. We assigned point(s) for the three risk factors by referring to each hazard ratio of the multivariate analysis as shown in the Table. Risk scores were calculated by adding each point(s), and patients were then successfully classified into 4 risk groups: low (score 0-1), intermediate (score 2), high (score 3), and very high risk (score 4-5), with probabilities of PTLD at 2 years after HSCT of 0.3, 1.1, 3.0, and 8.6%, respectively (Figure). Although ex vivo TCD is described as a risk factor for PTLD as well as ATG, it was not identified as a significant risk factor for PTLD in our cohort, probably due to the small number of the affected patients. This scoring system enables us to predict higher risk patients before HSCT. The close monitoring of EBV-DNA may be beneficial for the early diagnosis of these patients and more rapid initiation of treatment interventions, such as rituximab and EBV-specific cytotoxic T cells. Disclosures Mori: Janssen: Honoraria; Novartis Pharma: Research Funding; Taisho Toyama Pharmaceutical Co: Honoraria; CHUGAI: Honoraria; Kyowa Hakko Kirin: Honoraria; MSD: Honoraria; Novartis Pharma: Honoraria; Asahi Kasei: Research Funding; SHIONOGI: Honoraria; Pfizer: Honoraria; Japan Blood Products Organization: Honoraria; Shire Japan: Honoraria; Astella Pharma: Honoraria; Celgene: Honoraria; MSD: Research Funding; Eisai: Honoraria; Ono: Honoraria. Kanda:Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Tanaka:Pfizer: Honoraria; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis Pharma: Honoraria. Ichinohe:Celgene: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Mundipharma: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion Pharmaceuticals: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis.: Honoraria; Nippon Shinyaku Co.: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding. Suzuki:Celgene: Honoraria; Sawai Pharmaceutical: Honoraria; Ohtsuka: Honoraria; MSD: Research Funding; Meiji Seika Pharma: Honoraria; Takeda Pharmaceuticals: Honoraria; Shionogi: Honoraria; Novartis: Honoraria; Mochida Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy.
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