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The standard of care for diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, its ideal dose intensity varies among cases.This review provides the latest insights on the dose intensity of R-CHOP for DLBCL patients. Specifically, we discussed the optimal dose intensity for elderly patients, the optimal number of treatment cycles for limited or advanced-stage diseases, and the role of dose-intensified therapies or adding targeted inhibitors.Performing a comprehensive or simplified geriatric assessment can distinguish elderly DLBCL patients who will likely benefit from curative R-CHOP. Very elderly or medically unfit patients may need dose reduction in R-CHOP; the Age, Comorbidities, and Albumin index may aid decision-making. Four cycles of R-CHOP followed by two rituximab cycles comprise a new standard for low-risk, limited-stage DLBCL patients. Compared to eight cycles, six cycles of R-CHOP have similar efficacy and fewer toxicities for advanced-stage DLBCL. Dose-intensified therapy is not recommended in most DLBCL cases but may be considered for patients with double (or triple)-hit lymphoma. Applying targeted inhibitors and not merely escalating R-CHOP dose intensity through molecular subtyping will improve the treatment outcome for DLBCL.Diffuse large B-cell lymphoma (DLBCL) is one of the most common blood cancers. Patients with DLBCL are usually treated with a standard (immuno-) chemotherapy called R-CHOP, which stands for rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin, and prednisone. Of these, cyclophosphamide and doxorubicin are particularly toxic but effective. Therefore, the dosages of these drugs are adjusted according to the patient’s body size. However, the ideal amounts of these drugs (dose intensity) can vary from case to case. For instance, the regular dose intensity of R-CHOP is too toxic for some people, such as very older patients. Furthermore, ideal total amounts of these drugs, that is, ideal cycle numbers of R-CHOP, are also different between patients with limited disease and advanced disease. Therefore, oncology/hematology researchers have been seeking the optimal dose intensity of R-CHOP in each patient with DLBCL for years. The goal of this review is to provide the latest insights on the ideal dose intensity of R-CHOP in DLBCL treatment. In this article, we discuss: how R-CHOP was established as the standard of care for DLBCL, how to identify candidates for standard R-CHOP among older patients, how to adjust the dose intensity of R-CHOP for patients who are not candidates for standard R-CHOP, optimal cycle number of R-CHOP for limited-disease DLBCL, optimal cycle number of R-CHOP for advanced DLBCL, how to treat patients with a large mass, and the role of more intensive therapies other than R-CHOP in DLBCL treatment. Finally, we demonstrate how experts determined the dose intensity of R-CHOP for some example cases with DLBCL.

Background: Some chemotherapeutic agents cause carnitine deficiency, which causes general fatigue. However, there is no study on carnitine deficiency in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) therapy. Objective: In this study, we investigated carnitine concentrations in patients with CML receiving TKI therapy. Method: This study included patients with well-controlled CML. Total carnitine and free carnitine concentrations were evaluated using the enzyme cycling method. The brief fatigue inventory (BFI) and cancer fatigue scale (CFS) were used to assess general fatigue developed during TKI therapy. Results: Fifty-five patients on TKI therapy were included. Of these, 12 (21.8%) patients had low free carnitine concentrations. Free carnitine concentrations were higher in men than in women. Younger age was closely associated with lower free carnitine concentrations. TKI type, TKI dose, treatment response, or therapy duration were not associated with free carnitine concentrations. None of the scores (the global fatigue score with the BFI and CFS score) correlated with carnitine concentrations. Concentrations of free carnitine in patients in the treatment-free remission group were slightly higher than those in the TKI group, with only 9.1% having a low concentration of free carnitine. Conclusion: Carnitine deficiency is probably not a major cause of general fatigue but may occur in patients with CML receiving TKI therapy.

Background/Aim: We assessed the prognosis of patients with refractory or relapsed multiple myeloma (RRMM) by focusing on the change in absolute lymphocyte counts (ALCs) after lenalidomide and dexamethasone (Ld) initiation. Patients and Methods: In total, 72 patients with RRMM were treated with Ld. ALCs were evaluated before treatment and at 1, 2, and 3 months after Ld initiation. The median ALCs in the entire cohort before and at 1, 2, 3 months after Ld initiation were 1,131, 1,059, 1,222, and 1,162/μl, respectively. Results: ALCs before Ld initiation did not affect time to next treatment (TNT) or overall survival (OS). However, the patients with ALCs equal to or greater than the median at 3 months showed relatively better TNT than those with lower lymphocyte counts, with a significant difference. OS was also significantly longer in patients with higher ALCs. Conclusion: Immunomodulation by lenalidomide may improve prognosis in patients with RRMM.

Background Validation and standardization of methodologies for microbial community measurements by high-throughput sequencing are needed to support human microbiome research and its industrialization. This study set out to establish standards-based solutions to improve the accuracy and reproducibility of metagenomics-based microbiome profiling of human fecal samples. Results In the first phase, we performed a head-to-head comparison of a wide range of protocols for DNA extraction and sequencing library construction using defined mock communities, to identify performant protocols and pinpoint sources of inaccuracy in quantification. In the second phase, we validated performant protocols with respect to their variability of measurement results within a single laboratory (that is, intermediate precision) as well as interlaboratory transferability and reproducibility through an industry-based collaborative study. We further ascertained the performance of our recommended protocols in the context of a community-wide interlaboratory study (that is, the MOSAIC Standards Challenge). Finally, we defined performance metrics to provide best practice guidance for improving measurement consistency across methods and laboratories. Conclusions The validated protocols and methodological guidance for DNA extraction and library construction provided in this study expand current best practices for metagenomic analyses of human fecal microbiota. Uptake of our protocols and guidelines will improve the accuracy and comparability of metagenomics-based studies of the human microbiome, thereby facilitating development and commercialization of human microbiome-based products.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS-directed therapy or standard therapy alone. CNS-directed therapy was associated with a significantly better 2-year CNS-free survival (100% vs. 63%

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

We report the complete genome sequence of Flavonifractor plautii JCM 32125T (=VPI 0310T). The genome consists of a single circular chromosome of 3,985,392 bp (G+C content, 60.9%) and was predicted to contain 3 complete sets of rRNA genes, 63 tRNA genes, and 3,764 protein-coding sequences.

We report a complete genome sequence of Collinsella aerofaciens JCM 10188T (=VPI 1003T). The genome consists of a circular chromosome (2,428,218 bp with 60.6% G+C content) and two extrachromosomal elements. The genome was predicted to contain 5 sets of rRNA genes, 58 tRNA genes, and 2,079 protein-encoding sequences.

We announce the complete genome sequence of Megamonas funiformis JCM 14723T (YIT 11815T). The genome consists of a circular chromosome (2,522,577 bp, 31.5% G+C content) and a plasmid of 46,189 bp (29.4% G+C content). The genome was predicted to contain 6 rRNA operons, 53 tRNA genes, and 2,440 protein-coding sequences.

We report a complete genome sequence of Blautia producta JCM 1471T. The genome consists of a single circular chromosome of 6,197,116 bp with a G+C content of 45.7%. The genome was annotated as containing 5 complete sets of rRNA genes, 70 tRNA genes, and 5,516 protein-coding sequences.

Nodal marginal zone lymphoma (NMZL) is a form of nodal B-cell lymphoma exhibiting proliferation of abnormal lymphocytes at the circumference of the mantle zone in the lymph nodes. Although the outcome of patients with this disease is often favorable, we recently encountered a patient with a CD5-positive NMZL who was resistant to chemotherapy. A 67-year-old woman complaining of systemic lymph node swelling was referred to our hospital. After biopsy of the neck lymph node, she was diagnosed with CD5-positive NMZL. Disease progression was revealed after 16 months, and she was initially treated with chemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP). However, this therapy was ineffective. Subsequent therapy with rituximab and bendamustine also failed to induce remission. A rebiopsy revealed that the NMZL had transformed into a diffuse large B-cell lymphoma. This patient died after 2 years from the initial diagnosis due to lymphoma progression. Cases of CD5-positive NMZL are rare; thus, it is difficult to study the clinical implications of CD5 expression in this disease. Here we describe the current understanding of CD5 expression in NMZL.

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

Although it is well known that platelet depletion is one of the major adverse events related to tyrosine kinase inhibitor (TKI) therapy, the effect of TKIs on thrombopoietin (TPO), a stimulating factor for thrombopoiesis, has not been examined to date. In this study, we investigated the effect of TKIs on the levels of plasma TPO concentration in patients with well-controlled chronic myeloid leukemia receiving imatinib or dasatinib and those in treatment-free remission (TFR). Blood samples for blood cell counts and plasma TPO levels were obtained from 23 dasatinib-treated patients before and 1 h after intake, 11 patients treated with imatinib before and 2 h after intake, and nine TFR patients. Levels of plasma TPO were determined by using enzyme-linked immunosorbent assays. Levels of TPO were significantly inversely correlated with platelet counts in the entire cohort (r = − 0.568, p

We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy.

We report the case of a 53-year-old male with a history of acute myelogenous leukemia, who suffered the rupturing of a right-sided pulmonary artery pseudoaneurysm combined with pneumonia. He underwent a right-sided lower lobectomy. The resected lung tissue demonstrated a mycotic pseudoaneurysm of a pulmonary artery branch together with a filamentous fungal infection. Pseudoaneurysms are caused by the breaching of all layers of a blood vessel wall. The extravasated blood is trapped by the surrounding extravascular tissue or clots. Cladosporium was detected during a polymerase chain reaction-based analysis followed by DNA sequencing of formalin-fixed paraffin-embedded lung tissue samples. Although previous cases of pulmonary artery pseudoaneurysms caused by fungal infections, e.g., Candida or Aspergillus sp., have been reported, to the best of our knowledge this is the first case to involve cladosporiosis.

In the present study, the effect of immunophenotyping on the prognoses of patients with multiple myeloma (MM) treated with bortezomib plus dexamethasone was investigated. The study involved 46 patients with MM, and analyzed the prognostic significance of the expression of cluster of differentiation (CD)45, CD56 and mature plasma cell (MPC)-1, and other factors including the International Staging System (ISS) stage, age, gender, the immunoglobulin subtype and the treatment line number prior to bortezomib treatment. Although CD56 and MPC-1 expression did not appear to affect the time to next treatment (TNT) or overall survival rate (OS), the univariate analysis determined that CD45 positivity was an adverse prognostic factor for TNT and OS, and that being male was significantly associated with inferior TNT and OS. Multivariate analyses determined that CD45 expression was prognostically significant for TNT and OS. In conclusion, CD45 positivity is an adverse prognostic factor in MM patients treated with bortezomib. The data from the present study demonstrate the clinical importance of classifying MM cells immunophenotypically to determine the prognoses of patients.

The use of bortezomib in the clinic has significantly improved outcomes for patients with multiple myeloma (MM), even those harboring high-risk cytogenetic abnormalities or those classified in the high-risk category according to the International Staging System (ISS). In this study, we analyzed the association between immunophenotyping on myeloma cells and the clinical outcomes of patients who received bortezomib-based regimens as first-line therapy. Immunophenotypic analysis before bortezomib therapy was performed by flow cytometry, and whether the immunophenotyping results influenced the clinical outcomes of the patients was investigated. Seventy-four newly diagnosed patients with MM were included in this study. We found that the expression of MPC-1 significantly predicted the time to next therapy (TNT), with a longer TNT in the MPC-1 positive group (p = 0.005), whereas it did not affect overall survival (OS; p = 0.773). In addition, we found that CD45-positivity was associated with shorter TNT (p = 0.0432). Following ISS assessment at treatment initiation, patients who were classified as stage I showed a slightly longer OS compared to those at stage II or III; however, these results were not significant (p = 0.0987). Furthermore, multivariate analysis revealed the prognostic significance of MPC-1 expression, as MPC-1-negativity was associated with a worse TNT. The combination of MPC-1 and CD45 status more sensibly predicted the TNT for bortezomib therapy. Our results demonstrate the clinical importance of immunophenotyping on myeloma cells to determine patient prognoses in this era of novel therapeutic agents.

Background/aim Autologous hematopoietic stem cell transplantation (ASCT) after high-dose chemotherapy is used to treat relapsed malignant lymphomas. Radiation therapy (RT) is applied after ASCT. We compared the incidence of myelosuppression after RT with and without autologous peripheral blood stem cell transplantation (auto-PBSCT). Patients and methods We retrospectively analyzed 20 patients with malignant lymphomas who received RT, six of whom underwent auto-PBSCT. Univariate analysis using Pearson's Chi-squared test and multivariate analysis using the Cox proportional hazards regression model were performed to determine correlations between the development of grade two or more leukopenia and clinical factors. Results Among patients with auto-PBSCT, grade two or more leukopenia occurred in five. The incidence of grade two or more leukopenia was significantly higher in patients with auto-PBSCT than in those without (p=0.014). Conclusion Hematopoietic functions after auto-PBSCT may be more vulnerable to RT than normal hematopoietic functions.

Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL.

Co-expression of MYC and BCL2 proteins in diffuse large B-cell lymphoma (DLBCL), or 'double-expressor lymphoma' (DEL), results in poor patient prognosis, but the significance of DEL when aggressive treatments are applied remains uncertain. We performed a retrospective analysis of 40 patients with de novo DLBCL, who were categorized as being at high/high-intermediate risk according to the age-adjusted International Prognostic Index. Patients underwent an R-Double-CHOP regimen, a dose-intensified immunochemotherapy with or without consolidative high-dose chemotherapy followed by autologous stem cell transplantation. According to immunohistochemical analysis, 10 (25%) patients were categorized as having DEL, showing positivity for MYC (≥40%) and BCL2 (≥50%). The 3 year progression-free survival and overall survival of the DEL group were significantly worse compared with those of the non-DEL group (30% vs. 63%, p = 0.019 and 40% vs. 82%, p = 0.006, respectively). These results suggest that advanced DEL may need discrete treatment strategies.

The clinical significance of concurrent expression of MYC and BCL2 protein, known as "double-expressor lymphoma" (DEL), among patients with relapsed or refractory aggressive B-cell lymphomas, remains unclear. A retrospective analysis was performed of 38 patients treated with a salvage treatment consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone followed by consolidative high-dose chemotherapies. A total of 17 cases (45%) were categorized as DEL using immunohistochemical assay with a cut-off value of positivity of 40% for MYC and 50% for BCL2, respectively. DEL was associated with a lower overall response rate (35% vs 71%, p = 0.0481), worse 2-year progression-free survival (9% vs 67%, p = 0.001) and overall survival (35% vs 71%, p = 0.037). This analysis suggests that DEL is common among patients with relapsed/refractory aggressive B-cell lymphomas and that such patients require novel treatment strategies.

A central venous catheter (CVC) is a catheter placed into a large vein, and is used for chemotherapy administration. However, there is little confirmatory data on which antiseptic—such as chlorhexidine or povidone-iodine (PI) —is more protective against CVC-related infectious complications in patients receiving intensive chemotherapy. We aimed to compare the effectiveness of 1% chlorhexidine gluconate in 70% alcohol (CH) vs. PI for skin disinfection before CVC insertion in patients receiving intensive chemotherapy. Methods We used either CH or 10% PI as skin antiseptics before CVC insertion, and assessed which agent was more protective against CVC-related infection. The participants were 112 patients with haematologic malignancies who underwent chemotherapy; a total of 292 CVCs were inserted over this period. Blood cultures were obtained when febrile neutropenia occurred. The CVC was removed and the catheter-tip qualitatively cultured when catheter-related infection was suspected. The cumulative incidence of febrile neutropenia, microbial growth from blood or catheter-tip culture, and catheter-related blood stream infection (CRBSI) was evaluated retrospectively. A univariate Cox proportional hazards model showed that CH significantly alleviated infectious complications. Notably, no case of CRBSI occurred in the CH group. Multivariate analysis, adjusted for prolonged neutropenia (>15 days) and older age (>52 years), also showed significant reduction in the cumulative incidence of microbial growth from catheter-tips in the CH group (hazard ratio = 0.146, 95% confidence interval: 0.023–0.502, p = 0.0008). Disinfection using CH, compared with PI, can potentially decrease catheter-related infection without causing adverse skin reactions in patients with haematologic malignancies.

We have developed and characterized a bacterial consortium that reductively dechlorinates trichloroethene to ethene. Quantitative PCR analysis for the 16S rRNA and reductive dehalogenase genes showed that the consortium is highly enriched with Dehalococcoides spp. that have two vinyl chloride reductive dehalogenase genes, bvcA and vcrA, and a trichloroethene reductive dehalogenase gene, tceA. The metagenome analysis of the consortium by the next generation sequencer SOLiD 3 Plus suggests that a Dehalococcoides sp. that is highly homologous to D. mccartyi 195 and equipped with vcrA and tceA exists in the consortium. We isolated this Dehalococcoides sp. and designated it as D. mccartyi UCH-ATV1. As the growth of D. mccartyi UCH-ATV1 is too slow under isolated conditions, we constructed a consortium by mixing D. mccartyi UCH-ATV1 with several other bacteria and performed metagenomic sequencing using the single molecule DNA sequencer PacBio RS II. We successfully determined the complete genome sequence of D. mccartyi UCH-ATV1. The strain is equipped with vcrA and tceA, but lacks bvcA. Comparison with tag sequences of SOLiD 3 Plus from the original consortium shows a few differences between the sequences. This suggests that a genome rearrangement of Dehalococcoides sp. occurred during culture.

The introduction of tyrosine kinase inhibitors has dramatically improved outcomes for many patients with chronic myeloid leukemia (CML), but some cases are resistant to this treatment. To compare the prognostic performance of Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scores, patient outcomes and treatment responses were investigated following the European LeukemiaNet (ELN) 2013 recommendations. Seventy-three patients with newly diagnosed chronic-phase CML (CML-CP) treated with any tyrosine kinase inhibitor as initial therapy were analyzed. All scoring systems significantly predicted treatment response at 3 and 6 months; however, only the EUTOS score significantly predicted treatment response at 12 months, following the ELN 2013 recommendations. The 5-year event-free survival rates were 93 and 35 % in the low- and high-risk groups according to the EUTOS score (P

We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1-159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0-82.1) and 57.0% (95% CI, 39.5-71.2), respectively. Chronic renal impairment, therapy-related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed.

Here, we report the draft genome sequence of Thermogemmatispora onikobensis NBRC 111776 T , an aerial mycelium- and spore-forming thermophilic bacterium belonging to the class Ktedonobacteria . The genome contains five biosynthetic gene clusters coding for secondary metabolites, such as terpene, thiopeptide, lantipeptide, nonribosomal peptide, and lassopeptide, suggesting the potential to produce secondary metabolites.

Background : In myeloproliferative neoplasms, especially essential thrombocythemia (ET), platelet (Plt) counts and von Willebrand factor (vWF):Ristocetin cofactor (RCo) levels have been reported to be inversely correlated. However, there have been no reports of the comparison of high vs. low values of JAK2 allele burden and necessary of Plt counts reduction to achieve vWF:RCo levels ≥50%, which is required for major surgery. We investigated the correlation between vWF level and Plt counts for JAK2V617F mutation positive (JAK2V617F+) polycythemia vera (PV) and ET (allele burdens ≥50% and Method: We recruited patients with PV and ET who were diagnosed per the 2008 World Health Organization criteria at 3 hospitals since 2011 to 2018. All patients were analyzed at Juntendo University for JAK2 (V617F, exson12), CALR, and MPL mutations. We collected data of JAK2V617F+ or CALR+ patients. Triple-negative mutations of ET were excluded in this study because it is difficult to differentiate between ET and secondary thrombocytosis. We analyzed the correlation between Plt counts and vWF:RCo levels for three mutation groups mutations (JAK2V617F allele burden ≥50%, Results: We collected 146 PV and ET patients. Among 54 PV patients, 50 had JAK2V617F+, 3 had JAK2 exon 12, and 1 had a triple-negative mutation(s) in PV patients. Among 92 ET patients, 53 had JAK2V617F+, 35 had CALR+ (22 del52, 12 ins5 and 1 del34), and 4 had MPL mutations in ET patients. vWF:RCo levels were weakly inversely correlated with Plt counts in patients with JAK2V617F+ PV and ET from whom blood samples were obtained for the first time after enrolling in this study (Ps=-0.531 and Ps=-0.439, respectively). In contrast, vWF:RCo levels and Plt counts in patients with CALR+ ET showed a strong inverse correlation (Ps=-0.762). Interestingly, 3/50 PV and 4/53 ET patients with JAK2V617F mutations showed vWF:RCo levels >150% (normal vWF:RCo levels range: 50-150%). Furthermore, 3/50 PV and 1/53 ET patients with Plt counts 150% or During the entire observation period, 8/50 and 7/53 patients with JAK2V617F+ PV and ET, respectively, and 1/35 patients with CALR+ ET had vWF:RCo levels >150%. One case of JAK2V617F+ ET (allele burden When Plt counts were controlled to 30%. However, 13/86 patients did not achieve 50%, which is the standard for safely performing the major surgical procedures prescribed in most guidelines. In patients whose Plt counts controlled to Conclusion: For patients with CALR+ ET, we propose that vWF:RCo levels can be predicted based on Plt counts; however, it is difficult to predict vWF:RCo levels by Plt counts in JAK2V617F+ PV and ET patients because the inverse correlation between vWF:RCo levels and Plt counts was weak. Overactivation of vWF:RCo levels was often observed in JAK2+ PV and ET. Moreover, in 1 case, the patient exhibited only age as the risk factor for the complication of thrombosis. Because of these findings, overactivation of vWF:RCo levels may be one of the reasons for thrombotic events in JAK2V617F+ PV and ET. In addition, it was also found that cases of JAK2V617F+ allele burden ≥50% in PV and ET should be careful for hemorrhage in major surgery, even if Plt counts were controlled Disclosures No relevant conflicts of interest to declare.

The taxonomic properties of strain DC2a-G7T, a Gram-negative, ovoid to rod-shaped, gellan gum-lysing bacterium, were examined. The 16S rRNA gene sequence similarity showed that DC2a-G7T is a member of the phylum Verrucomicrobia and the closest type strain of a species with a validly published name is Verrucomicrobium spinosum DSM 4136T, with a sequence similarity of 91.2 %. In addition to this similarity value lower than 95 %, the absence of prostheca, the orangey-red colony colour and the compositions of the major menaquinones and polar lipids also supported the differentiation of this bacterium from the genus Verrucomicrobium . Here, we propose the name Roseimicrobium gellanilyticum gen. nov., sp. nov. for the isolate. The type strain of Roseimicrobium gellanilyticum is DC2a-G7T ( = NBRC 108606T = DSM 25532T).

A thermotolerant ammonia-oxidizing bacterium strain JPCCT2 was isolated from activated sludge in a thermal power station. Cells of JPCCT2 are short non-motile rods or ellipsoidal. Molecular phylogenetic analysis of 16S rRNA gene sequences demonstrated that JPCCT2 belongs to the genus Nitrosomonas with the highest similarity to Nitrosomonas nitrosa Nm90 (100%), Nitrosomonas sp. Nm148 (99.7%), and Nitrosomonas communis Nm2 (97.7%). However, G+C content of JPCCT2 DNA was 49.1 mol% and clearly different from N. nitrosa Nm90, 47.9%. JPCCT2 was capable of growing at temperatures up to 48 °C, while N. nitrosa Nm90 and N. communis Nm2 could not grow at 42°C. Moreover, JPCCT2 grew similarly at concentrations of carbonate 0 and 5 gL(-1). This is the first report that Nitrosomonas bacterium is capable of growing at temperatures higher than 37°C.

Background: Elderly acute myeloid leukemia (AML) patients and patients with higher-risk myelodysplastic syndromes (MDS) have a much poorer prognosis than younger patients despite intensive chemotherapy. Methods: Ten patients with higher-risk MDS and 12 patients with AML over 65 years of age were enrolled into this study and received oral induction therapy with cytarabine ocfosfate and etoposide. Results: The therapy response rates were 60% in the MDS group and 41.7% in the AML group. The difference in overall survival among MDS and AML patients was not statistically significant. The difference in the median survival times of the responsive and nonresponsive groups, which included MDS and AML patients, was statistically significant (790 and 174 days, respectively). Conclusions: Based on a comparison of the data of this therapy in elderly higher-risk MDS patients versus elderly AML patients, we conclude that this therapy is well tolerated and can be cost-effective and useful for higher-risk MDS in elderly patients.

In this study, the impact of plasma cell maturity on the prognoses of multiple myeloma (MM) patients in the era of novel agents was investigated. Myeloma cell maturity was classified via immunophenotyping: myeloma cells showing mature plasma cell 1 (MPC-1)-positive and CD49e-positive cells were considered mature type; MPC-1-positive and CD49e-negative cells were considered intermediate type; and MPC-1-negative cells were considered immature type. This study included 87 newly diagnosed MM patients who were initially treated with bortezomib and/or chemotherapy. Myeloma cell maturity was a critical factor affecting overall survival (OS) in the cohort, with median OS not reached in mature-type, 50 months in intermediate-type, and 20 months in immature-type cells. Multivariate analysis showed that immature type and stage III according to the International Staging System were both independent prognostic factors affecting OS. The findings of this study demonstrate the clinical importance of myeloma cell classification according to immunophenotyping using MPC-1 and CD49e antibodies to determine patient prognosis in this era of novel therapeutic agents.

We performed a clinical trial to investigate the efficacy and safety of arbekacin (ABK), a unique aminoglycoside with activity against methicillin-resistant Staphylococcus aureus (MRSA), in patients with hematological malignancies complicated by high-risk infections. ABK was administered intravenously at a dose of approximately 5 mg/kg with various broad-spectrum β-lactams, followed by therapeutic drug monitoring (TDM). A total of 54 febrile or infectious episodes were registered, and TDM was performed in 44 (81%) cases. The absolute neutrophil count was below 500/μl in 49 (91%) cases, and cytotoxic chemotherapy was being administered in 47 (87%) cases. Before initiation of ABK, 52 (96%) patients had received fluoroquinolones (n = 37) and/or broad-spectrum β-lactams (n = 34). There were 10 cases of documented infections including one of MRSA pneumonia, and 44 cases of febrile neutropenia. The efficacy at the end of treatment was 80% for all patients, and efficacy was significantly higher in patients attaining maximum concentrations ≥ 16 µg/ml or receiving TDM-guided dose-adjustment of ABK (n = 19, 95 vs. 71%, P = 0.039). Renal toxicity was observed in six cases (11%) but was generally acceptable. This study demonstrated that TDM-guided ABK administration may be applicable under limited conditions for patients with hematological malignancies.

The published sequence of the 16S rRNA gene of Thiomonas cuprina strain Hö5 (=DSM 5495T) (GenBank accession no. U67162) was found to be erroneous. The 16S rRNA genes from the type strain held by the DSMZ since 1990 (DSM 5495T =NBRC 102145T) and strain Hö5 maintained frozen in the Universität Regensburg for 23 years (=NBRC 102094) were sequenced and found to be identical, but to show no significant similarity to the U67162 sequence. This also casts some doubt on the previously published 5S and 23S rRNA gene sequences (GenBank accession nos U67171 and X75567). The correct 16S rRNA gene sequence showed 99.8 % identity to those from Thiomonas delicata NBRC 14566T and ‘Thiomonas arsenivorans’ DSM 16361. The properties of these three species are re-evaluated, and emended descriptions are provided for the genus Thiomonas and the species Thiomonas cuprina.

The taxonomic positions of two bacterial strains, MBIC01146(T) and MBIC01099, isolated from marine environments of Japan and Palau, respectively, were determined by using a polyphasic approach. The bacteria were aerobic, motile, Gram-negative rods and formed star-shaped aggregations. The G+C content of the genomic DNA ranged from 58.5 to 58.7 mol%. The major respiratory quinone was ubiquinone-10 and the predominant cellular fatty acids were C(16 : 0), C(18 : 1)omega6c and C(18 : 1)omega7c. 16S rRNA gene sequence analyses based on both neighbour-joining and maximum-parsimony methods revealed that strains MBIC01146(T) and MBIC01099 were positioned within the cluster comprising Ruegeria atlantica and Silicibacter lacuscaerulensis within subgroup alpha-3 of the Proteobacteria. The phenotypic and chemotaxonomic characteristics of the novel strains were similar to those of Ruegeria atlantica; however, DNA-DNA hybridization tests showed that the isolates represented an independent species. The isolates could be differentiated from Ruegeria atlantica based on several characteristics. Therefore, strains MBIC01146(T) and MBIC01099 are considered to represent a novel species of the genus Ruegeria, for which the name Ruegeria mobilis sp. nov. is proposed. The type strain is MBIC01146(T) (=NBRC 101030(T)=CIP 109181(T)). An emended description of Ruegeria atlantica Uchino et al. 1999 is also given.

Sulfurospirillum strains UCH001 and UCH003 were isolated from anaerobic cis -1,2-dichloroethene-dechlorinating microbial consortia derived from groundwater in Japan. Here, we report the complete genome sequences of strains UCH001 and UCH003.

The transfer of Thiobacillus delicatus to the genus Thiomonas as a distinct species, Thiomonas delicata (type strain NBRC 14566T), is confirmed by its morphological and physiological properties, DNA–DNA hybridization and the grouping of its 16S rRNA gene sequence with those of other species of the genus. An emended formal description of Thiomonas delicata is given. The status of Thiomonas cuprina DSM 5495T as a member of the genus is reconsidered.

Even after the advent of rituximab, clinical outcomes of conventional immuno-chemotherapy for high-risk diffuse large B-cell lymphoma (DLBCL) remain unsatisfactory. We retrospectively evaluated the efficacy and safety of R-Double-CHOP (R-D-CHOP), consisting of rituximab (375 mg/m(2), day -2), cyclophosphamide (750 mg/m(2), day 1, 2), doxorubicin (50 mg/m(2), day 1, 2), vincristine [1.4 mg/m(2) (maximum 2.0 mg/body), day 1], and prednisolone (50 mg/m(2), day 1-5), followed by consolidation high-dose chemotherapy. This treatment was given to 51 de novo DLBCL patients with a median age of 54 (range 19-65), who were categorized as high/high-intermediate risk by the age-adjusted International Prognostic Index. Treatment was given every 3 weeks up to three courses. The overall response and the complete response rate for R-D-CHOP were 94 and 78 %, respectively. A total of 30 responders proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT), whereas 16 received high-dose methotrexate (HD-MTX) alternatively. The 3-year overall survival and the event-free survival for all patients were 78 and 61 %, respectively. Major adverse events included hematological toxicities, but there were no treatment-related deaths during the observation period. We conclude that the R-D-CHOP regimen followed by HDC/ASCT or HD-MTX is a promising treatment option for younger patients with highly advanced DLBCL.

Background Granulocyte colony-stimulating factor (G-CSF) promotes proliferation, survival, and differentiation of myeloid-linage leukemic cells, as well as normal hematopoietic cells. Terminal granulocytic differentiation can be induced in acute promyelocytic (APL) cell line HT93A by G-CSF and all-trans retinoic acid (ATRA). Because the detailed mechanism has never been shown, we investigated the signal transduction pathway in granulocytic differentiation by G-CSF, alone or in combination with ATRA. Methods HT93A cell viability and growth were investigated by trypan blue exclusion assay. Cell differentiation was assessed by CD11b and CD34 expressions. Intracellular protein expressions were also evaluated by flow cytometry after fixation and permeabilization. Results ATRA (100 nM) induced granulocytic differentiation (upregulation of CD11b and downregulation of CD34) and the effect was potentiated by addition of G-CSF, while G-CSF alone had no effect on HT93A cells. The addition of G-CSF to ATRA had little or no effect on NB4 and THP-1 cells in comparison to ATRA alone. G-CSF receptor expression was reduced by ATRA treatment in a time-dependent manner. After 5 days’ incubation with ATRA, the expression levels of signal transducer and activator of transcription (STAT) 3, and phosphorylated STAT3 and STAT5, were significantly reduced. STAT5 was strongly activated by G-CSF stimulation in ATRA-pretreated cells in comparison to untreated cells. In contrast, STAT3 showed no response to G-CSF. Janus kinase (JAK) inhibitor ruxolitinib (320 nM) had little or no effect on ATRA-induced differentiation, but eliminated the enhancing effect of G-CSF, as evidenced by the levels of CD11b and CD34 expression. These results suggest G-CSF activates STAT5 through the JAK pathway in combination with ATRA, resulting in myeloid differentiation in HT93A cells. Conclusions In conclusion, activation of the JAK-STAT pathway is likely essential for inducting differentiation in the APL cell line HT93A; thus, monitoring its expression and activation is important for predicting clinical efficacy and understanding the mechanisms of cytokine-dependent myelopoiesis, proliferation, and differentiation of acute myeloid leukemia.

A novel Gram-stain positive, non-motile, non-sporeforming coccus-shaped, obligately anaerobic bacterium was isolated from a fecal sample of an individual residing in a traditional Peruvian community. The organism was characterized using biochemical, chemotaxonomic and phylogenetic methods. Comparative 16S rRNA gene sequence analyses and phenotypic characteristics demonstrated that the organism was biochemically and phenotypically related, but distinct, from a group of organisms referred to as the Gram-stain positive anaerobic cocci (GPAC). The major cellular fatty acids of the novel isolate were determined to be C 16:0 (18.3%), C 18:1 ω 9c (39.8%), C 18:2 ω 6,9c /C 18:0 ANTE (13.2%). Fermentation end products from PYG are acetate and formate. Cell-wall peptidoglycan was found to be A4α (L-Lys-L-Ala-L-Glu) and the G + C content was determined to be 38.4 mol%. Based on the phenotypic, chemotaxonomic, and phylogenetic results, Ezakiella peruensis gen. nov., sp. nov., is now proposed. The type strain is M6.X2 T (DSM 27367 T = NBRC 109957 T = CCUG 64571 T ).

A thermotolerant ammonia-oxidizing bacterium strain JPCCT2 was isolated from activated sludge in a thermal power station. Cells of JPCCT2 are short non-motile rods or ellipsoidal. Molecular phylogenetic analysis of 16S rRNA gene sequences demonstrated that JPCCT2 belongs to the genus Nitrosomonas with the highest similarity to Nitrosomonas nitrosa Nm90 (100%), Nitrosomonas sp. Nm148 (99.7%), and Nitrosomonas communis Nm2 (97.7%). However, G+C content of JPCCT2 DNA was 49.1 mol% and clearly different from N. nitrosa Nm90, 47.9%. JPCCT2 was capable of growing at temperatures up to 48 °C, while N. nitrosa Nm90 and N. communis Nm2 could not grow at 42°C. Moreover, JPCCT2 grew similarly at concentrations of carbonate 0 and 5 gL(-1). This is the first report that Nitrosomonas bacterium is capable of growing at temperatures higher than 37°C.

The bootstrapped 16S rDNA sequence-based neighbor-joining phylogeny has suggested that the marine species of the genus Agrobacterium have no relation to the terrestrial Agrobacterium species. Agrobacterium atlanticum IAM 14463(T) (a superscript (T)=type strain), Agrobacterium ferrugineum IAM 12616(T), Agrobacterium gelatinovorum IAM 12617(T), Agrobacterium meteori IAM 14464(T), Agrobacterium stellulatum IAM 12621(T) and IAM 12614, and the invalidly published marine species "Agrobacterium kieliense" IAM 12618 occupy an independent position in the a-subclass of the Proteobacteria. Based on 16S rDNA sequencing and on chemotaxonomic, morphological, and physiological studies, we propose the transfer of A. atlanticum, A. gelatinovorum, and Roseobacter algicola to the genus Ruegeria gen. nov. as Ruegeria atlantica comb. nov., Ruegeria gelatinovora comb. nov., and Ruegeria algicola comb. nov., respectively; of strains of A. stellulatum to the genus Stappia gen. nov. as Stappia stellulata comb. nov. and Stappia aggregata sp. nov., nom. rev., respectively; and of "A. kieliense" to the genus Ahrensia gen. nov. as Ahrensia kieliense sp. nov., nom. rev. Agrobacterium meteori is assigned to be a synonym of A. atlanticum.