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There are several psychosocial and ethical issues surrounding the decision making of living kidney transplant donors. This study aimed to determine what health care professionals (HPs) consider in their clinical practice and their attitudes toward donors' decision-making processes.Face-to-face semistructured interviews were conducted with 15 HPs. A thematic analysis was performed to categorize the thematic elements of the transcripts. All procedures were approved by the relevant review board and conducted in accordance with the Declaration of Helsinki.Six main categories-maintaining family relationships, improving donor understanding, supporting voluntary decision making, setting the environment for the examination, having different attitudes toward the donor's intentions, and resisting confirmation of intent-were identified. The HPs provided diverse considerations to respect the donors' autonomy.In clinical practice, there is a lack of practical methods to confirm living donors' levels of understanding and spontaneity, suggesting that these methods need to be established. Factors related to family functioning may reflect the unique culture of Japan, and this may be indicative of the need to consider treatment based on cultural values.

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New-type sulfolane gel electrolytes exhibited high battery performance owing to chemical and physical control of Li2Sn dissolution and diffusion properties.

Objectives Currently, active euthanasia is legalized in only 7 countries worldwide. These countries have encountered problems in its implementation. The study aims to summarize the practical clinical problems in the literature on active euthanasia. Methods A systematic literature review was conducted using 140 works consisting of 130 articles from PubMed and EthxWeb and data from 10 euthanasia laws. Results After reviewing the specific problems reported to be associated with euthanasia in each country, 5 problems were extracted: many ambiguous conditions with room for interpretation, insufficient assurance of voluntariness, response to requests for euthanasia due to psychological distress, conscientious objection, and noncompliance by medical professionals. Significance of results Multiple ambiguous conditions that are open to interpretation can result in a “slippery slope phenomenon.” An insufficient guarantee of voluntariness violates the principle of respect for autonomy, which is the underlying justification for euthanasia. In cases of euthanasia due to mental anguish, a distinction between a desire for death caused by psychological pain alone prompted by mental illness and a desire for death caused by mental symptoms prompted by physical illness is essential. Conscientious objection should remain an option because of the heavy burden placed on doctors who perform euthanasia. Noncompliance by medical professionals due to ignorance and conflicts regarding euthanasia is contrary to procedural justice.

It has been reported that aqueous lithium ion batteries (ALIBs) can operate beyond the electrochemical window of water by using a superconcentrated electrolyte aqueous solution. The liquid structure, particularly the local structure of the Li+, which is rather different from conventional dilute solution, plays a crucial role in realizing the ALIB. To reveal the local structure around Li+, the superconcentrated LiTFSA (TFSA: bis(trifluoromethylsulfonil)amide) aqueous solutions were investigated by means of Raman spectroscopic experiments, high-energy X-ray total scattering measurements, and the neutron diffraction technique with different isotopic composition ratios of 6Li/7Li and H/D. The Li+ local structure changes with the increase of the LiTFSA concentration; the oligomer ([Lip(TFSA)q](p-q)+ (q > 2) forms at the molar fraction of LiTFSA (xLiTFSA) > 0.25. The average structure can be determined in which two water molecules and two oxygen atoms of TFSA anion(s) coordinate to the Li+ in the superconcentrated LiTFSA aqueous solution (LiTFSA)0.25(H2O)0.75. In addition, the intermolecular interaction between the neighboring water molecules was not found, and the hydrogen-bonded interaction in the solution should be significantly weak. According to the coordination number of the oxygen atom (TFSA or H2O), a variety of TFSA- and H2O coordination manners would exist in this solution; in particular, the oligomer is formed in which the monodentate TFSA cross-links Li+.

Neutron diffraction measurements on 6Li/7Li isotopically substituted 10 and 33 mol % *LiTFSA (lithium bis(trifluoromethylsulfonyl)amide)-AN-d3 (acetonitrile-d3) and 10 and 33 mol % *LiTFSA-DMF-d7(N,N-dimethylformamide-d7) solutions have been carried out in order to obtain structural insights on the first solvation shell of Li+ in highly concentrated organic solutions. Structural parameters concerning the local structure around Li+ have been determined from the least squares fitting analysis of the first-order difference function derived from the difference between carefully normalized scattering cross sections observed for 6Li-enriched and natural abundance solutions. In 10 mol % LiTFSA-AN-d3 solution, 3.25 ± 0.04 AN molecules are coordinated to Li+ with a intermolecular Li+···N(AN) distance of 2.051 ± 0.007 A. It has been revealed that 1.67 ± 0.07 AN molecules and 2.00 ± 0.01 TFSA- are involved in the first solvation shell of Li+ in the 33 mol % LiTFSA-AN solution. The nearest neighbor Li+···NAN and Li+···OTFSA- distances are obtained to be r(Li+···N) = 2.09 ± 0.01 A and r(Li+···O) = 1.88 ± 0.01 A, respectively. The first solvation shell of Li+ in the 10 mol % LiTFSA-DMF-d7 solutions contains 3.4 ± 0.1 DMF molecules with an intermolecular Li+···ODMF distance of 1.95 ± 0.02 A. In highly concentrated 33 mol % LiTFSA-DMF-d7 solutions, there are 1.3 ± 0.2 DMF molecules and 3.2 ± 0.2 TFSA- in the first solvation shell of Li+ with intermolecular distances of r(Li+···ODMF) = 1.90 ± 0.02 A and r(Li+···OTFSA-) = 2.01 ± 0.01 A, respectively. The Li+···TFSA- contact ion pair stably exists in highly concentrated 33 mol % LiTFSA-AN and -DMF solutions.

Methotrexate (MTX) in combination with a calcineurin inhibitor has been commonly used for prophylaxis of graft-versus-host disease (GVHD) following umbilical cord blood transplantation (UCBT) in Japan. However, the appropriate prophylactic MTX dosage in UCBT has not been established to date. To determine the preferential GVHD prophylaxis in UCBT, this study retrospectively investigated the administration of short-term MTX for 2 days versus 3 days. Of 103 adult patients submitted to UCBT enrolled in the study, 73 received tacrolimus (TAC) with 2 days of MTX given at 10 mg/m2 on day 1 and 7 mg/m2 on day 3 (very short-term [vs] MTX), whereas 30 patients received TAC with 3 days of MTX given at 10 mg/m2 on day 1, 7 mg/m2 on day 3, and 7 mg/m2 on day 6 (short-term [s] MTX). In univariate analysis, neutrophil engraftment was shown to be significantly better (P = .039) in the vsMTX/TAC group. Among high-risk patients, the vsMTX/TAC group also exhibited earlier neutrophil engraftment (P = .042); however, the incidence of acute GVHD was higher in the vsMTX/TAC group (P = .035) on univariate analysis. In multivariate analysis, compared with sMTX/TAC, vsMTX/TAC was associated with lower risk of relapse (hazard ratio, .27; 95% confidence interval, .11 to .64; P = .003) . These results suggest that vsMTX/TAC can be appropriate GVHD prophylaxis after UCBT, especially in higher-risk patients.

Hemotropic mycoplasmas are common pathogens in animals, but it remains unclear what role these pathogens play in human infections. We report clinical and biologic characterization of Candidatus Mycoplasma haemohominis infection in a 42-year-old man in Japan. The patient had severe hemophagocytic syndrome 1 month after an accidental needlestick injury. Metagenomic deep sequencing identified Candidatus M. haemohominis and determined its draft genome for an isolate from serum of the patient. A high copy number of the Candidatus M. haemohominis genome was detected in serum and bone marrow samples. Electron microscopy examination showed morphologic characteristics of Candidatus M. haemohominis. Levofloxacin monotherapy induced resistance caused by a gyrase A gene mutation in the quinolone resistance–determining region, but a combination treatment with moxifloxacin and minocycline was effective. We identified Candidatus M. haemohominis in a patient who had life-threatening symptoms related to multiple organ infection. Human infection with this mycoplasma might occur more frequently than has been generally recognized.

Lithium–glyme solvate ionic liquids (Li–G SILs), which typically consist of a lithium-ion (Li+) solvated by glymes of oligoethers and its counter anion, are expected as promising electrolytes for l...

The refined disease risk index (R-DRI) is a well-designed prognostic parameter that is based on only the disease type and status and is used for stratifying patients undergoing allogeneic hematopoietic stem cell transplantation (allo HSCT) into 4 risk groups. However, the application of the R-DRI for rare diseases has remained unclear.We evaluated 135 patients who underwent allo HSCT for hematological malignancies including rare diseases, such as acute leukemia of ambiguous lineage, acute T-cell leukemia/lymphoma, extranodal natural killer T-cell lymphoma, and lymphoblastic lymphoma, at our institute.According to the R-DRI, overall survival (OS) and progression-free survival at 2 years for patients with the low, intermediate, high, and very high groups were 66.7% and 66.7%, 60.8% and 56.0%, 27.1% and 23.7%, and 5.9% and 5.1%, respectively (P .0001 and P .0001, respectively). OS showed no significant difference between B-cell non-Hodgkin lymphoma (B-NHL) and T-cell non-Hodgkin lymphoma (T-NHL) (P = .71). Moreover, OS at 1 year was 80%, 14.3%, 60%, and 0% for the intermediate risk group, the very high-risk group of B-NHL, the intermediate risk group, and the high-risk group of T-NHL, respectively (P = .035).We showed the applicability of the R-DRI for hematological malignancies, including rare disorders. However, we suggest that T-NHL patients may be better to be assigned between the nodal group and the extranodal group in the R-DRI.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

It has been reported that aqueous lithium ion batteries (ALIBs) can operate beyond the electrochemical window of water by using a superconcentrated electrolyte aqueous solution. The liquid structure, particularly the local structure of the Li

In a previous work, we have found that the pseudo-protic ionic liquid N-methylimidazolium acetate, [C(1)HIm] [OAc] or [Hmim] [OAc], mainly consists of the electrically neutral molecular species N-methylimidazole, C(1)Im, and acetic acid, AcOH, even though the mixture has significant ionic conductivity. This system was revisited by employing isotopic substitution Raman spectroscopy (ISRS) and pulsed field gradient (PFG) NMR self-diffusion measurements. The ISRS and PFG-NMR results obtained fully confirm our earlier findings. In particular, the self-diffusion coefficient of the hydroxyl hydrogen atom in AcOH is identical to that of the methyl hydrogen atoms within the experimental uncertainty, consistent with very little ionization. Therefore, a proton conduction mechanism similar to the Grotthuss mechanism for aqueous acid solutions is postulated to be responsible for the observed electrical conductivity. Laity resistance coefficients (r(ij)) are calculated from the transport properties, and the negative values obtained for the like-ion interactions are consistent with the pseudo-ionic liquid description, that is, the mixture is indeed a very weak electrolyte. The structure and rotational dynamics of the mixture were also investigated using high-energy X-ray total scattering experiments, molecular dynamics simulations, and dielectric relaxation spectroscopy. Based on a comparison of activation energies and the well-known linear free energy relationship between the kinetics and thermodynamics of autoprotolysis, we propose for [C(1)HIm] [OAc] a Grotthus-type proton conduction mechanism involving fast AcOH/AcO- rotation as a decisive step.

Inflammatory cytokines play a role in hematopoiesis and development of myelodysplastic syndromes (MDS). Although increased serum levels of inflammatory cytokines are associated with poor survival in MDS patients, clinical management does not include assessment of inflammation. We investigated the significance of inflammation in MDS using serum C-reactive protein (CRP) levels, an indicator of the degree of systemic inflammation that can be used in routine practice. We hypothesized that serum CRP levels can be used to further classify low-risk MDS. We conducted a retrospective analysis of 90 patients with low-risk MDS, defined by the international prognostic scoring system (IPSS). We examined the prognostic relevance of CRP and known prognostic factors at diagnosis. Increased serum CRP (≥ 0.58 mg/dL) was associated with poor survival (hazard ratio [HR]: 17.63, 95% confidence interval [CI] 5.83–53.28, P

Development of the electrolyte solution plays a key role in realization for lithium-sulfur (Li–S) battery. The lithium ion local structure and the liquid structures of an electrolyte solution have direct influence on the battery performance because of the electromotive force, the charging/discharging speed and the life time. The activity for the free solvent directly contributes to the electrode potential in the concentrated electrolyte such as the solvate ionic liquid. Lithium-glyme solvate ionic liquid consists of only the glyme-solvated lithium ion and its counter ion; similarly a super-concentrated electrolyte solution contains no full solvated Li+ ion. However, it is unclear whether both electrolyte solutions should be regarded the same. From a thermodynamic point of view, the activity and/or the activity coefficient for the solvent is useful for the distinction among them. In this chapter, the liquid structures and the thermodynamic parameters like an activity coefficient are described for solvate ionic liquid.

To clarify proton conduction mechanism in protic ionic liquids (PILs) and

Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (P = .001), a higher risk of engraftment failure (P = .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (P = .0009 and P = .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (P = .0017 and P = .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.

Lithium-glyme solvated ionic liquids (Li-G SILs) and superconcentrated electrolyte solutions (SCESs) are expected to be promising electrolytes for next-generation lithium secondary batteries. The former consists of only the oligoether glyme solvated lithium ion and its counteranion, and the latter contains no full solvated Li

Rapid immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for clinical outcome prediction. In most studies, immune recovery after allo-HSCT is monitored via peripheral blood. However, few reports regarding the status of absolute lymphocyte subsets in the bone marrow (BM) microenvironment have been undertaken. Therefore, we evaluated the clinical impact of immune recovery in the early period following allo-HSCT using BM samples. We showed that delayed natural killer cell recovery was independently associated with a poor prognosis for overall survival (hazard ratio [HR], 3.07; 95% confidence interval [CI], 1.37- 6.89; P = .007), progression-free survival (HR, 3.42; 95% CI, 1.47-7.94; P = .004), and nonrelapse mortality (HR, 6.68; 95% CI, 1.82-25.0; P = .004) by multivariate analysis. In addition, low NK cell counts were associated with the presence of 1 or more bacterial, viral, or fungal infections. Our results indicate that investigating absolute lymphocyte subsets in BM in the early phase following allo-HSCT can be useful for predicting and improving survival outcomes.

Bendamustine has demonstrated favourable efficacy in relapsed or refractory indolent lymphoma and mantle cell lymphoma. We retrospectively evaluated the pre-treatment clinical and laboratory factors and their correlation with the clinical outcome of these lymphomas. We analysed 53 patients who had been treated with bendamustine alone (n = 6) or rituximab plus bendamustine (n = 47). The overall response rate was 81.1%, with a complete response (CR) rate of 39.6%. The CR rate was significantly low in patients who had elevated levels of soluble interleukin-2 receptor (p = 0.024) and C-reactive protein (CRP; p = 0.004). The 1-year overall survival (OS) rate was 79.3%. An elevated CRP was associated with a short OS (p = 0.056). The present findings suggest that the lymphoma microenvironment and immune response were involved in the effects of bendamustine. These findings are also important in order to understand the pathophysiology of refractory lymphoma and to find effective strategies using bendamustine.

Isotropic Raman scattering and time-of-flight neutron diffraction measurements were carried out for concentrated LiTFSA-EC solutions to obtain structural insight on solvated Li+ as well as the structure of contact ion pair, Li+···TFSA–, formed in highly concentrated EC solutions. Symmetrical stretching vibrational mode of solvated Li+ and solvated Li+···TFSA– ion pair were observed at ν = 168–177 and 202–224 cm–1, respectively. Detailed structural properties of solvated Li+ and Li+···TFSA– contact ion pair were derived from the least-squares fitting analysis of first-order difference function, ΔLi(Q), between neutron scattering cross sections observed for 6Li/7Li isotopically substituted 10 and 25 mol % *LiTFSA-ECd4 solutions. It has been revealed that Li+ in the 10 mol % LiTFSA solution is fully solvated by ca. 4 EC molecules. The nearest neighbor Li+···O(EC) distance and Li+···O(EC)═C(EC) bond angle are determined to be 1.90 ± 0.01 A and 141 ± 1°, respectively. In highly concentrated 25 mol % LiTFSA-EC ...

Although follicular lymphoma (FL) is a pathological entity characterized by relatively uniform histological and molecular findings, its clinical course is highly variable. Establishment of therapeutic strategies based on a simple and practical prognostic model is important. C-reactive protein (CRP) is an adverse prognostic marker for various tumors and aggressive lymphomas. However, the significance of serum CRP levels as a prognostic index in low-grade lymphomas, such as FL, has not been thoroughly investigated. We retrospectively analyzed the relationship between serum CRP levels at diagnosis and the prognosis in patients with FL (n = 61) undergoing rituximab-containing chemotherapy. Elevated CRP levels showed a significant association with elevated fibrinogen (P = 0.002) in univariate analysis. Patients with higher CRP levels (> 5 mg/L) had a significantly shorter progression-free survival in multivariate analysis (P = 0.044). We concluded that serum CRP levels are important in prognostic stratification of patients with FL.

Cardiac involvement during lymphoma often causes complications, including arrhythmia. A 68-year-old male with cardiac tamponade was diagnosed with diffuse large B-cell lymphoma with cardiac involvement based on the presence of the tumor mass in the myocardium and lymphoma cells in the pericardial effusion. He developed atrial fibrillation, ventricular tachycardia, and atrial flutter after initiating chemotherapy. Following chemotherapy, sinus rhythm was restored without invasive treatment for arrhythmia, while the cardiac mass disappeared. No recurrent arrhythmias were observed. In lymphoma with cardiac involvement, unexpected arrhythmias can emerge after initiation of chemotherapy, which could potentially be related to accelerated cardiac remodeling owing to the rapid relief of cardiac damage. Follow-up using electrocardiogram is thus necessary during chemotherapy for cardiac lymphoma, despite the absence of arrhythmia at the time of diagnosis.

Hyponatremia occurs while receiving bortezomib-containing combination therapy in multiple myeloma (MM) ; however, the mechanism of hyponatremia remains unclear. A 65-year-old female with MM was treated with bortezomib, lenalidomide, and dexamethasone. Fourteen days after chemotherapy initiation, she developed hyponatremia (serum sodium, 127 mEq/l, compared with 136 mEq/l before chemotherapy) with plasma hypo-osmolality and urine hyper-osmolality. She exhibited neither dehydration nor adrenal insufficiency. Her serum arginine vasopressin peptide (AVP) level was 1.5 pg/ml. She was diagnosed with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), wherein causative roles of inflammatory cytokines were strongly suggested in the development because (1) SIADH was triggered by the cessation of the dexamethasone treatment and (2) hyponatremia was successfully treated with prednisolone, which was administered for the complication of drug eruption. Perhaps, bortezomib-induced immune reactions could be involved in a subset of hyponatremia during bortezomib-containing antimyeloma chemotherapy.

After allogeneic stem cell transplantation (alloSCT), several immune checkpoints play an important role in the antileukemic immune response in the bone marrow (BM) microenvironment. However, immune checkpoint expression levels in the BM have not been reported after alloSCT in patients with acute myeloid leukemia (AML). We investigated the clinical impact of immune checkpoint expression in BM samples after alloSCT for AML. Higher expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) was associated with a decreased incidence of acute graft-versus-host disease (P = .048) and poor overall (P = .046) and progression-free survival (P = 0.024). In addition, higher expression of TIGIT at engraftment after alloSCT was correlated with a decreased number of natural killer cells in BM (P = .019). Monitoring TIGIT expression in the BM could be useful for predicting outcome after alloSCT for AML. Our findings raise the possibility that blockade of TIGIT would improve survival.

Aberrant expression of the interleukin-3 receptor alpha chain (IL3RA or CD123) is frequently observed in patients with a subset of leukemic disorders, including acute myeloid leukemia (AML), particularly in leukemia stem cells. We analyzed the relationships between immunohistochemical (IHC) expression, including that of CD123, and clinical outcomes. This study involved a retrospective analysis of 48 patients diagnosed with de novo AML (M0–M5, n = 48) at our hospital between February 2008 and September 2015. Among patients with de novo AML, CD123 expression was associated with a failure to achieve complete response (CR) to initial induction chemotherapy (P = 0.044) and poor overall survival (OS) (P = 0.036). This is the first study using IHC to demonstrate that CD123 expression is associated with a poor CR rate and poor OS in de novo AML patients. These results support previous reports using flow cytometry (FCM). CD123 expression may thus be useful for assessing AML patients’ prognoses. At the time of diagnosis, CD123 expression analysis using IHC may represent a clinically useful assessment for de novo AML patients.

T1 colorectal carcinomas (CRCs) are an initial site of metastatic spread. Various risk factors for lymph node metastasis have been investigated in T1 CRCs. However, the major step in the entire process of metastasis remains unclear. In terms of carcinoma invasion and metastasis, matrix metalloproteinases (MMPs) have recently gained increasing attention. Notably, MMP-7 is frequently overexpressed in CRCs, but its implication has not been determined in T1 CRCs yet. The present study aimed to clarify the associations between the pathological risk factors of T1 CRCs and MMP-7. In the current study, 211 lesions of T1 CRC that were resected endoscopically or surgically at Showa University Northern Yokohama Hospital (Yokohama, Japan) between April 2008 and December 2009 were retrospectively analyzed. MMP-7 was immunostained and evaluated by its frequency of expression. Pathological factors of T1 CRCs were analyzed in association with MMP-7 expression. Furthermore, the ultrastructural alterations of carcinoma invasion were examined using low vacuum-scanning electron microscopy (LV-SEM). MMP-7 expression was associated with venous invasion (P=0.005), and LV-SEM revealed the disappearance of the normal structure of collagen and elastic fibers of veins invaded by tumor cells expressing MMP-7. At the invasive front, MMP-7 has a vital role in carcinoma invasion, correlating with venous invasion of T1 CRCs.

Isotropic Raman scattering and time-of-flight neutron diffraction measurements were carried out for concentrated LiTFSA-EC solutions to obtain structural insight on solvated Li

Studies showed red cell distribution width (RDW) can improve the detection of morphological changes in red blood cells and the understanding of their contribution to dyserythropoiesis in myelodysplastic syndrome (MDS). The purpose of the study was to evaluate dyserythropoiesis in MDS by RDW analysis and to explore the utility of RDW in clinical practice. We retrospectively analyzed laboratory and clinical data of 101 patients (59 patients was refractory anemia (RA) according to the French-American-British (FAB) classification). In patients with RA, RDW was showed weak inverse correlation with both hemoglobin concentration (Hb) (rs = −0.37, P = 0.0035) and mean corpuscular hemoglobin concentration (MCHC) (rs = −0.36, P = 0.0047). On the other hand, RDW was showed weak correlation with the number of ringed sideroblasts in bone marrow (rs = 0.31, P = 0.023). The increased RDW (≥15.0%) was associated with shorter overall survival (OS) (P = 0.0086). In patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t), effect of RDW on OS was less evident. These results suggested that increased RDW might reflect dyserythropoiesis, associated with deregulated hemoglobin synthesis and iron metabolism in MDS. Furthermore, increased RDW may have potential to be a prognostic significance in RA.

Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.

Cord blood transplantation (CBT) is an alternative approach to allogeneic stem cell transplantation. However, CBT is associated with issues including pre-engraftment immune reaction (PIR), engraftment syndrome (ES), and graft failure (GF). Tacrolimus (TAC) and short-term methotrexate (sMTX: days 1, 3, 6, and/or 11) are used for graft-versus-host disease (GVHD) prophylaxis during CBT; however, sMTX does not accelerate neutrophil engraftment. Therefore, we hypothesized that lower doses of sMTX [very-short-term MTX (vsMTX): 10 and 7mg/m(2) on days 1 and 3, respectively] with TAC reduce the risk of GF without increasing post-transplantation immune reactions during CBT. We retrospectively analyzed 40 patients who received TAC with vsMTX for GVHD prophylaxis. PIR and ES developed in 4 patients. The cumulative incidence of neutrophil engraft at day 60 was 92.5%. No cases of primary graft failure were noted. The cumulative incidence of grades II-III GVHD was 48.1% at day 100, and the cumulative 100-day incidence of nonrelapse mortality was 12.5%. This study suggests that TAC with vsMTX reduces the risk of PIR and ES during CBT and stimulates neutrophil engraftment, but may be associated with slightly higher aGVHD compared with calcineurin inhibitor and sMTX. Therefore, we recommend vsMTX plus TAC as an option for GVHD prophylaxis during CBT.

Both clonal hematopoiesis as defined by genomic alteration and morphological cell dysplasia is a hallmark of pathology of myelodysplastic syndrome (MDS). Studies showed that, red cell distribution width (RDW), a quantitative non-subjective index of red cell anisocytosis, has diagnostic significance in anemia associated with MDS. Our recent study showed that increase of RDW has close association with dyserythropoiesis and also shorter overall survival (OS) in refractory anemia (Leuk Res 2018;67:56-59). To explore the clinical significance of RDW in MDS without increased blasts, we examined the details of correlation between RDW and morphological dysplasia which characterize MDS. We retrospectively analyzed 101 MDS patients, including 66 patients without increased blasts (blasts in the bone marrow of less than 5% and the peripheral blood of 1% or less). RDW was calculated using automated blood cell analyzer. Dysplasia was assessed according to the WHO 2008 classification by different two investigators. 100 cells (at least 25 cells) of myeloid and erythroid series were counted. At least 25 cells of megakaryocyte were also counted. Karyotype of bone marrow cells was analyzed by using routine G-band technique and categorized according to MDS cytogenetic scoring system. Correlations of RDW and clinical variables were analyzed. Based on previous study, MDS patients was divided into two groups, RDW-H (RDW was 15% or more, 48 cases) and RDW-L (RDW was lower than 15%, 18 cases). Comparisons of dysplasia or OS between these two groups were analyzed. In MDS without increase of blasts, weak inverse correlation was found between RDW and hemoglobin (rs = −0.31, P = 0.01). RDW was correlated with the presence of ring sideroblasts (RS) in the bone marrow (rs = 0.40, P = 0.001), and also weakly correlated with budding of nucleus of erythroblasts (rs = 0.33, P = 0.007). Dysgranulopoiesis was less observed than either dyserythropoiesis or dysmegakaryopoiesis (P Table showed the subtype of MDS, details of morphological dysplasia. Between two groups, RDW-H showed significantly higher percentages of dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis. The increased RDW (≥15.0%) was associated with shorter OS (P = 0.02) (hazard ratio, 1.15e + 9 (95% confidence interval = 2.49-2.49)) (Figure). In contrast, there was no association between RDW and OS in MDS patients with increased blasts. Earlier studies showed increase of RDW was evident in refractory anemia with ring sideroblasts (RARS) which showed erythrocyte anisocytosis called dimorphism. Revised WHO classification (2017) defined MDS-RS with single lineage dysplasia (MDS-RS-SLD) which is characterized with specific mutation of splicing factors, such as SF3B1 and with favorable prognosis. This classification also defined MDS-RS with multi lineage dysplasia (MDS-RS-MLD) which has additional dysplasia in myeloid and/or megakaryocyte lineage in addition to RS. Pathology of MDS-RS-MLD is still to be remained. Our findings partly agree the earlier observations, showing close association between red cell anisocytosis evaluated with increase of RDW and the presence of RS. Furthermore, RDW-H group contained MDS with dysplasia of myeloid and/or megakaryocyte lineage not limited to the erythroid dysplasia(s) with RS. RDW could discriminate MDS-MLD with poor prognosis from MDS-SLD with favorable prognosis. To explore the significance of RDW in MDS, it is necessary to study large number of patient combined with genetic analysis. Nevertheless, RDW is potentially simple and useful laboratory parameters in clinical practice in MDS, representing hematopoietic defect (ineffective hematopoiesis), associated with iron metabolism and hemoglobin synthesis in MDS. Disclosures No relevant conflicts of interest to declare.

In the present retrospective single-center study, we examined the efficacy and safety of eltrombopag, a thrombopoietin (TPO) -receptor agonist (TPO-RA), and found clinical factors associated with its efficacy in Japanese patients with chronic immune thrombocytopenia (ITP). According to the definition of a response, which is to attain a platelet count of more than 50,000/μL at least once during eltrombopag treatment, 42 enrolled patients were divided into two groups: responders (29 patients, 69%) and non-responders (13 patients, 31%). In analyses of the clinical and laboratory data of these two groups, we extracted two factors that are significantly associated with a better response to eltrombopag, which have not been recognized previously, namely, (1) an older age of patients at eltrombopag initiation (≥ 70 years old) and (2) normal or decreased cellularity of iliac bone marrow (BM) biopsy at diagnosis. The significance of patient age contradicts previous findings from studies in which the Caucasian population was the major focus. However, factors such as changes of pharmacokinetics might modulate the effects of eltrombopag in older patients in Japan because East Asians show higher bioavailability of eltrombopag by as-yet-unknown mechanisms. BM cellularity in ITP may represent an impairment and/or lower responsiveness of pluripotent hematopoietic stem cells, not limited to the megakaryocyte (MgK) -platelet axis, to endogenous TPO, because recent evidence shows that TPO-RA can successfully restore hematopoiesis in aplastic anemia. These results should be useful for the therapeutic use of TPO-RA for ITP and also related thrombocytopenia in Japan.

Rituximab, anti-CD20 monoclonal antibody, shows anti-lymphoma effects by either activating host immune mechanism against lymphoma cells such as ADCC and CDC or suppressing signal(s) important for growth of B-cell lymphoma. Accumulated evidence shows de-regulated PI3K-AKT pathway is important therapeutic target in B-cell lymphoma. Although studies suggested suppression of PI3K-AKT pathway is possibly critical in rituximab-induced anti-lymphoma signals, details of molecular mechanisms covering CD20-mediated signals and PI3K-AKT pathway are still unknown. We analyzed signals in B-cell lymphoma cell line, SD07, which had bi-allelic deletions of both CD20(MS4A1) and PTEN gene. Briefly, SD07 was established from a patient with diffuse large B-cell lymphoma(DLBCL)who showed refractory CD20-negative relapse(Eur.J. Haematol. 2012). We transiently restored protein expression of either or both of CD20 and PTEN by electroporation of expression plasmid having cDNA of those genes in SD07. In this experiment, expression of both proteins were clearly detected by western blot until 72 hours after transfection. CD20 protein was also detectable on cell surface of SD07 cells by flow cytometric(FCM) analysis at comparable levels of those of Daudi cells after transfection on CD20 cDNA. Our previous study showed expression of both c-myc RNA and protein, as judged by FCM, was induced by transient transfection of CD20 cDNA in SD07 cells. Western blot analysis also showed significant increase of myc protein 24hrs after transfection (vector=13.7±0.2, CD20=14.5±0.4, P 24 hours after transfection, de-phosphorylation and down-regulation of retinoblastoma(RB) protein expression was evident only in SD07 cells transfected with both CD20 and PTEN, but not with either alone. Rituximab also augmented down-regulation of RB protein in SD07 cells transfected with both CD20 and PTEN. After transfection, in vitro cell growth of SD07, as evaluated by MTT, was as follows;vector=4.6±0.3, CD20=4.8±0.3(P=NS), PTEN=4.1±0.2(P 72 hours after transfection, by FCM, SD07 transfected with both CD20 and PTEN showed significant increase of subG1 DNA content potion compared with cells transfected with either alone(vector=2.5±0.2%,CD20=5.3±0.2%,PTEN=8.8 ±0.5%,CD20+PTEN= 16.1±0.6, P significantly increase of cells in subG1 in SD07 with transfected with both CD20 and PTEN(18.6±0.5%,P Accordance with proliferative effect of CD20 in SD07, transfection of CD20 alone produced significant increase of phosphorylation of AktSer473(vector=11.2±2.3, CD20=13.3±2.3,pAkt/total Akt,P In summary, although data is limited in a cell line, it clearly shows rituximab-induced CD20-mediated signals and suppression of PI3K-AKT pathway by tumor suppressor PTEN cooperatively inhibits growth and induce apoptosis of DLBCL cell line, SD07. Myc protein is critical molecules in this particular cooperative pathways. The present result partly agree studies which showed that inhibition of PI3K-AKT signaling and down-regulation of myc is important in PTEN-induced cytotoxicity in GCB(germinal center B cell)type DLBCL. In addition, we show here myc is not only for PTEN, but also involved in rituximab-induced anti-lymphoma effect. The present result provide a rationale for combination of rituximab and PI3K inhibitor in the treatment of DLBCL. In this context, myc is a candidate of the therapeutic target in rituximab-based immunochemotherapy for B cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Introduction Approximately 70%-90% patients receiving hematopoietic stem-cell transplantation (HSCT) have oral mucositis (OM). HSCT-induced OM is a major complication of preparative regimens. The oral cavity of healthy individuals harbor several bacterial species. For example, the cheek and tongue harbor a number of Streptococcus species, while the predominant genera in the saliva are Prevotella, Streptococcus, and Veillonella. The resident flora are considered to be deeply linked with OM because they prevent colonization by exogenous organisms having pathogenic potential for local and systemic infections. However, the precise bacterial substitution occurring in HSCT patients with OM remains unclear. Here, we prospectively examined oral bacterial flora changes using VITEK MSTM (SYSMEX bioMérieux Co., Ltd., Tokyo, Japan)-an automated mass spectrometry (MS) microbial-identification system using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) technology. It can detect about 650 bacterial and 105 fungal species. We aimed to determine whether oral microbial in HSCT can be detected by VITEK MSTM. Patient and Methods This prospective study included 16 patients (10 males, 6 females; median age 52 years) who underwent HSCT for hematological malignancies (auto-PBSCT = 3 patients, allo-PBSCT = 3 patients, CBT = 10 patients; preparative regimen: MAC = 11 patients, RIC = 2 patients, auto = 3 patients) in our hospital between December 2015 and July 2016. All were treated in reverse isolation in a laminar airflow-equipped room and received drugs to prevent bacterial, fungal, and herpes virus infection. We used VITEK MS for analyzing oral bacterial flora. OM was diagnosed according to NCICTCAE v4.0 and WHO scale, and oral health was assessed using the Revised Oral Assessment Guide (ROAG). Microbial samples were obtained using swabs from bilateral buccal mucosa, palate, and tongue. Samples were then incubated at 37‹C for 72-96 hours both aerobically and anaerobically. Finally, VITEK MS was used to identify bacterial species in samples. We evaluated the patients before initiating preparative regimen (1st), day −1 before HSCT (2nd), 7 days after HSCT (3rd), 14 days after HSCT (4th), and 30 days after HSCT (5th). Results The percentage of patients with high-grade OM (CTCAE Grade 2-5, and WHO Grade 1-4) increased in days 7-14 and decreased at day 30 (Table). Total bacterial species numbers gradually decreased from days -1 through to 30. Many Streptococcus sp could be detected at the 1st or 2nd time point, but these speciesgradually decreased and were replaced with coagulase-negative staphylococci (CNS; Staphylococcus epidermidis in 10 patients, S. haemolyticus in 5 patients, S. lentus in 3 patients, andS.warneri in 3 patients). Before HSCT, Prevotella sp and Veillonella sp in the oral flora were detected in 10 and 9 patients, respectively. However, by 14 days after HSCT, Prevotella sp and Veillonella sp were isolated less often than other points. Candida sp was detected only after the preparative regimen. Discussion and Conclusion This is the first prospective study to demonstrate microbial substitution in oral bacterial spices in HSCT patients using VITEK MS. VITEK MS allowed for the reliable identification of clinically relevant bacteria. We found that the oral bacterial species changed from Streptococcus sp, Prevotella sp, or Veillonella sp to CNS or Candida sp after HSCT. Our results suggest that oral microbial substitution possibly underlies high-grade OM after HSCT. We also suspect that microbial substitution is partly modified by antibiotics, considering that all study patients were treated with antimicrobial agents (including beta-lactam antibiotics). Indeed, the presence of many beta-lactam sensitive Streptococcus sp decreased, whereas that of beta-lactam resistant strains (CNS and Candida sp)increased. Finally, this study involved a small and heterogeneous patient population with varying characteristics. Therefore, our results require confirmation in a larger number of patients over a longer period. Disclosures Hironaka: MEXT Supported Program for the Strategic Research Foundation at Private Universities: Research Funding.

Background: The aberrant expression of the interleukin-3 receptor (IL3RA or CD123) alpha chain is frequently observed in a subset of leukemic disorders, including acute myeloid leukemia (AML), particularly in leukemia stem cells. Using flow cytometric (FCM) analysis, studies have shown that increased CD123 expression is associated with a poor prognosis of AML. Although FCM is a sensitive technique, the analysis may be limited in a clinical setting because live leukemia cells are required. Immunohistochemistry (IHC) is a more useful alternative compared with FCM because it can be tested long after specimens are collected; however, it is less sensitive. Here we evaluated the impact of blast CD123 expression via IHC analysis for the prognosis of AML. Patients and methods: This study was performed as a retrospective analysis of 70 patients who were diagnosed with de novo AML (M0-M5, n = 48) and AML with myelodysplasia-related changes (MRC) (n = 22) at our hospital from February 2008 to September 2015. The median age at diagnosis was 64.5 years (range: 21-93 years). The median follow-up period was 498 days (range: 2-3052 days). Morphological findings were obtained using HE stains of 3-µm sections. Formalin-fixed, paraffin-embedded specimens were used for immunohistochemical analysis. We analyzed the relationships between the patients' clinical outcome and CD123, p53, CD34, CD71, CD56, and c-kit expressions. [(CD123, CD34, CD71, CD56, and c-kit immunostained slides were defined as positive if >10% of the blast cells had a moderate to strong membranous staining. p53 was evaluated as positive when more than 5% of the cells were positively stained. For each case, the following data were obtained: patient age (>60 years or Results: Of the 70 cases, percentages of the positive immunohistochemical study dates were as follows: CD123: 25.7%; p53: 30%; CD34: 52.8%; CD71: 46.3%; CD56: 25.7%; and c-kit: 77.1%. There were 48 cases with de novo AML: CD123: 29.1%; p53: 75%; CD34: 52%; CD71: 37.5%; CD56: 27%; and c-kit: 79.1%. Moreover, there were 22 cases with MRC: CD123: 18.1%; p53: 31.8%; CD34: 54.5%; CD71: 66.6%; CD56: 22.7%; and c-kit: 72.7%. CD71 is highly expressed in MRC than de novo AML (P = 0.036). Among all patients, the CR rate following first induction therapy was 62.3%. Age (≥60 years), high p53 expression, disease (MRC), and poor karyotype were associated with induction failure (P = 0.011, P = 0.002, P Conclusion: This is the first study to demonstrate that CD123 expression using IHC is associated with poor a CR rate and OS in de novo AML patients; however, this association was not observed in MRC patients. Our results suggest that CD123 expression may predict the refractory to induction therapy and poor OS in de novo AML. Moreover, these results support previous reports using FCM. Therefore, CD123 expression may become one of the important factors used to characterize leukemia blasts and predict the prognosis of AML. In addition, novel therapy with antibodies targeting CD123 is currently under development. Therefore, we suggest that an analysis of CD123 expression using IHC is a clinically important assessment for de novo AML patients at the time of diagnosis. Disclosures No relevant conflicts of interest to declare.

Background: Bendamustine has demonstrated a favorable efficacy and toxicity profile in relapsed or refractory indolent lymphoma. Limited information is available regarding the prognostic factors (particularly laboratory parameters) of bendamustine treatment, although studies have shown a relationship between the hampered effect of bendamustine and an increase in lactate dehydrogenase (LDH) levels. Therefore, we retrospectively evaluated clinical and laboratory factors immediately prior to initiating bendamustine treatment and analyzed its correlation with the clinical outcome among patients with relapsed or refractory indolent lymphoma. Patients and methods: We analyzed 55 relapsed or refractory indolent lymphoma patients who had been treated with bendamustine alone (n = 19) or rituximab plus bendamustine (n = 36) at our hospital from 2000 to 2015. The median age at diagnosis was 65 years and the median follow-up period was 552.5 days. Histological analysis revealed follicular lymphoma (n = 21), mantle cell lymphoma (n = 10), MALT lymphoma (n = 7), lymphoplasmacytoid lymphoma (n = 5), and other low-grade B cell lymphomas (n = 4). We further analyzed the relationships between the clinical outcome [overall response rate (ORR), complete response (CR), progression-free survival (PFS), and overall survival (OS)] and clinical data, including sex, patient age (≥65 years), performance status (≥2), IPI (≥HI), FLIPI (≥HI), no. of previous therapies (≥2), prior purine analogue treatment, response to last treatment, and laboratory parameters [white blood cell count (≥5000/µl), lymphocyte count (≥1000/µl), platelet count (≥10000/µl), LDH (elevated or normal), sIL-2R (elevated or normal), and CRP (elevated or normal)], before starting bendamustine treatment. Results: The median number of cycles of bendamustine was 4 (range: 1-8). The ORR was 80.3% with a CR of 39.2%. Moreover, the CR rate was significantly worse in patients who had elevated sIL-2R and CRP, high or high-intermediate IPI scores, and a high WBC count (P = 0.002, P < 0.001, P = 0.072, and P < 0.046, respectively). Among follicular lymphoma patients, elevated CRP was only associated with a low CR rate (P = 0.028). In multivariate analysis, sIL-2R, CRP, and a high WBC count were all significantly associated with a worse CR rate (P = 0.044, P = 0.002, and P = 0.032, respectively). The 1- and 2- year OS rates were 80.3% and 76.1%, respectively. The OS was significantly higher in a group of the patients who obtained CR after bendamustine, were treated with rituximab plus bendamustine, and did not receive prior purine analogue treatment (P = 0.007, P = 0.008, and P < 0.001, respectively). An elevated CRP was associated with worse OS (P = 0.055). In multivariate analysis, only CR after bendamustine was significantly associated with improved OS (P = 0.023). The 1- and 2-year PFS rates were 69.2% and 60.5%, respectively. PFS was significantly better in patients who obtained CR after bendamustine treatment, had a normal CRP, had not received more than 2 previous therapies, and had a good performance status (P < 0.001, P = 0.007, P = 0.031, and P = 0.033, respectively). In multivariate analysis, any prognosis factors were significantly associated with PFS. Conclusion: This is the first study to demonstrate a correlation between laboratory parameters (i.e., CRP and sIL-2R) and the clinical outcome in patients with relapsed or refractory indolent lymphoma who were treated with bendamustine. In this study, CRP and sIL-2R levels as well as the WBC count were associated with the CR rate. In addition, the CRP levels were associated with OS and PFS, but LDH levels were not associated with any clinical outcomes. Previous studies have reported that the elevation of serum CRP and sIL-2R levels were associated with poor OS or PFS in patients who were treated with rituximab combined with CHOP in diffuse large B-cell lymphoma or follicular lymphoma. Our study indicates that serum CRP and sIL-2R levels are also important laboratory parameters for patients with indolent lymphoma who underwent bendamustine treatment. Disclosures No relevant conflicts of interest to declare.