Influence of FOXP3 single-nucleotide polymorphism after allogeneic hematopoietic stem cell transplantation.

The impact of FOXP3 single-nucleotide polymorphisms (SNP) on clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly understood. We investigated the relationship between a FOXP3 SNP (rs3761548) and clinical outcomes in 91 patients with hematological malignancies after allo-HSCT. Multivariate analysis showed that risk of severe chronic graft-versus-host disease (cGVHD) was significantly higher in patients with the FOXP3-3279C/A or FOXP3-3279A/A genotype than those with the FOXP3-3279C/C genotype [hazard ratio (HR), 2.69; 95% confidence interval (CI) 1.14-6.31; p = 0.023]. Therefore, FOXP3 at SNP rs3761548 can be a useful marker for predicting the occurrence of severe cGVHD.

[Acquired thrombotic thrombocytopenic purpura during durvalumab monotherapy for non-small cell lung cancer].

Immune checkpoint inhibitor (ICI)-induced thrombocytopenias are rare immune-related adverse events (irAE), but ICI-related thrombotic thrombocytopenic purpura (TTP) is extremely rare. A 79-year-old woman with non-small cell lung cancer received maintenance therapy with the anti-human PD-L1 monoclonal antibody durvalumab. Four weeks after the last infusion, she developed overt TTP. Remission was achieved by plasma exchange and prednisolone, and the patient has now been recurrence-free for over 12 months. To our knowledge, this is the first report of TTP occurring as an irAE of durvalumab.

Perceptions of Psychosocial and Ethical Issues and the Psychological Characteristics of Donors in the Clinical Setting of Living Kidney Donors: A Qualitative Study.

BACKGROUND: There are several psychosocial and ethical issues surrounding the decision to be a living kidney donor. The present study aimed to determine the perceptions of psychosocial and ethical issues that living kidney donors may have, and analyze their psychological characteristics. METHODS: Face-to-face semi-structured interviews were conducted with 15 donors. Thematic analysis was then performed to categorize the thematic elements of the transcripts. All procedures were approved by the relevant review board. RESULTS: Four main categories were identified: Awareness of family dynamics, barriers to a proper understanding, contrasting psychological effects of recipient presence in clinical practice, insufficient information explained in informed consent. CONCLUSION: Donors felt that they took on the "role as a care giver" for the recipient and were less aware of themselves as patients. This is a new concept that has not been shown in previous studies. Donors exist within the recipient and family, and the range of their autonomy may go beyond the traditional concept of autonomy and be rooted in relational autonomy. This study suggested that medical treatment in the presence of the recipient promotes the relational autonomy of the donor.

[CD5- and CD10-positive MYC and BCL2 double-expressor diffuse large B-cell lymphoma with MYD88L265P mutation: a case report and literature review].

A 75-year-old man who had lymphadenopathy was admitted to our hospital. Histopathological examination of cervical lymph node biopsy specimens showed diffuse proliferation of lymphoma cells with large nuclei. In immunohistochemistry, the lymphoma cells were positive for CD5, CD10, CD20, BCL2, BCL6, and MYC. The patient was diagnosed with CD5- and CD10-positive diffuse large B-cell lymphoma (DLBCL). MYD88L265P mutations have been detected in DLBCL. Partial response was achieved after six courses of R-THP-COP therapy. However, the patient died because of disease progression 18 months after the diagnosis. On autopsy, lymphoma cells were found in the lymph nodes throughout the body, central nervous system, adrenals, and skin. CD5- and CD10-positive DLBCL account for 0.5-1% of DLBCL cases and have a very poor disease prognosis. This is a rare case of CD5- and CD10-positive DLBCL with MYC and BCL2 expressions harboring MYD88L265P mutation.

Identifying practical clinical problems in active euthanasia: A systematic literature review of the findings in countries where euthanasia is legal.

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.

Psychosocial and Ethical Behaviors and Attitudes of Health Care Professionals in the Clinical Setting of Living Kidney Donors: A Qualitative Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Tools for studying ion solvation and ion pair formation in ionic liquids: isotopic substitution Raman spectroscopy.

Isotopic H/D or 6/7Li substitution Raman spectroscopy was applied to new kinds of ionic liquids; N-methylimidazole (C1Im) and acetic acid (CH3COOH) as the pseudo-protic ionic liquid (pPIL), and both of the neat and the 2,2,3,3-tetrafluoropropyl ether (HFE) diluted Li-glyme solvate ionic liquids (SIL) [Li(Gn)][TFSA] (Gn, glyme n = 3 or 4); TFSA, bis(trifluoromethanesulfonyl)amide) to clarify the proton transfer or the Li+ solvation/ion pair formation. The isotopic substitution Raman (ISR) spectra were obtained as the difference between the samples containing the same composition except the substituted isotope. The calculated and theoretical ISR spectra were also evaluated for comparison. With the C1Im-CH3COOH(D) pPIL, the Raman bands attributable to the C1Im/C1HIm+ gave signals of differential shape, and they were well reproduced with the curve fitting by taking the small amount of C1HIm+ and CH3COO- generation into consideration. The ISR spectra for the SIL were well explained by the formation of the Li-TFSA contact ion pair (CIP) and the solvent shared ion pair (SSIP) in the [Li(G3)][TFSA] SIL. In addition, the ISR spectra for the HFE-diluted [Li(G4)][TFSA] SIL clearly proved that the HFE hardly coordinates to the Li+ in the HFE-diluted SIL. Here, the ISR spectroscopy is proposed as a new tool for studying the ion solvation and the ion pair formation in ionic liquids.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

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.

Increased serum C-reactive protein is an adverse prognostic factor in low-risk myelodysplastic syndromes.

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 < 0.001) both overall and among the 73 patients with low-risk MDS as defined by the revised IPSS (HR: 28.05, 95% CI 6.15-128.04, P < 0.001). Increased CRP might predict poor prognosis and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in patients with low-risk MDS.

Local Structure of Li+ in Superconcentrated Aqueous LiTFSA Solutions.

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+.

Characteristics and predictors of post-transplant-associated hemophagocytic lymphohistiocytosis in adults.

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.

Effect of Brønsted Acidity on Ion Conduction in Fluorinated Acetic Acid and N-Methylimidazole Equimolar Mixtures as Pseudo-protic Ionic Liquids.

To clarify proton conduction mechanism in protic ionic liquids (PILs) and pseudo-PILs (pPILs), equimolar mixtures of N-methylimidazole (C1Im) with fluorinated acetic acids were investigated by Raman spectroscopy, X-ray scattering, and dielectric relaxation spectroscopy (DRS). Only the ionic species exist in the equimolar mixture of C1Im and HTFA (HTFA: trifluoroacetic acid). On the other hand, the equimolar mixture of C1Im and HDFA (HDFA: difluoroacetic acid) consists of both ionic and electrically neutral species. In particular, not only the electrostatic but also van der Waals interactions with the F atoms were observed in the liquid structures of both [C1hIm+][TFA-] and [C1hIm+][DFA-]. The concept for proton conduction mechanism that we have proposed in previous study was revisited; the proton conduction mechanism could be classified with two linear free energy relationship lines for proton exchange reaction and translation/rotation of proton carriers. Our results exhibit that the proton conduction mechanism changes from proton hopping to vehicle mechanism with increasing acidity of an acid HA in PILs.

Solvation Structure of Li+ in Concentrated Acetonitrile and N,N-Dimethylformamide Solutions Studied by Neutron Diffraction with 6Li/7Li Isotopic Substitution Methods.

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 Å. 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 Å and r(Li+···O) = 1.88 ± 0.01 Å, 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 Å. 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 Å and r(Li+···OTFSA-) = 2.01 ± 0.01 Å, respectively. The Li+···TFSA- contact ion pair stably exists in highly concentrated 33 mol % LiTFSA-AN and -DMF solutions.

Elevated C-reactive protein level is associated with poor prognosis in follicular lymphoma patients undergoing rituximab-containing chemotherapy.

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.

Speciation Analysis and Thermodynamic Criteria of Solvated Ionic Liquids: Ionic Liquids or Superconcentrated Solutions?

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+ ion by the solvents due to the extremely high Li salt concentration. Although both of them are similar to each other, it is still unclear that both should be room-temperature ionic liquids. To distinctly define them, speciation analyses were performed with the Li-G SIL and the aqueous SCES to evaluate the free solvent concentration in these solutions with a new Raman/infrared spectral analysis technique called complementary least-squares analysis. Furthermore, from a thermodynamic point of view, we investigated the solvent activity and activity coefficient in the gas phase equilibrated with sample solutions and found they can be good criteria for SILs.

Comparative Study of Tacrolimus and Short-Term Methotrexate: 2-Day versus 3-Day Methotrexate as Graft-versus-Host-Disease Prophylaxis after Umbilical Cord Blood Transplantation in Adults.

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.

Candidatus Mycoplasma haemohominis in Human, Japan.

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.

Refined Disease Risk Index for Hematological Malignancies, Including Rare Disorders, After Allogeneic Stem Cell Transplantation.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

[Development of cardiac tamponade and emergence of arrhythmia during chemotherapy for diffuse large B-cell lymphoma].

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.