A model of heterogeneous undercooled liquid and glass accounting for temperature-dependent nonexponentiality and enthalpy fluctuation.

Dynamic heterogeneity is a fundamental characteristic of glasses and undercooled liquids. The heterogeneous nature causes some of the key features of systems' dynamics such as the temperature dependence of nonexponentiality and spatial enthalpy fluctuations. Commonly used phenomenological models such as Tool-Narayanaswamy-Moynihan (TNM) and Kovacs-Aklonis-Hutchinson-Ramos fail to fully capture this phenomenon. Here we propose a model that can predict the temperature-dependent nonexponential behavior observed in glass-forming liquids and glasses by fitting standard differential scanning calorimetry curves. This model extends the TNM framework of structural relaxation by introducing a distribution of equilibrium fictive temperature (Tfe) that accounts for heterogeneity in the undercooled liquid. This distribution is then frozen at the glass transition to account for the heterogeneous nature of the glass dynamics. The nonexponentiality parameter ßKWW is obtained as a function of temperature by fitting the Kohlrauch-Williams-Watts (KWW) equation to the calculated relaxation function for various organic and inorganic undercooled liquids and glasses. The calculated temperature dependent ßKWW shows good agreement with the experimental ones. We successfully model the relaxation dynamics far from equilibrium for two silicate systems that the TNM model fails to describe, confirming that temperature dependent nonexponentiality is necessary to fully describe these dynamics. The model also simulates the fluctuation of fictive temperature δTf during isothermal annealing with good qualitative agreement with the evolution of enthalpy fluctuation reported in the literature. We find that the evolution of enthalpy fluctuation during isothermal annealing heavily depends on the cooling rate, a dependence that was not previously emphasized.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

Analysis of risk factors for fatal renal complications after allogeneic hematopoietic cell transplantation.

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy.

BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

[Manufacturing results of tisagenlecleucel for acute lymphoblastic leukemia: a survey by the CAR-T cell therapy taskforce of the Japan Society of Transfusion Medicine and Cell Therapy].

The frequency of the manufacturing failure of chimeric antigen receptor (CAR)-T cell therapy in clinical practice is unknown. To clarify the current state of how likely CAR-T cell production is to succeed or fail for B-cell acute lymphoblastic leukemia (B-ALL), we analyzed cases in which the production of tisagenlecleucel was performed for patients with B-ALL at 15 facilities in Japan from October 2019 to March 2022. Total 81 patients (47 males and 34 females) were analyzed. The median age at apheresis was 13 years (1-25) with a median number of prior treatments of 4 (1-9). The numbers of patients with histories of allogeneic transplantation, inotuzumab ozogamicin, or blinatumomab treatments were 51 (63.0%), 26 (32.1%), and 37 (45.7%), respectively. The median blast percentage and CD3+ cell counts in peripheral blood were 0% (0-91.5), and 611/µl (35-4,210) at apheresis, and the median number of CD3+ cells shipped was 2.2×109 (0.5-8.3). While cases with a history of heavy prior treatment before apheresis were included, no manufacturing failures were observed. Continuing to monitor the status of manufacturing failures is necessary as the number of B-ALL cases treated with CAR-T cell therapy increases.

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan.

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (

Fast crystallization below the glass transition temperature in hyperquenched systems.

Many phase change materials (PCMs) are found to crystallize without exhibiting a glass transition endotherm upon reheating. In this paper, we review experimental evidence revealing that these PCMs and likely other hyperquenched molecular and metallic systems can crystallize from the glassy state when reheated at a standard rate. Among these evidences, PCMs annealed below the glass transition temperature Tg exhibit slower crystallization kinetics despite an increase in the number of sub-critical nuclei that should promote the crystallization speed. Flash calorimetry uncovers the glass transition endotherm hidden by crystallization and reveals a distinct change in kinetics when crystallization switches from the glassy to the supercooled liquid state. The resulting Tg value also rationalizes the presence of the pre-Tg relaxation exotherm ubiquitous of hyperquenched systems. Finally, the shift in crystallization temperature during annealing exhibits a non-exponential decay that is characteristic of structural relaxation in the glass. Modeling using a modified Turnbull equation for nucleation rate supports the existence of sub-Tg fast crystallization and emphasizes the benefit of a fragile-to-strong transition for PCM applications due to a reduction in crystallization at low temperature (improved data retention) and increasing its speed at high temperature (faster computing).

Romidepsin-induced durable remission for relapsed nodal peripheral T-cell lymphoma with T follicular helper phenotype after allogeneic hematopoietic cell transplantation.

Patients with recurrent peripheral T-cell lymphoma (PTCL) after allogeneic hematopoietic cell transplantation (HCT) have dismal outcomes. Nodal PTCL with the T follicular helper phenotype (PTCL-TFH) is uniquely sensitive to histone deacetylase inhibitors compared to non-TFH phenotypes. We report the case of a 19-year-old man who experienced recurrence of PTCL-TFH shortly after allogeneic HCT and subsequently achieved durable remission with romidepsin. Before HCT, the patient had refractory disease after CHOP and ESHAP chemotherapies but achieved a partial response after two cycles of romidepsin as salvage treatment. HLA-haploidentical peripheral blood stem cell transplantation was performed using conditioning with fludarabine 180 mg/sqm, melphalan 80 mg/sqm, and total body irradiation 2 Gy, and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide. One month after HCT, disease progression was observed in the lung. Romidepsin was readministered every 2 weeks at a reduced dose of 12 mg/sqm. After two cycles of romidepsin, the patient achieved a complete metabolic response without severe GVHD or other non-hematological toxicities. Romidepsin was discontinued after seven treatment cycles due to prolonged lymphopenia. The patient remains in complete remission 30 months after the last dose of romidepsin. Our experience suggests that romidepsin could be safely administered soon after allogeneic transplantation.

Lenalidomide treatment for recurrent adult T-cell leukemia/lymphoma after allogeneic hematopoietic cell transplantation.

Patients with recurrent adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic cell transplantation (allo-HCT) have a dismal prognosis. We retrospectively evaluated the safety and efficacy of lenalidomide (LEN) in 11 consecutive patients with recurrent ATL after allo-HCT. The median time from allo-HCT to ATL recurrence was 111 days (range, 20-1476), and that from allo-HCT to the initiation of LEN was 162 days (range, 43-1560). The median initial daily dose of LEN was 10 mg (range, 5-25), and the median duration of LEN treatment was 37 days (range, 3-1078). Three patients (27%) achieved complete response and two (18%) achieved partial response (PR). The rates of complete or PR according to the involved site were 57% for skin and 50% for nodal or extranodal lesions. With a median follow-up of 1033 days (range, 601-1465) among survivors, the 1-year probability of overall survival (OS) after ATL recurrence was 55%. Grade ≥3 toxicities included cytopenia (n = 4), superficial vein thrombosis (n = 1), and deep vein thrombosis (n = 1). Graft-versus-host disease (GVHD) newly developed in five patients (45%) and worsened in four patients (36%). The median duration from the initiation of LEN to GVHD onset or worsening was 5 days (range, 1-9). GVHD was manageable in all patients. Seven patients received mogamulizumab (MOG) for recurrent ATL before LEN treatment. The overall response rates to LEN were 57% in patients who had previously received MOG and 25% in those who had not. The 1-year probabilities of OS after recurrent ATL were 71% in patients who had previously received MOG and 25% in those who had not. Although cytopenia and GVHD are common among patients with recurrent ATL after allo-HCT, LEN may improve survival. Administering MOG before LEN may augment treatment efficacy in the allo-HCT population.

Adenovirus disease after hematopoietic cell transplantation: A Japanese transplant registry analysis.

We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.

Outcomes of hematopoietic cell transplantation for transformed follicular lymphoma.

This study characterized the outcomes of patients who underwent hematopoietic cell transplantation (HCT) for transformed follicular lymphoma (tFL), and clarified the association of low-dose anti-thymocyte globulin use with outcomes after allogeneic HCT. The retrospective study cohort included 74 consecutive patients who underwent autologous (n = 23) or allogeneic (n = 51) HCT at our center from 2000 to 2017. Compared with the allogeneic HCT group, the autologous HCT group underwent fewer systemic regimens before HCT (median 2 vs. 5, p < 0.001) and were more likely to have chemosensitive disease at HCT (100% vs. 82%, p = 0.05), while age, sex and HCT-specific comorbidity index were similar between the two groups. With a median follow-up of 5.8 years among survivors, the 5-year probability of progression-free survival was 64% after autologous HCT and 55% after allogeneic HCT (p = 0.21). The 5-year cumulative incidence of non-relapse mortality was 0% after autologous HCT and 9.5% after allogeneic HCT (p = 0.062). The 5-year cumulative incidence of disease progression was similar between autologous and allogeneic HCT (36% vs. 36%, respectively, p = 0.88). In the allogeneic HCT group, the use of low-dose anti-thymocyte globulin was associated with a lower incidence of severe acute GVHD but not with an increased risk of mortality or disease progression. More than half of patients with early phase chemosensitive tFL and approximately half of those with advanced-phase tFL achieved long-term progression-free survival with autologous and allogeneic HCT, respectively. Disease progression was the major cause of treatment failure after both types of HCT. Further strategies are needed to reduce the risk of disease progression.

Extended aging of Ge-Se glasses below the glass transition temperature.

Germanium selenide glasses of compositions spanning the whole glass-formation range are aged at room temperature for up to 20 years. A prominent enthalpy relaxation process is observed in all glasses, and its structural origin is analyzed by Raman spectroscopy. The structural relaxation is manifested in the Raman spectra as a decrease in the ratio of edge- to corner-sharing GeSe4/2 tetrahedral units. This structural evolution can be explained in terms of configurational entropy and density changes. Changes in Raman features and enthalpy follow an identical stretched exponential relaxation function characteristic of aging in glasses. The compositional dependence of enthalpy relaxation after 20 years is in agreement with kinetic considerations based on the glass transition temperature of each glass. The relaxation behavior and heat capacity curves are consistent with standard glass relaxation models for all compositions. These results indicate that the non-reversing enthalpy obtained by modulated differential scanning calorimetry (MDSC), which suggests the existence of non-aging glasses, is not a reliable measure of the ability of a glass to relax. Instead, it is suggested that an interpretation of MDSC data in terms of complex heat capacity provides a more complete and reliable assessment of the relaxation properties of glasses.

Effect of donor type on volume of blood transfusions required after allogeneic hematopoietic cell transplantation.

We reviewed blood product use in 729 consecutive allogeneic hematopoietic cell transplantation (allo-HCT) recipients at our center to assess the volume of red blood cells (RBCs) and platelets required after allo-HCT. The median number of bags required by day 30 was 4 for RBCs (range 0-22) and 9.5 for platelets (0-53). Multivariate analysis showed that related peripheral blood stem cell transplantation (PBSCT) required a significantly lower RBC transfusion volume by day 30 compared to unrelated bone marrow transplantation (UBMT). PBSCT from haplo-identical related donors and cord blood transplantation (CBT) required a significantly greater RBC transfusion volume. For platelet transfusion, related and unrelated PBSCT required a significantly lower volume than UBMT, and CBT a greater volume. Other factors independently associated with greater RBC transfusion volume were male sex, disease status other than complete remission, and major ABO mismatch. For platelet transfusion, these were male sex, disease status, and HCT-specific comorbidity index of 1. Although the burden of blood transfusions may not be the most important factor when choosing a donor type, our findings may provide a foundation for nationwide strategies to prepare blood products and inform aspects of national healthcare expenditures.

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). METHODS: In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. RESULTS: A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60 days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584 copies/mL vs 587 copies/mL; P < .0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P = 1.00, Fisher's exact test) or oral mucosal GVHD (P = .71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. CONCLUSION: Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

[Successful treatment of very severe late-onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin, steroids, and control of intra-abdominal pressure].

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).

[Miliary tuberculosis with markedly elevated soluble interleukin-2 receptor levels mimicking intravascular large B-cell lymphoma].

An 81-year-old woman with type 2 diabetes mellitus presented to our hospital due to anorexia, leg edema, and respiratory distress. Laboratory results revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and markedly elevated soluble interleukin-2 receptor levels. Computed tomography showed ground-glass opacities and consolidation in both lung fields, but no lymphadenopathy was noted. Intravascular large B-cell lymphoma (IVLBCL) was considered as a differential diagnosis; therefore, bone marrow and random skin biopsy were performed. Her respiratory condition deteriorated, with the occurrence of acute respiratory distress syndrome, disseminated intravascular coagulation, hemophagocytic syndrome, and further alveolar hemorrhage. Methylprednisolone pulse therapy was performed, but did not improve the patient's condition. On hospital day 6, the acid-fast bacterial smear of the sputum using the Gaffky scale was 2, and on the next day, tuberculosis DNA was detected in the polymerase chain reaction. In the bone marrow biopsy, multiple epithelioid cell granulomas were found; thus, the patient was diagnosed with miliary tuberculosis. Although anti-tuberculosis therapy was started immediately, she died on hospital day 22. The soluble interleukin-2 receptor level increased up to 19,400 U/ml. The differential diagnosis should be cautiously made because miliary tuberculosis can mimic IVLBCL.

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.

Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-Like Receptors and Cytokines in Pneumococcal Pneumonia.

Excessive activation of neutrophils results in the release of neutrophil elastase (NE), which leads to lung injury in severe pneumonia. Previously, we demonstrated a novel immune subversion mechanism involving microbial exploitation of this NE ability, which eventually promotes disruption of the pulmonary epithelial barrier. In the present study, we investigated the effect of NE on host innate immune response. THP-1-derived macrophages were stimulated with heat-killed Streptococcus pneumoniae or lipopolysaccharide in the presence or absence of NE followed by analysis of toll-like receptor (TLR) and cytokine expression. Additionally, the biological significance of NE was confirmed in an in vivo mouse intratracheal infection model. NE downregulated the gene transcription of multiple cytokines in THP-1-derived macrophages through the cleavage of TLRs and myeloid differentiation factor 2. Additionally, NE cleaved inflammatory cytokines and chemokines. In a mouse model of intratracheal pneumococcal challenge, administration of an NE inhibitor significantly increased proinflammatory cytokine levels in bronchoalveolar lavage fluid, enhanced bacterial clearance, and improved survival rates. Our work indicates that NE subverts the innate immune response and that inhibition of this enzyme may constitute a novel therapeutic option for the treatment of pneumococcal pneumonia.

[Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib].

Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs.

[Neurolymphomatosis due to enteropathy-associated T-cell lymphoma clinically diagnosed by FDG-PET/CT and subsequently confirmed by autopsy].

A 59-year-old man who complained of abdominal pain was referred to our hospital. Computed tomography (CT) revealed mesenteric lymph node swelling and intestinal perforation. Histopathological study of the resected ileum and lymph node demonstrated diffuse proliferation of medium-sized atypical lymphocytes. Immunohistochemistry results were positive for cluster of differentiation (CD) 3, CD8, and CD56 cells, negative for CD5 and CD4 cells, and negative for Epstein-Barr virus-encoded RNA-fluorescent in situ hybridization (EBER-FISH). It also revealed the expression of γδ T-cell receptors. On the basis of these findings, enteropathy-associated T-cell lymphoma (EATL) was diagnosed. Although the patient received two courses of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) therapy, facial nerve and lower limb paralysis manifested. Magnetic resonance imaging (MRI) and lumbar puncture revealed central nervous system invasion of the EATL. Despite intrathecal chemotherapy and high-dose cytarabine therapy, the patient's neurological symptoms deteriorated. Fluorodeoxyglucose positron emission tomography (FDG-PET) /CT scan showed the accumulation of FDG along both median and sciatic nerves, and he was diagnosed with neurolymphomatosis (NL). He died on day 120 after admission. Autopsy specimens exhibited infiltration of lymphoma cells in the median and sciatic nerves. Although only one case of suspected NL in a patient with type 2 EATL has been previously reported, we clinically diagnosed NL using FDG-PET/CT and confirmed the diagnosis by autopsy. This case is valuable in terms of the pathological diagnosis of NL.