Activation of nucleotide-binding oligomerization domain 2 by muramyl dipeptide negatively regulates Toll-like receptor 9-mediated colonic inflammation through the induction of deubiquitinating enzyme A expression.

Mutations in nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease (CD). Although NOD2 activation contributes to the maintenance of intestinal homeostasis through the negative regulation of pro-inflammatory cytokine responses mediated by Toll-like receptors (TLRs), the effects of NOD2 activation on interferon (IFN)-α responses induced by TLR9 have been poorly defined. To explore the cross-talk between NOD2 and TLR9, human monocytes or dendritic cells (DCs) were stimulated with NOD2 and/or TLR9 ligands to measure IFN-α production. The severity of dextran sodium sulfate (DSS)-induced colitis was compared in mice treated with NOD2 and/or TLR9 ligands. Expression of IFN-α and IFN-stimulated genes (ISGs) was examined in the colonic mucosa of patients with inflammatory bowel disease (IBD). NOD2 activation reduced TLR9-induced IFN-α production by monocytes and DCs in a deubiquitinating enzyme A (DUBA)-dependent manner. Activation of DUBA induced by the co-stimulation of TLR9 and NOD2 inhibited Lys63-linked polyubiquitination of TRAF3 and suppressed TLR9-mediated IFN-α production. NOD2 activation in hematopoietic cells protected mice from TLR9-induced exacerbation of DSS-induced colitis by down-regulating IFN-α responses and up-regulating DUBA expression. Colonic mucosa of patients with active and remitted IBD phases was characterized by the enhanced and reduced expression of ISGs, respectively. Expression levels of IFN-α and IL-6 positively correlated in the active colonic mucosa of patients with ulcerative colitis and CD, whereas DUBA expression inversely correlated with that of IFN-α in patients with CD. Collectively, these data suggest that DUBA-dependent negative effect of NOD2 on TLR9-mediated IFN-α responses contributes to the maintenance of intestinal homeostasis.

Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

BACKGROUND: Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. METHODS: The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. RESULTS: In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. CONCLUSIONS: PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Expression levels of cellular inhibitor of apoptosis proteins and colitogenic cytokines are inversely correlated with the activation of interferon regulatory factor 4.

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.

ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses.

Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn's disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine-threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.

[Durable remission following donor lymphocyte infusion for post-transplant relapse of acute myeloid leukemia developing from secondary myelofibrosis].

Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.

Next-generation sequencing in two cases of de novo acute basophilic leukaemia.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34+ , CD203c- , CD117+ , CD123dim+ ) and basophils (CD34- , CD203c+ , CD117± , CD123+ ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33+ , CD34+ , CD123- ) and basophils (CD33+ , CD34+ , CD123+ ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

Successful treatment with famciclovir for varicella zoster virus infection resistant to acyclovir.

Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo, and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase.

Orthognathic Surgery in Hereditary Angioedema With Normal C1 Inhibitor: A Clinical Response to Concentrated C1 Inhibitor Against Angioedema Attack.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by episodes of localized swelling, often of life-threatening severity. HAE due to C1 inhibitor (C1-INH) deficiency is common and is divided into types 1 and 2, but HAE with normal C1-INH is exceedingly rare. Herein, we describe the case of a patient with HAE with normal C1-INH undergoing orthognathic surgery. A 24-year-old woman came to our hospital with a diagnosed jaw deformity and commenced preoperative orthodontic treatment before scheduled orthognathic surgery. During the preoperative period, she experienced mild hoarseness. The hoarseness worsened, and computed tomography revealed mild laryngeal edema. Serum C1-INH, C3, C4, and CH50 levels were normal. Her younger sister had reportedly experienced a similar episode of lip edema previously. These findings supported a diagnosis of HAE with normal C1-INH. She underwent orthognathic surgery in close consultation with a hematologist and anesthesiologist at the age of 33 years. The surgery was completed without complications. She reported throat tightness 4 days after surgery, although her facial swelling was consistent with the procedure performed and was not remarkable. Concentrated C1-INH was administered, and the throat tightness slowly resolved within approximately 1 hour. Twenty-five days after surgery, she was discharged with reduced facial swelling. In the present case, orthognathic surgery was performed successfully in a patient with the exceedingly rare condition of HAE with normal C1-INH, in close consultation with a hematologist and an anesthesiologist. Postoperative throat tightness was successfully treated via the administration of concentrated C1-INH. Concentrated C1-INH administration can be considered in patients with HAE and normal C1-INH who experience angioedemic attack, keeping in mind that it may be slow to take effect.

Changes in tonsillolith characteristics detected in a follow-up CT study.

BACKGROUND: Tonsilloliths are related clinically to halitosis and tonsillar abscess. However, the dynamics of tonsilloliths over time are unknown. The aim of the study was to evaluate change in the characteristics of tonsilloliths in a time-dependent fashion by follow-up computed tomography (CT). METHODS: Tonsilloliths were analyzed in 326 CT scan pair sets of initial and at least two follow-up CT examinations of patients with whole palatine tonsils and various diseases of the oral and maxillofacial regions. RESULTS: Over the follow-up period, 12.1% of tonsilloliths disappeared. Approximately 26.1% of tonsilloliths changed in size during follow-up, mostly increasing in size. In tonsilloliths that showed enlargement, the mean (± standard deviation) growth rate was 0.61 ± 0.41 mm per year. Approximately 37.3% of tonsilloliths changed position during the follow-up period; of these, movement was toward the respiratory tract in 92% at a mean rate of - 1.38 ± 1.59 mm per year. The calcification levels of almost all tonsilloliths showed dynamic change: HU number increased in 84.3% and decreased in 12.7% of tonsilloliths over the follow-up period. The mean rate of HU increase was 63.8 ± 96.3 HU/year, and the mean rate of HU decrease was - 38.4 ± 66.8 HU/year. CONCLUSIONS: The calcification levels of all tonsilloliths showed dynamic fluctuation, and a tendency for excretion of tonsilloliths from the body. Their dynamics over time suggest that tonsilloliths may be in a permanently active phase which functions to remove foreign matter.

The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey.

BACKGROUND: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs. METHODS: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis. RESULTS: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect. CONCLUSIONS: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.

Lymphopenia at diagnosis predicts survival of patients with immunodeficiency-associated lymphoproliferative disorders.

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n = 26; other iatrogenic immunodeficiency-associated LPD, n = 45) were reviewed and analyzed. The median age at diagnosis was 63 years (range, 3-83). Diffuse large B cell lymphoma was the most common subtype (n = 33), followed by Hodgkin lymphoma (n = 12), B cell monomorphic LPD not specified (n = 11), and polymorphic LPD or early-phase diseases (n = 15). The median follow-up period for survivors was 2.5 years and overall survival (OS) and progression-free survival (PFS) at 2.5 years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/µL) at diagnosis predicted inferior OS (HR, 3.72; P = 0.043) and PFS (HR, 3.82; P = 0.012). Serum albumin values also strongly affected OS (> 3.18 g/dL vs. ≤ 3.18 g/dL; HR, 0.21; P = 0.010) and PFS (HR, 0.26; P = 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds.

Lymphocyte Area Under the Curve as a Predictive Factor for Viral Infection after Allogenic Hematopoietic Stem Cell Transplantation.

Viral infection is a serious complication that can greatly affect patient mortality and morbidity after allogenic hematopoietic stem cell transplantation (allo-HSCT). For the early identification of patients at high risk for viral infection, we evaluated the impact of lymphocyte area under the curve (AUC) value as a new predictive factor for early immune reconstitution after allo-HSCT against viral infection. This study included 286 patients who underwent their first allo-HSCT at Kyoto University Hospital between 2005 and 2017. Lymphocyte AUC from day 0 to day +15 was calculated in the analysis of human herpesvirus 6 (HHV-6), and lymphocyte AUC from day 0 to day +30 was calculated in the analysis of other viruses (cytomegalovirus [CMV], adenovirus, BK virus, JC virus, and varicella zoster virus). The risk factors for each viral reactivation/infection were assessed by multivariate analysis. The median age at transplantation was 51years (range, 17 to 68 years). The median lymphocyte AUC was 63/µL (range, 0 to 5620/µL) at day +15 and 3880 (range, 0 to 118,260/µL) at day +30. An increase in lymphocyte AUC was significantly associated with a high frequency of HHV-6 reactivation (P = .033) and a low frequency of CMV antigenemia (P = .014). No apparent association was found between lymphocyte AUC and reactivation/infection of other viruses. Aplastic anemia as a primary disease (hazard ratio [HR], 5.34; P < .001) and cord blood as a donor source (HR, 3.05; P = .006) were other risk factors for HHV-6 reactivation. Other risk factors for CMV antigenemia included the occurrence of acute graft-versus-host disease (HR 2.21; P < .001) and recipient age (HR 1.55; P = .017). Higher lymphocyte AUC at day +30 was significantly associated with low treatment-related mortality (HR, .47; P = .045). Lymphocyte AUC may be a good predictive factor for immune reconstitution against CMV reactivation. It also provides valuable information for predicting HHV-6 reactivation and treatment-related mortality.

Effect of laminar air flow and building construction on aspergillosis in acute leukemia patients: a retrospective cohort study.

BACKGROUND: The preventive effect of laminar air flow (LAF) on aspergillosis has been observed in patients with hematological malignancies. However, the short follow-up period limits the interpretation of study results. METHODS: To assess the preventive effect of long-term LAF use on aspergillosis in its long-term use, we retrospectively analyzed 124 acute leukemia patients at our hospital between January 2005 and March 2016. We compared the incidence of aspergillosis before (May 2008) and during the construction of a new building (June 2008-January 2010) and in the early (February 2010-March 2014) and late (April 2014-March 2016) periods after moving to a new hematology ward with an LAF system. The 2008 European Organization for Research and Treatment of Cancer and Mycosis Study Group criteria were used for the diagnosis of aspergillosis. RESULTS: Fourteen patients were diagnosed with possible, probable, or definite aspergillosis. Cumulative incidence rates of aspergillosis at day 180 were 12.4, 24.9, 9.3, and 25.1% before construction, during construction, in the early period after moving to a new ward, and in the late period after moving to a new ward, respectively (p = 0.106). Multivariate analysis showed that the LAF system tended to reduce the risk of aspergillosis in the early period (before construction vs. early period; hazards ratio (HR) = 1.97, p = 0.463 and during construction vs. early period;HR = 3.42, p = 0.184), but the risk increased in the late period (late vs. early period, HR = 5.65, p = 0.035). CONCLUSIONS: Building construction might increase the risk of aspergillosis. Short-term LAF use might reduce aspergillosis risk, but its long-term use is inadequate, although we could not exclude the possibility of increased risks in the recent period due to continued improvements in the different areas of our hospital. Strict maintenance, more effective LAF system, and optimization of aspergillosis prophylaxis may be necessary.

Neutropenia and renal dysfunction due to intravesical cidofovir for virus-associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations.

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.

Impact of cumulative steroid dose on infectious diseases after allogenic hematopoietic stem cell transplantation.

BACKGROUND: Systemic steroid is used to treat various transplant-related complications after allogenic hematopoietic stem cell transplantation (allo-HSCT). However, measures to evaluate its impact on infections are still limited. Hence, we examined the cumulative steroid dose used within 30 days after transplant as a predictor of future risk of infections. METHODS: This study included 226 patients who underwent their first allo-HSCT at Kyoto University Hospital between 2005 and 2015. RESULTS: Sixty-one patients received transplantation from related donors, 106 received unrelated BMT and 59 received unrelated single-unit CBT. Patients were categorized into three groups according to the cumulative steroid dose in terms of prednisolone: no-steroid group (n = 174), low-dose group (≤7 mg/kg) (n = 22) and high-dose group (>7 mg/kg) (n = 30). In a multivariate analysis, high-dose steroid administration was associated with cytomegalovirus (CMV) antigenemia (HR 1.91, P = 0.037) and bacteremia (HR 2.59, P = 0.053). No impact was found on the occurrence of invasive fungal infection. CONCLUSION: High-dose cumulative steroid could predict high risks of bacteremia and CMV antigenemia. Additional anti-bacterial agents for fever and regular measurement of CMV antigen are recommended for whom with systemic steroid administration even after neutrophil engraftment.

Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells.

In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-ß1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.

[Successful treatment with recombinant thrombomodulin in transplant-associated thrombotic microangiopathy following HLA-haploidentical transplantation].

In March 2009, a 17-year-old woman was first diagnosed with acute myelogenous leukemia and myelodysplasia-related changes. She underwent chemotherapy and allogeneic hematopoietic stem cell transplantation, which resulted in complete remission. However, she experienced relapse, and remission was achieved each time with repeated transplantation. In September 2014, a human leukocyte antigen (HLA)-haploidentical transplantation, which was the fifth allogeneic transplantation, was performed to treat the third relapse. Platelet transfusion refractoriness, hemolytic anemia with schistocytes, and renal dysfunction were observed from approximately the day of engraftment; therefore, transplantation-associated thrombotic microangiopathy (TA-TMA) was diagnosed. Recombinant human soluble thrombomodulin (rTM) was administered, and fresh-frozen plasma (FFP) was infused; this resulted in gradual improvement of TA-TMA. Treatment with rTM and FFP was discontinued on the 70th day after transplantation. Because the HLA-haploidentical transplantation was the fifth allogeneic transplantation, the risk of aggravation of TA-TMA was very high. Combined treatment with rTM and FFP, however, resulted in improvement of TA-TMA. Further investigation of similar cases is necessary for clarifying the usefulness of rTM for TA-TMA.

Impact of the Use and Type of Antibiotics on Acute Graft-versus-Host Disease.

The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days -14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P = .0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P = .043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth-generation cephalosporins than in those who did not (31% versus 16%, P = .018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD.