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The value of galactomannan (GM) antigen detection in the diagnosis of invasive aspergillosis (IA) was examined retrospectively in 124 patients with hematological disorders in this study. In this population, although 21 patients (16.9%) had at least two consecutive positive GM tests, 14 patients were found to have false-positive results. Of these 14 patients with false-positive results, 11 had a diagnosis of multiple myeloma. Multivariate analysis revealed that immunoglobulin G myeloma was the only independent patient risk factor of false-positivity. [ABSTRACT FROM AUTHOR]

A 65-year-old man with multiple lymphadenopathies was diagnosed with IgG4-related disease (IgG4-RD) based on findings of a cervical lymph node biopsy and an elevated serum IgG4 level. Treatment was initiated after the onset of autoimmune pancreatitis, and he achieved remission. He developed diffuse large B-cell lymphoma one year later. Pericardial involvement of lymphoma resulted in cardiac tamponade, and he died before histopathological confirmation of lymphoma was made due to a lethal arrhythmia caused by massive involvement of lymphoma into the myocardium. Because patients with IgG4-RD might have an increased risk of malignant diseases, including lymphoma, histopathological examinations should be considered at any time during the course of IgG4-RD.

The nitrogen isotopic composition of nitrogen oxide (NOx) is useful for estimating its sources and sinks. Several methods have been developed to convert atmospheric nitric oxide (NO) and/or nitrogen dioxide (NO2) to nitrites and/or nitrates for collection. However, the collection efficiency and blanks are poorly evaluated for many collection methods. Here, we present a method for collecting ambient NOx (NO and NO2 simultaneously) with over 90% efficiency collection of NOx and low blank (approximately 0.5 μM) using a 3 wt% hydrogen peroxide (H2O2) and 0.5 M sodium hydride (NaOH) solution. The 1σ uncertainty of the nitrogen isotopic composition was ± 1.2 ‰. The advantages of this method include its portability, simplicity, and the ability to collect the required amount of sample to analyze the nitrogen isotopic composition of ambient NOx in a short period of time. Using this method, we observed the nitrogen isotopic compositions of NOx at the Tsukuba and Yoyogi sites in Japan. The averaged δ15N(NOx) value and standard deviation (1σ) in the Yoyogi site was (-2.7 ± 1.8) ‰ and in the Tsukuba site was (-1.7 ± 0.9) ‰ during the sampling period. The main NOx source appears to be the vehicle exhaust in the two sites., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kamezaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231-484) days, and the duration of response was 330 (range 65-659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL., (© 2022. The Author(s).)

Competing Interests: None.

Prednisolone, used as a standard initial treatment for immune thrombocytopenia (ITP), is an important risk factor for osteoporosis. To investigate the prevention of glucocorticoid-induced osteoporosis (GIO) in elderly ITP patients receiving prolonged steroid therapy, associations between GIO prevention and the real-world data of score changes of a dual-energy X-ray absorptiometry (DXA) scan, FRAX® and the Garvan tool during the initial loading of prednisolone were examined. In our institute, 22 ITP patients aged ≥ 70 years received 0.5−1.0 mg/kg prednisolone for 2−3 weeks as the initial ITP treatment between 2014 and 2021. The femoral neck bone mineral density (BMD) measured by DXA scan was entered into FRAX® to define the risk-adapted approach to bisphosphonate during the initial loading of prednisolone. Bisphosphonate was administered according to <−1.0 femoral neck BMD T-score measured by DXA scan. Worse scores of FRAX® and the Garvan tool were associated with bisphosphonate use for short-term fracture prevention in primary GIO; however, there were no incidents of fracture or significant differences in probabilities determined by FRAX® and the Garvan tool. During the initial loading of prednisolone, prescribing bisphosphonate might prevent the reduction in BMD in elderly patients with ITP receiving prolonged steroid therapy.

A new system was developed for measuring sulfur isotopes δ 33 S and δ 34 S from atmospheric carbonyl sulfide (COS) on small air samples of several liters, using pre-concentration and gas chromatography - isotope ratio mass spectrometry (GC-IRMS). Measurements of COS isotopes provide a tool for quantifying the COS budget, which will help towards better understanding climate feedback mechanisms. For a 4 liter sample at ambient COS mixing ratio, ~500 parts per trillion (ppt), we obtain a reproducibility error of 2.1 ‰ for δ 33 S and 0.4 ‰ for δ 34 S. After applying corrections, the uncertainty for an individual ambient air sample measurement is 2.5 ‰ for δ 33 S and 0.9 ‰ for δ 34 S. The ability to measure small samples allows application to a global-scale sampling program with limited logistical effort. To illustrate the application of this newly developed system, we present a timeseries of ambient air measurements, during the fall and winter of 2020 and 2021 in Utrecht, the Netherlands. The observed background values were δ 33 S = 1.0 ± 3.4 ‰ and δ 34 S = 15.5 ± 0.8 ‰ (VCDT). The maximum observed COS mixing ratios was only 620 ppt. This, in combination with the relatively high δ 34 S suggests that the Netherlands receives little COS-containing anthropogenic emissions. We observed a change in COS mixing ratio and δ 34 S with different air mass origin, as modelled with HYSPLIT backward trajectory analyses. An increase of 40 ppt in mean COS mixing ratio was observed between fall and winter, which is consistent with the expected seasonal cycle in the Netherlands. Additionally, we present the results of samples from a highway tunnel to characterize vehicle COS emissions and isotopic composition. The vehicle emissions were small, with COS/CO 2 being 0.4 ppt/ppm; the isotopic signatures are depleted relatively to background atmospheric COS., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Baartman SL et al.)

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation., (© 2021. Japanese Society of Hematology.)

Background: Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis., Methods: We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis., Results: In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 10 9 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 10 9 /L, respectively), whereas severe platelet decrease (<50 × 10 9 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 10 9 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings., Conclusion: Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis., (© 2021 Wiley Periodicals LLC.)

Carbonyl sulfide (OCS), the most abundant sulfur-containing gas in the atmosphere, is used as a proxy for photosynthesis rate estimation. However, a large missing source of atmospheric OCS has been inferred. Sulfur isotope measurements ( 34 S/ 32 S ratio and δ 34 S) on OCS are a feasible tool to distinguish OCS sources from oceanic and anthropogenic emissions. Here we present the latitudinal (north-south) observations of OCS concentration and [Formula: see text]S within Japan. The observed [Formula: see text]S of OCS of 9.7 to 14.5‰ reflects source and sink effects. Particularly in winter, latitudinal decreases in [Formula: see text]S values of OCS were found to be correlated with increases in OCS concentrations, resulting an intercept of (4.7 ± 0.8)‰ in the Keeling plot approach. This result implies the transport of anthropogenic OCS emissions from the Asian continent to the western Pacific by the Asian monsoon outflow. The estimated background [Formula: see text]S of OCS in eastern Asia is consistent with the [Formula: see text]S of OCS previously reported in Israel and the Canary Islands, suggesting that the background [Formula: see text]S of OCS in the Northern Hemisphere ranges from 12.0 to 13.5‰. Our constructed sulfur isotopic mass balance of OCS revealed that anthropogenic sources, not merely oceanic sources, account for much of the missing source of atmospheric OCS., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular (LV) dysfunction due to anthracycline-induced cardiotoxicity (AIC) has been believed to be irreversible. However, this has not been confirmed and standard medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers may lead to its recovery., Methods and Results: We thus retrospectively studied 350 cancer patients receiving anthracycline-based chemotherapy from 2001 to 2015 in our institution. Fifty-two patients (14.9%) developed AIC with a decrease in LV ejection fraction (LVEF) of 24.1% at a median time of 6 months [interquartile range (IQR) 4-22 months] after anthracycline therapy. By multivariate analysis, AIC was independently associated with cardiac comorbidities including ischemic heart disease, valvular heart disease, arrhythmia, and cardiomyopathy [odds ratio (OR) 6.00; 95% confidence interval (CI) 2.27-15.84, P = 0.00044), lower baseline LVEF (OR per 1% 1.09; 95% CI 1.04-1.14, P = 0.00034). During the median follow-up of 3.2 years, LV systolic dysfunction recovered among 33 patients (67.3%) with a median time of 4 months (IQR 2-6 months), which was independently associated with the introduction of standard medical treatment for HF (OR 9.39; 95% CI 2.27-52.9, P = 0.0014) by multivariate analysis., Conclusion: Early initiation of standard medical treatment for HF may lead to LV functional recovery in AIC.

Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P = .049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P = .036), whereas there was no significant difference among the latter 2 groups (P = .889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication., (Copyright © 2018. Published by Elsevier Inc.)

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Antiemetic effects and safety of granisetron or palonosetron alone and in combination with a corticosteroid against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with Hodgkin lymphoma receiving adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy., Methods: A total of 39 patients were eligible for this study. Before ABVD therapy, granisetron or palonosetron was intravenously administered with or without a corticosteroid (dexamethasone or hydrocortisone) and aprepitant. The proportions of patients with complete control (CC) during the overall (0-120 h after the start of ABVD therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CC was defined as no vomiting and no use of antiemetic rescue medication with only grade 0-1 nausea., Results: Granisetron and palonosetron were administered in 21 and 18 patients, respectively. The CC rate during the acute, delayed and overall phases was not statistically different between the two groups. The CINV was completely controlled during overall phase in 58.3% of patients receiving granisetron or palonosetron in combination with a corticosteroid, whereas in 11.1% of those without co-treatment of a corticosteroid ( P  < 0.05). There were significantly higher frequencies of anorexia, leucopenia and neutropenia in the palonosetron group. There is a statistically significant difference in the frequency of febrile neutropenia between presence and absence of a corticosteroid ( p  = 0.024)., Conclusion: These findings suggested that a combination use of a corticosteroid with a 5-HT 3 receptor antagonist was preferable for CINV control in patients with Hodgkin lymphoma receiving ABVD therapy, although the careful management of febrile neutropenia is required., Trial Registration: The study approval numbers in the institution; 24-12 and 24-359. Registered April 17, 2012 and June 21, 2012., Competing Interests: This study was conducted with the approval of Kyushu University Graduate School and Faculty of Medicine (approval Nos. 24–928027 and 24–359 of the institutional review board).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Carbonyl sulfide (COS) is one of the major sources of stratospheric sulfate aerosols, which affect the global radiation balance and ozone depletion. COS-degrading microorganisms are ubiquitous in soil and important for the global flux of COS. We examined the sulfur isotopic fractionation during the enzymatic degradation of COS by carbonyl sulfide hydrolase (COSase) from Thiobacillus thioparus THI115. The isotopic fractionation constant ( 34 ɛ value) was -2.2±0.2‰. Under experimental conditions performed at parts per million by volume level of COS, the 34 ɛ value for intact cells of T. thioparus THI115 was -3.6±0.7‰, suggesting that, based on Rees' model, the 34 ɛ value mainly depended on COS transport into the cytoplasm. The 34 ɛ value for intact cells of T. thioparus THI115 was similar to those for Mycobacterium spp. and Williamsia sp., which are known to involve the conserved region of nucleotide sequences encoding the clade D of β-class carbonic anhydrase (β-CA) including COSase. On the other hand, the 34 ɛ value was distinct from those for bacteria in the genus Cupriavidus. These results provide an insight into biological COS degradation, which is indispensable for estimating the COS global budget based on the isotope because of the significant contribution of COS degradation by microorganisms harboring β-CA family enzymes.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) has a curative potential for myelofibrosis (MF) patients; however, its association with a high therapy-related mortality (TRM) remains a big obstacle that needs to be overcome. Ruxolitinib (RUXO), a novel JAK1/2 inhibitor, can be used as a bridging therapy until allo-SCT can be performed to reduce TRM. We herein report a RUXO-treated MF patient who developed recurrent subcutaneous Sweet's disease (SSD) that was successfully treated by the administration of systemic glucocorticoids. We performed allo-SCT as previously scheduled, resulting in a good clinical course without deterioration of SSD. RUXO administration, as well as MF itself, might therefore sometimes cause this rare non-infectious event.

Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet). These immature cells gradually increased to a peak level (mean 2.6% per white blood cells) with triplet therapy, and disappeared immediately after therapy cessation. The numbers of circulating CD34 + cells and colony-forming cells derived from peripheral blood mononuclear cells increased after triplet therapy compared with those in patients treated by either bortezomib or immunomodulatory drugs plus dexamethasone. Furthermore, triplet regimen downregulated the expression of CXCR4, a chemokine receptor essential for bone marrow retention, on CD34 + cells, suggesting an unexpected effect on normal hematopoietic stem/progenitor cells through the reduced interaction with the bone marrow microenvironment. Our observations suggest that combination use should be carefully evaluated to exert synergistic anti-myeloma effects while avoiding unexpected adverse events.

In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma.

Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.

Rationale: Triple oxygen and nitrogen isotope ratios in nitrate are powerful tools for assessing atmospheric nitrate formation pathways and their contribution to ecosystems. N 2 O decomposition using microwave-induced plasma (MIP) has been used only for measurements of oxygen isotopes to date, but it is also possible to measure nitrogen isotopes during the same analytical run., Methods: The main improvements to a previous system are (i) an automated distribution system of nitrate to the bacterial medium, (ii) N 2 O separation by gas chromatography before N 2 O decomposition using the MIP, (iii) use of a corundum tube for microwave discharge, and (iv) development of an automated system for isotopic measurements. Three nitrate standards with sample sizes of 60, 80, 100, and 120 nmol were measured to investigate the sample size dependence of the isotope measurements., Results: The δ 17 O, δ 18 O, and Δ 17 O values increased with increasing sample size, although the δ 15 N value showed no significant size dependency. Different calibration slopes and intercepts were obtained with different sample amounts. The slopes and intercepts for the regression lines in different sample amounts were dependent on sample size, indicating that the extent of oxygen exchange is also dependent on sample size. The sample-size-dependent slopes and intercepts were fitted using natural log (ln) regression curves, and the slopes and intercepts can be estimated to apply to any sample size corrections. When using 100 nmol samples, the standard deviations of residuals from the regression lines for this system were 0.5‰, 0.3‰, and 0.1‰, respectively, for the δ 18 O, Δ 17 O, and δ 15 N values, results that are not inferior to those from other systems using gold tube or gold wire., Conclusions: An automated system was developed to measure triple oxygen and nitrogen isotopes in nitrate using N 2 O decomposition by MIP. This system enables us to measure both triple oxygen and nitrogen isotopes in nitrate with comparable precision and sample throughput (23 min per sample on average), and minimal manual treatment. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We performed laboratory incubation experiments on the degradation of gaseous phase carbonyl sulfide (OCS) by soil bacteria to determine its sulfur isotopic fractionation constants ((34)ε). Incubation experiments were conducted using strains belonging to the genera Mycobacterium, Williamsia, and Cupriavidus isolated from natural soil environments. The (34)ε values determined were -3.67 ± 0.33‰, -3.99 ± 0.19‰, -3.57 ± 0.22‰, and -3.56 ± 0.23‰ for Mycobacterium spp. strains THI401, THI402, THI404, and THI405; -3.74 ± 0.29‰ for Williamsia sp. strain THI410; and -2.09 ± 0.07‰ and -2.38 ± 0.35‰ for Cupriavidus spp. strains THI414 and THI415. Although OCS degradation rates divided by cell numbers (cell-specific activity) were different among strains of the same genus, the (34)ε values for same genus showed no significant differences. Even though the numbers of bacterial species examined were limited, our results suggest that (34)ε values for OCS bacterial degradation depend not on cell-specific activities, but on genus-level biological differences, suggesting that (34)ε values are dependent on enzymatic and/or membrane properties. Taking our (34)ε values as representative for bacterial OCS degradation, the expected atmospheric changes in δ(34)S values of OCS range from 0.5‰ to 0.9‰, based on previously reported decreases in OCS concentrations at Mt. Fuji, Japan. Consequently, tropospheric observation of δ(34)S values for OCS coupled with (34)ε values for OCS bacterial degradation can potentially be used to investigate soil as an OCS sink.

A 74-year-old woman with refractory adult T-cell leukemia/lymphoma (ATLL) received three courses of mogamulizumab. Despite obtaining complete remission, she thereafter presented with progressive ascites. An analysis of the ascites and laboratory tests revealed no evidence of ATLL invasion, infectious disease, or liver cirrhosis. The mogamulizumab concentrations were maintained in the ascites at approximately 10-15% of that in the plasma. Mogamulizumab was considered to be a plausible pathogenesis of her ascites. To the best of our knowledge, this is the first report suggesting mogamulizumab-induced ascites.

Autosomal dominant distal renal tubular acidosis (dRTA) is a rare disorder caused by a mutation in the AE1 gene encoding the chloride-bicarbonate (Cl - /HCO 3 - ) anion exchanger 1 (AE1). Most patients with this disorder present with clinical symptoms in adulthood and their phenotype is milder than that of those with autosomal recessive dRTA. In this report, we describe a Japanese family with autosomal dominant dRTA in which the mother and her daughter presented with severe symptoms caused by hypokalemia at 2 years of age. The heterozygous AE1 mutation G609R, which is a known causative mutation of dRTA, was identified in both patients. To our knowledge, this is the first report of a Japanese family with autosomal dominant type dRTA caused by an AE1 mutation. We, therefore, propose that alterations of AE1 should be considered causative of autosomal dominant dRTA even if typical symptoms appear during early childhood and the clinical features are severe.

Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MS-LCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.

FLT3 is one of the most frequently mutated genes in acute leukemias. However, the role in leukemogenesis of wild-type (wt) FLT3, which is highly expressed in many hematologic malignancies, is unclear. We show here that in mouse models established by retroviral transduction of leukemic fusion proteins, deletion of Flt3 strongly inhibits MLL-ENL and to lesser extent p210(BCR-ABL)-induced leukemogenesis, but has no effect in MLL-AF9 or AML1-ETO9a models. Flt3 acts at the level of leukemic stem cells (LSCs), as a fraction of LSCs in MLL-ENL, but not in MLL-AF9-induced leukemia, expressed Flt3 in vivo, and Flt3 expression on LSCs was associated with leukemia development in this model. Furthermore, efficiency of MLL-ENL, but not of MLL-AF9-induced leukemia induction was significantly enhanced after transduction of Flt3(+) compared to Flt3(-) wt myeloid progenitors. However, Flt3 is not required for immortalization of bone marrow cells in vitro by MLL-ENL and does not affect colony formation by MLL-ENL LSCs in vitro, suggesting that in vitro models do not reflect the in vivo biology of MLL-ENL leukemia with respect to Flt3 requirement. We conclude that wt Flt3 plays a role in leukemia initiation in vivo, which is, however, not universal., (Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Objective: We examined the therapeutic strategies for treating mild gastrointestinal (GI) graft-versus-host disease (GVHD) using oral beclomethasone dipropionate (BDP) in 15 Japanese patients based on the donor source. The primary objective was to determine the efficacy and toxicity of oral BDP combined with/without low-dose prednisone (PSL)., Methods: Oral BDP was administered with 1 mg/kg/d of PSL in patients undergoing bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT; n=11), and the dose of PSL was tapered off after 22 days. Oral BDP alone was administered in patients undergoing cord blood stem cell transplantation (CBSCT; n=4). The primary endpoint was the rate of treatment success on day 49, as measured according to the improvement or complete resolution of GI symptoms without additional treatment. The secondary endpoints included treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 3.0, the rate of treatment discontinuation due to toxicity, the rate of relapse of acute GVHD by day 100 and the incidence of bacterial, fungal or viral infection, including cytomegalovirus (CMV) antigenemia., Results: Treatment success was achieved in seven of the 11 (64%) patients undergoing BMT or PBSCT and in all four patients (100%) undergoing CBSCT. Subsequent adverse events included herpes zoster infection, catheter-associated sepsis and CMV enteritis; all affected patients responded well to treatment., Conclusion: The use of a risk-stratified treatment strategy with oral BDP depending on the stem cell source is effective in patients with mild GI-GVHD.

Unlabelled: Transient marrow expansion of normal B-cell precursors, termed hematogones, is occasionally observed after hematopoietic stem cell transplantation (HSCT). To understand the clinical significance of this phenomenon, we enumerated hematogones in 108 consecutive patients who received allogeneic HSCT for the treatment of hematologic malignancies, including acute myelogenous leukemia, advanced myelodysplastic syndromes, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Hematogone quantitation was performed at the time of complete donor engraftment (median day 25 and 32 in patients who received bone marrow and cord blood cell transplants, respectively). Hematogones were polyclonal B cells, and their frequencies correlated positively with blood B-cell numbers, and inversely with donors’ but not recipients' age, suggesting that hematogones reflect cell-intrinsic B-cell potential of donor cells. Interestingly, patients developing hematogones that comprised > 5% of bone marrow mononuclear cells constituted a group with significantly prolonged overall survival and relapse-free survival, irrespective of their primary disease or donor cell source. In addition, patients with > 5% hematogones developed severe acute graft-versus-host diseases less frequently, which may contribute toward their improved survival. We therefore conclude that the amount of hematogones at the time of engraftment may be a useful tool in predicting the prognosis of patients treated with allogeneic HSCT., Key Points: Quantitation of hematogones at engraftment is useful to predict prognosis of patients treated with allogeneic stem cell transplantation.

A 66-year-old man presented with a six-month history of periodic fever. A CT scan of the chest and abdomen performed at another hospital one month before admission disclosed no evidence of inflammation or tumor, and at admission he had no symptoms other than the periodic fever. FDG-PET/CT demonstrated increased FDG uptake in multiple vertebrae, ribs, scapulae, pelvis, and femurs. A core needle biopsy of the vertebra showing increased FDG uptake was performed, and he was diagnosed with primary osseous Hodgkin lymphoma. ABVD therapy was begun and the fever resolved immediately. After 6 cycles of ABVD, he achieved complete remission and has maintained remission for five years since diagnosis. Primary osseous Hodgkin lymphoma is rare and its lack of distinguishing clinical and radiological features makes it difficult to achieve an early differential diagnosis. FDG-PET/CT is a useful tool for detecting tumors when periodic fever suggests the possibility of malignant disease but when specific symptoms are absent.

Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB., (Copyright © 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)