Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.

Adiponectin Enhances Antibacterial Activity of Hematopoietic Cells by Suppressing Bone Marrow Inflammation.

Obesity has been shown to increase the morbidity of infections, however, the underlying mechanisms remain largely unknown. Here we demonstrate that obesity caused adiponectin deficiency in the bone marrow (BM), which led to an inflamed BM characterized by increased tumor necrosis factor (TNF) production from bone marrow macrophages. Hematopoietic stem and progenitor cells (HSPCs) chronically exposed to excessive TNF in obese marrow aberrantly expressed cytokine signaling suppressor SOCS3, impairing JAK-STAT mediated signal transduction and cytokine-driven cell proliferation. Accordingly, both obese and adiponectin-deficient mice showed attenuated clearance of infected Listeria monocytogenes, indicating that obesity or loss of adiponectin is critical for exacerbation of infection. Adiponectin treatment restored the defective HSPC proliferation and bacterial clearance of obese and adiponectin-deficient mice, affirming the importance of adiponectin against infection. Taken together, our findings demonstrate that obesity impairs hematopoietic response against infections through a TNF-SOCS3-STAT3 axis, highlighting adiponectin as a legitimate target against obesity-related infections.

Isolated massive pleural effusion as a manifestation of chronic graft versus host disease successfully treated with corticosteroid.

Isolated pleural effusion is a rare manifestation of chronic graft versus host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). We herein report a 58-year-old woman presenting with massive pleural effusion approximately 1 year after allogeneic HSCT, who was successfully treated with corticosteroid. She had discontinued tacrolimus approximately 1 month before she presented with pleural effusion, which was attributed to cGVHD after a thorough exclusion process. This case illustrates a unique manifestation of atypical cGVHD and highlights the need for prompt therapy initiation.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.

Toxic shock like syndrome caused by Streptococcus agalactiae bacteremia during treatment for multiple myeloma.

Toxic shock-like syndrome (TSLS) is a life-threatening hyperinflammatory complication caused by Streptococcus species infections. We reported the first case of TSLS caused by primary bacteremia of Streptococcus agalactiae during chemotherapy for multiple myeloma. A 74-year-old woman, who received combination chemotherapy of elotuzumab, pomalidomide, and dexamethasone for treatment-refractory multiple myeloma, was transported to our hospital under comatose and septic shock. Her blood culture detected Streptococcus agalactiae, and considering the progressive multiorgan failure, she was diagnosed with TSLS. Empiric antibiotic treatment with meropenem and respiratory and circulatory support were quickly initiated, resulting in an almost complete recovery of organ functions. It should be noted that with the advances of chemotherapy, the risk of infection is becoming more diverse.

Cerebral toxoplasmosis complicating lymphoplasmacytic lymphoma in partial remission.

Toxoplasma gondii can develop toxoplasmic encephalitis (TE) in immunodeficient conditions such as AIDS and after organ transplantation. While some cases of TE with malignant lymphoma were reported, these cases occurred immediately after chemotherapy or when their diseases were active. Here we report the first Case of TE that occurred in patient who was in partial remission (PR) of lymphoplasmacytic lymphoma (LPL) for two years. A 76-year-old man was referred to our institute because of disturbance of consciousness, right arm weakness and paresthesia. A computed tomography (CT) scan detected multiple nodules in his brain. Magnetic resonance imaging (MRI) of the head detected multiple gadolinium-enhancing parenchymal lesions with hyperintense signals on T2-and diffusion-weighted images, located in both cerebral and cerebellar hemispheres. Blood test and cerebrospinal fluid (CSF) findings were unremarkable. His rapidly deteriorating consciousness precluded a chance of brain biopsy. Considering the limited efficacy of antimicrobials and the imaging findings that could be compatible with the diagnosis of malignant lymphoma, we suspected central nerve system (CNS) recurrence of LPL. Although chemotherapy was initiated, he died of respiratory failure just after chemotherapy. A pathological autopsy showed his cause of death was TE. To our knowledge, this is the first case of TE in long-term PR of malignant lymphoma. TE should be suspected when patients with malignant lymphoma present unexplained neurologic symptoms regardless of their treatment efficacy of lymphoma. (226/250 words).

High D-index during mobilization predicts poor mobilization of CD34+ cells after anti-lymphoma salvage chemotherapy.

BACKGROUND: Performing stem cell collection after mobilization chemotherapy was a well-balanced strategy between anti-tumor effect and efficient collection of CD34+ cells, but deep and prolonged nadir exposed patients to risk of febrile neutropenia. Febrile neutropenia was known to be associated with lower yields of CD34+ cells, but quantitative data referring to association between yields of CD34+ cells and severity of neutropenia was lacking. We hypothesized that D-index, which was developed for quantitative evaluation of severity of neutropenia especially in the field of hematologic malignancies, could predict yields of CD34+ cells. METHODS: We performed a single center, retrospective analysis of patients with relapsed or refractory aggressive lymphoma who were mobilized with ESHAP or modified ESHAP. We evaluated the association between yields of CD34+ cells at first apheresis and D-index. RESULTS: Thirty-six patients were included, and we demonstrated that yields of CD34+ cells from patients with higher D-index were significantly lower than those from patients with lower D-index. Multivariate linear regression analysis and logistic regression analysis also demonstrated the significant predictive power of D-index. Further, D-index was significantly correlated to platelet count before starting mobilization chemotherapy. Platelet count was known to predict yields of CD34+ cells, and combination of platelet count and D-index could identify patients with lowest CD34+ yields. CONCLUSION: D-index could predict yields of CD34+ cells and it seemed that its predictive power was not less than that of platelet count. Prospective studies including more heterogeneous patients were needed to validate our study.

Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation.

Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.

Severe cellulitis caused by Achromobacter xylosoxidans after allogeneic hematopoietic stem cell transplantation.

Achromobacter xylosoxidans (A. xylosoxidans) is an aerobic gram-negative bacillus and often isolated from aquatic environments. It is supposed to cause infections in patients with malignancy or immunodeficiency. It causes various healthcare-associated infections, but cellulitis is rare. Herein, we report the first case of sever cellulitis by A. xylosoxidans after allogeneic hematopoietic stem cell transplantation (HSCT). A 49-year-old man underwent allogeneic HSCT from 8/8 HLA-matched unrelated donor with myeloablative conditioning for relapsed acute myeloid leukemia. He developed skin chronic graft versus host disease 11 months after HSCT. During the prolonged treatment with prednisolone and cyclosporine, he developed cellulitis on his left leg and admitted to our hospital. Blood and exudate culture revealed A. xylosoxidans. Although empirical therapy with cefepime was ineffective, his symptoms were dramatically improved after administration of meropenem. To our knowledge, this is the first case of A. xylosoxidans cellulitis after allogeneic HSCT. A. xylosoxidans should be considered as a possible cause of cellulitis in post-allogeneic HSCT patients on prolonged immunosuppressive therapy.

[Role of FDG-PET/CT in diffuse large B-cell lymphoma].

FDG-PET/CT has been widely used not only at the time of diagnosis of non-Hodgkin's lymphoma but also during and after treatment. With the help of large amount of data on Hodgkin's lymphoma, for which FDG-PET is extraordinarily useful, evidence is also rapidly accumulating for non-Hodgkin's lymphoma. Currently, there is a consensus that FDG-PET/CT is effective in stratifying the prognosis of non-Hodgkin's lymphoma in a PET-avid disease, especially diffuse large B-cell lymphoma (DLBCL). However, in the enormous evidence accumulated till date, the variability in the clinical conditions of the patients, timing, and the FDG-PET/CT assessment method makes it difficult to overlook and understand the complete picture. In this article, we will review the position of FDG-PET/CT in the response assessment of DLBCL, evolution of evaluation methods, and evidence for determining therapeutic efficacy using FDG-PET/CT and for modifying treatment based on the FDG-PET/CT results.

[Successful treatment of refractory chylothorax associated with diffuse large B-cell lymphoma by multidisciplinary care].

Chylothorax is an intrathoracic leakage of chyle due to thoracic duct damage. Malignant lymphoma is the most common nontraumatic cause of chylothorax. In March 2019, a 74-year-old woman presented to our department with bilateral pleural effusion and mesenteric/retroperitoneal masses. She was diagnosed with diffuse large B-cell lymphoma upon performing a biopsy. In May 2019, she was hospitalized for dyspnea due to pleural effusion, and thoracentesis revealed abundant chyle. Although the tumor shrunk after chemotherapy, chylothorax improvement was poor; thus, she could not be discharged. For the management of refractory chylothorax, lymphangiography, thoracic duct embolization, and pleurodesis were performed, and the chylothorax improved immediately. However, in May 2020, right chylothorax recurred without a relapse of malignant lymphoma, which did not improve with conservative treatment. Lymphangiography was performed again; however, treatment via the lymphatic vessels was difficult. Thus, pleurodesis was performed four times, after which the chylothorax regressed. Chylothorax is often refractory. When chemotherapy for malignant lymphoma does not improve chylothorax, multidisciplinary treatment is effective.

Adiponectin Enhances Quiescence Exit of Murine Hematopoietic Stem Cells and Hematopoietic Recovery Through mTORC1 Potentiation.

Myelotoxic injury, such as chemotherapeutic agents and ionizing radiation, unlocks the vigorous power of hematopoietic stem cells (HSCs) to replenish the hematopoietic system, making quiescent HSCs enter the cell cycle. Considering that both HSC-intrinsic and -extrinsic mechanisms enforce quiescence of HSCs, the drastic change in bone marrow (BM) environment after injury, represented by massive expansion of BM adipocytes, might trigger HSC activation. BM adipocytes, the major cellular component in the ablated marrow, however, reportedly suppress proliferation of hematopoietic cells, which may indicate the BM adipocytogenesis is an irrational response of injured organism. Given that adipose tissue is an endocrine organ with pleiotropic functions, we hypothesized that adipocyte-derived factors, especially adiponectin, an anti-inflammatory adipokine involved in regulation of granulopoiesis, are implicated in HSC activation. Myeloablative intervention increased BM adiponectin by multiple mechanisms, including adipocyte expansion and increased diffusion from the blood. Adiponectin-null (Adipoq -/- ) mice showed delayed hematopoietic recovery after BM injury, with Adipoq-/- HSCs more quiescent and defective in mammalian target of rapamycin complex 1 (mTORC1) activation. Recombinant adiponectin promoted not only HSC activation in vivo but cytokine-induced activation in vitro, and shortened the time for exit from quiescence in an mTORC1-dependent manner. These data illustrate a scarcely-reported example of a cell-extrinsic factor, adiponectin, enhancing quiescence exit of HSCs, and subsequent hematopoietic recovery. Our findings also highlight adipocytes as a source of adiponectin to ensure the proliferative burst of hematopoietic cells in ablated marrow. Stem Cells 2017;35:1835-1848.