Aortitis after switching short-acting granulocyte colony-stimulating factors in a lymphoma patient with HLA-B52.

Aortitis is a rare adverse event of granulocyte colony-stimulating factor (G-CSF) treatment. Several previous studies have described recurrent aortitis caused by re-administration of the same G-CSF. However, no previous studies have examined the safety of switching between short-acting G-CSFs in patients who develop aortitis. We report the case of a 55-year-old man with refractory diffuse large B-cell lymphoma, who developed G-CSF-associated aortitis. The aortitis was triggered by filgrastim and recurred after treatment with lenograstim. The patient possessed human leukocyte antigen B52, which has been implicated in Takayasu arteritis. In addition, a drug-induced lymphocyte stimulation test for lenograstim performed upon detection of recurrent G-CSF-associated aortitis produced a positive result. Our case suggests that switching from one short-acting G-CSF to another does not prevent recurrence of G-CSF-associated aortitis. Although the etiology of G-CSF-associated aortitis has not been fully elucidated, our case also suggests that some patients may be genetically predisposed to aortitis.

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report.

Patients with acute myeloid leukemia (AML) who have comorbidities have limited treatment options, thereby resulting in poor prognosis. Venetoclax, a specific B-cell lymphoma-2 inhibitor, has recently been approved for AML in combination with hypomethylating agents; however, only one report has described its use in patients undergoing dialysis. Herein, we report the effectiveness of combined venetoclax and azacitidine in a 73-year-old man with AML undergoing dialysis and who was ineligible for standard therapies. The safety of venetoclax and azacitidine in patients undergoing dialysis has been reported, and their combination may be a feasible option for patients with AML undergoing dialysis.

A Patient with Kabuki Syndrome Mutation Presenting with Very Severe Aplastic Anemia.

Kabuki syndrome (KS) is a rare congenital disorder commonly complicated by humoral immunodeficiency. Patients with KS present with mutation in the histone-lysine N-methyltransferase 2D (KMT2D) gene. Although various KMT2D mutations are often identified in lymphoma and leukemia, those encountered in aplastic anemia (AA) are limited. Herein, we present the case of a 45-year-old Japanese man who developed severe pancytopenia and hypogammaglobulinemia. He did not present with any evident malformations, intellectual disability, or detectable levels of autoantibodies. However, B-cell development was impaired. Therefore, a diagnosis of very severe AA due to a hypoplastic marrow, which did not respond to granulocyte colony-stimulating factor, was made. The patient received umbilical cord blood transplantation but died from a Pseudomonas infection before neutrophil engraftment. Trio whole-exome sequencing revealed a novel missense heterozygous mutation c.15959G >A (p.R5320H) in exon 50 of the KMT2D gene. Moreover, Sanger sequencing of peripheral blood and bone marrow mononuclear cells and a skin biopsy specimen obtained from this patient identified this heterozygous mutation, suggesting that de novo mutation associated with KS occurred in the early embryonic development. Our case showed a novel association between KS mutation and adult-onset AA.

[Refractory ascites developing in late-phase of cord blood transplantation improving with CART].

We managed a patient with acute myeloid leukemia (AML) who showed refractory ascites that developed in late-phase cord blood transplantation (CBT). The ascites obverted 5 months after CBT. The liver was atrophic, and serum hyaluronic acid was elevated at the onset, suggesting fibrotic changes in the liver. The ascites were transiently improved by cell-free and concentrated ascites reinfusion therapy (CART) and corticosteroid administration; however, the patient died from anasarca and recurrent AML 378 d after CBT. The etiology of the ascites is not well understood; therefore, additional studies on similar patients should be explored for proper management.

Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models.

Corticotropin-releasing factor (CRF) is a hormone secreted by the hypothalamus in response to stress, and CRF antagonists may be effective for the treatment of stress-related disorders including major depressive and anxiety disorders. Here, we investigated the in vivo pharmacological profile of N-cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508), a recently synthesized, orally active CRF1 receptor antagonist. Oral administration of a single dose of E2508 (3 or 10mg/kg), but not fluoxetine (30mg/kg), a selective serotonin reuptake inhibitor (SSRI), significantly shortened immobility time in rats in the forced swim test. E2508 (10, 30, or 100mg/kg) also showed an antidepressant-like effect in the forced swim test in mice, with no sedative or muscle relaxant effects for doses up to 100mg/kg. Moreover, E2508 (5 or 20mg/kg) significantly reduced anxiety-like behavior in the rat defensive burying test. Diazepam, a benzodiazepine anxiolytic agent, also showed an anxiolytic effect in the defensive burying test at the same dose that induced a muscle relaxant effect in mice. Administration of E2508 (30mg/kg) for 14 consecutive days did not affect sexual behavior. By contrast, fluoxetine (30mg/kg) administration for ≥7 consecutive days decreased sexual behavior. These results indicate that E2508 has both potent antidepressant-like and anxiolytic-like effects in rodent models, and is well tolerated compared with a commonly prescribed therapeutic SSRI or benzodiazepine.

Effect of Bosentan on systemic sclerosis-associated interstitial lung disease ineligible for cyclophosphamide therapy: a prospective open-label study.

OBJECTIVE: To evaluate the clinical benefits of the endothelin receptor antagonist bosentan on interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) who are ineligible for cyclophosphamide (CYC) therapy. METHODS: In this prospective open-label study, 9 patients with SSc and ILD received bosentan for 24 months. The main reasons for avoiding CYC included severely impaired lung function, long disease duration, and relapse after CYC treatment. Pulmonary function tests and Doppler echocardiograms were evaluated every 6 months, and high-resolution computed tomography (HRCT) was performed every 12 months. For an extended survival analysis, 17 historical controls who met the inclusion criteria at referral and had not used any immunosuppressive or antifibrotic agents thereafter were selected from the SSc database. RESULTS: Two patients did not finish the study; one developed vasculitis requiring high-dose corticosteroids and another died of bacterial pneumonia. The remaining 7 patients tolerated bosentan and completed the study period. There were trends toward mildly reduced forced vital capacity, total lung capacity, and diffusing capacity for carbon monoxide over time. Two patients developed pulmonary hypertension during the 24-month period. HRCT scores for ground-glass opacity, pulmonary fibrosis, and honeycomb cysts gradually increased. In the extended study, there was no difference in cumulative survival rate between the bosentan-treated and historical control groups. CONCLUSION: The gradual worsening of pulmonary function and HRCT findings in patients treated with bosentan was consistent with the natural course of SSc-associated ILD. This study does not support the use of bosentan for SSc-associated ILD even when CYC treatment is inadvisable.

Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension.

Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Recent accumulating evidence indicates a pathologic role for IL-6 in promoting proliferation of both smooth muscle and endothelial cells in the pulmonary arterioles, resulting in development of pulmonary arterial hypertension (PAH). Here, we describe a patient with mixed connective tissue disease and severe, refractory PAH. Her functional activity and hemodynamic parameters dramatically responded to tocilizumab, a humanized monoclonal antibody to human IL-6 receptor, which was aimed at treating multicentric Castleman's disease. It appears that IL-6 blockade may hold promise as an adjunct drug in treatment of PAH in idiopathic form as well as in association with connective tissue disease.