Sawako Nakachi

Effects of hippuristanol, an inhibitor of eIF4A, on adult T-cell leukemia

We evaluated the anti-adult T-cell leukemia (ATL) effects of hippuristanol, an eukaryotic translation initiation inhibitor from the coral Isis hippuris. Hippuristanol inhibited proliferation of HTLV-1-infected T-cell lines and ATL cells, but not normal peripheral blood mononuclear cells. It induced cell cycle arrest during G₁ phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and induced apoptosis by reducing the expression of Bcl-x(L), c-IAP2, XIAP and c-FLIP. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Hippuristanol also suppressed IkappaBalpha phosphorylation and depleted IKKalpha, IKKgamma, JunB and JunD, resulting in inactivation of NF-kappaB and AP-1. It also suppressed carbonic anhydrase type II expression. In addition to its in vitro effects, hippuristanol suppressed tumor growth in mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells. These preclinical data suggest that hippuristanol could be a potentially useful therapeutic agent for patients with ATL.

Development of a modified prognostic index for patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation

Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia-lymphoma in order to construct a new, large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor levels (> 5,000 U/mL), high adjusted calcium levels (≥ 12 mg/dL), and high C-reactive protein levels (≥ 2.5 mg/dL) were independent adverse prognostic factors used in the training set. We used these five variables to divide patients into three risk groups. In the validation set, median overall survival for the low-, intermediate-, and high-risk groups was 626 days, 322 days, and 197 days, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a promising new risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy.

Overexpression of caveolin-1 in adult T-cell leukemia

Caveolin-1 is implicated in the regulation of signal pathways. Adult T-cell leukemia (ATL) is a T-cell malignancy causatively associated with human T-cell leukemia virus type 1 (HTLV-1). To determine the role of caveolin-1 in leukemogenesis, we examined caveolin-1 expression levels in HTLV-1-infected T-cell lines and ATL cells. These cells expressed high levels of caveolin-1 compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Caveolin-1-positive ATL cells were detected in ATL lymph nodes and skin lesions, and caveolin-1 was also detected in the plasma of patients with ATL. Infection of a human T-cell line, an epithelial cell line, and normal PBMCs with HTLV-1 induced caveolin-1 expression. The viral protein Tax transcriptionally activated caveolin-1 gene through nuclear factor-kappaB and cAMP response element binding protein signal pathways. HTLV-1-infected T-cell lines, and ATL cells are known to be resistant to transforming growth factor beta (TGF-beta)-induced growth inhibition. Caveolin-1 was colocalized with TGF-beta type I receptor in HTLV-1-infected T-cell lines and suppressed TGF-beta signaling. Caveolin-1 knockdown in an HTLV-1-infected T-cell line exhibited susceptibility to TGF-beta. Thus, we describe a new function for Tax, repression of TGF-beta signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis.

Recurrence of Psoriasis Vulgaris Accompanied by Treatment with C-C Chemokine Receptor Type 4 (CCR4) Antibody (Mogamulizumab) Therapies in a Patient with Adult T cell Leukemia/ Lymphoma: Insight into Autoinflammatory Diseases

Adult T cell leukemia / lymphoma (ATL) is one of the most aggressive hematological malignancies caused by human T-lymphotropic virus type-I (HTLV-1). Mogamulizumab is a new defucosylated humanized monoclonal antibody agent which targets C-C chemokine receptor type 4 (CCR4) expressed occasionally on the surface of ATL cells. However, adverse events such as drug eruptions have also been highlighted, at least in part, via the dysfunction of regulatory T cells (Tregs). We herein report a pronounced recurrence of systemic psoriasis vulgaris accompanied by the treatment of mogamulizumab in a patient with ATL. Pathological examinations may suggest a mechanistic link between the recurrence of autoinflammatory diseases and anti-CCR4 antibody therapies.

Fatal pneumonia and viremia due to human parainfluenza virus type 1 in a patient with adult T-cell leukemia–lymphoma treated with mogamulizumab

Abstract We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia–lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram-negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy-induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV-1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab.

The clinical and phylogenetic investigation for a nosocomial outbreak of respiratory syncytial virus infection in an adult hemato-oncology unit

Although many reports have already shown RSV outbreaks among hemato‐oncology patients, genomic studies detecting similar RSV strains prior to an outbreak in the hospital are rare. In 2014, the University of the Ryukyus hospital hemato‐oncology unit experienced, and successfully managed, a respiratory syncytial virus (RSV) nosocomial outbreak. During the outbreak investigation, genotyping and phylogenetic analysis was used to identify a potential source for the outbreak. Nasopharyngeal swabs were tested for RSV using three tests: (1) rapid antigen test (RAT); (2) reverse transcriptase polymerase chain reaction (PCR); or (3) quantitative PCR (RT‐qPCR); a positive PCR reaction was considered a confirmed case of RSV. Phylogenetic analysis of the G protein was performed for outbreak and reference samples from non‐outbreak periods of the same year. In total, 12 confirmed cases were identified, including 8 hemato‐oncology patients. Patient samples were collected weekly, until all confirmed RSV cases returned RSV negative test results. Median time of suspected viral shedding was 16 days (n = 5, range: 8‐37 days). Sensitivity and specificity of the RAT compared with RT‐qPCR were 30% and 91% (n = 42). Phylogenetic analysis revealed nine genetically identical strains; eight occurring during the outbreak time period and one strain was detected 1 month prior. A genetically similar RSV detected 1 month before is considered one potential source of this outbreak. As such, healthcare providers should always enforce standard precautions, especially in the hemato‐oncology unit.

Clinical usefulness of FDG–PET/CT for the evaluation of various types of adult T-cell leukemia

ABSTRACT Purpose: The aim was to explore undefined useful indices for clinically grading adult T-cell leukemia (ATL) using [18F] 2-fluoro-2-deoxyglucose (FDG) – positron emission tomography/computed tomography (PET/CT). Methods: A total of 28 patients with ATL (indolent, 9; aggressive, 19) were enrolled; all patients with aggressive ATL underwent FDG–PET/CT before chemotherapy. Patients with indolent ATL underwent FDG–PET/CT at the time of suspected disease progression and/or transformation; some received lymph node biopsy. The quantitative parameters maximum standardized uptake values (SUVmax), and mean and peak SUV, metabolic tumor volume (MTV), and volume-based total lesion glycolysis were calculated with the margin threshold as 25%, and 50% of the SUVmax for all lesions. Results: All parameters except for MTV-25% showed significant differences (P ≤ 0.05) in differentiating the aggressive type from the indolent type of ATL. Areas under the curve for receiver-operating characteristic (ROC) analysis regarding the series of parameters investigated ranged from 0.75 to 0.92; this indicated relatively high accuracy in distinguishing the aggressive type from the indolent type. No malignant findings were detected in lymph node biopsies in indolent ATL patients with lymphadenopathy. Discussion: We performed evaluation of a line of parameters of FDG–PET, thereby demonstrating their significantly high accuracy for grading malignancy in ATL patients. In particular, low accumulation of FDG in indolent ATL patients with lymphadenopathy might predict that it is not a sign of disease transformation, but rather a reactive manifestation. Conclusion: FDG–PET/CT findings could be useful for clinically grading ATL. GRAPHICAL ABSTRACT

The intractable intra-abdominal hemorrhage with unknown etiology in a patient with severe hemophilia A.

Severe hemophilia patients are more likely to be complicated by intra-articular hemorrhage, subcutaneous hemorrhage, and intra-mascular hemorrhage. Spontaneous intra-abdominal hemorrhage is a rare fatal disease, which is an arterial bleeding of uncertain causes from vessel feeding arteries. In case the spontaneous intra-abdominal hemorrhage is complicated to severe hemophilia patients, the mortality rate increases considerably. We experienced a patient with severe hemophilia A, who made a full recovery from spontaneous intra-abdominal hemorrhagic shock by replacement therapy of coagulation factor VII, a noninvasive procedure.

Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study

There is controversy as to whether hyperuricemia is an independent risk factor for cardiometabolic diseases. The serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. In contrast, evidence has accumulated that locally‐ and systemically‐activated xanthine oxidase (XO), a rate‐limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus and metabolic syndrome (MetS).

Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T-cell leukemia/lymphoma

Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL.