Primary Pancreatic Mantle Cell Lymphoma Diagnosed via Endoscopic Ultrasound-Guided Fine-Needle Aspiration.

Primary pancreatic lymphomas (PPLs) are rare, and the histological classification of these tumors is difficult. To accurately diagnose and determine the appropriate treatment for PPLs, sufficient sample amounts are necessary. Here, we report a 73-year-old man with a primary pancreatic mantle cell lymphoma. Histological samples were obtained via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The tumor cells predominantly composed of atypical small to medium round cells, with diffuse immunoreactivity of CD20 and cyclin D1. In addition, immunoglobulin gene H chain rearrangement was detected. The patient underwent chemotherapy, resulting in complete remission. Eight years after the initiation of chemotherapy, the patient was still alive. EUS-FNA could be a useful and safe diagnostic modality for PPLs by providing enough samples for testing.

Bcl-2-negative IGH-BCL2 translocation-negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl-2-positive IGH-BCL2 translocation-positive follicular lymphoma.

AIMS: Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl-2 expression and IGH-BCL2 translocation. The clinicopathological features exhibited by Bcl-2-negative IGH-BCL2 translocation-negative FL of the thyroid (Bcl-2- /IGH-BCL2- tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl-2- /IGH-BCL2- tFL to investigate their epigenetic and genetic aberrations. METHODS AND RESULTS: The immunohistochemical profiles of epigenetic modifiers and the methylation status of histones were examined, including EZH2, MLL2/KMT2D, CBP/CREBBP, EP300, H3K27me3 and H3K4me3, in Bcl-2- /IGH-BCL2- tFL and Bcl-2-positive IGH-BCL2 translocation-positive FL of the thyroid (Bcl-2+ /IGH-BCL2+ tFL). Most Bcl-2- /IGH-BCL2- tFLs retained the positivity of epigenetic modifiers and lower expression of H3K27me3, although Bcl-2+ /IGH-BCL2+ tFLs exhibited aberrant immunohistochemical patterns of EZH2 and CBP/CREBBP and overexpression of H3K27me3. Samples from seven cases were further analysed using targeted sequencing, focusing on the exons of 409 key tumour suppressor genes and oncogenes. Bcl-2- /IGH-BCL2- tFLs do not have pathogenic mutations of epigenetic modifiers, such as EZH2, MLL2/KMT2D, MLL3/KMT2C, EP300 and ARID1A, which have been reported in FLs in the literature, whereas Bcl-2+ /IGH-BCL2+ tFLs are probably pathogenic/pathogenic missense mutations or frameshift mutations of these genes. Additionally, novel mutations in TET2 and EP400 were detected in Bcl-2- /IGH-BCL2- tFLs. CONCLUSIONS: Different genetic and epigenetic abnormalities might be involved in the oncogenesis of Bcl-2- /IGH-BCL2- tFLs from Bcl-2+ /IGH-BCL2+ tFLs and other FLs.

Pretreatment serum soluble interleukin-2 receptor level predicts survival in patients with newly diagnosed follicular lymphoma.

This retrospective, multicenter observational study investigated the prognostic value of pretreatment serum soluble interleukin-2 receptor (sIL-2R) level for outcomes of newly diagnosed follicular lymphoma (FL) grade 1-3a who required treatment at diagnosis. A total of 628 patients were recorded, and 502 of these were eligible for analysis. Patients were divided into four quartiles, based on their serum sIL-2R levels as follows: Q1 (sIL-2R < 520 IU/mL), Q2 (520 ≤ sIL-2R < 1030 IU/mL), Q3 (1030 ≤ sIL-2R < 2530 IU/mL) and Q4 (sIL-2R ≥ 2530 IU/mL). Using a multivariable Cox proportional-hazards model, we showed the adjusted probability of overall survival (OS) decreased with increasing serum sIL-2R levels (p for trend = .007). Similar trends were observed for disease-specific survival (DSS) and progression-free survival (PFS). In conclusion, pretreatment serum sIL-2R levels significantly and dose-dependently associate with worse outcomes (OS, DSS and PFS) of patients with newly diagnosed FL.

Different Immune Reconstitution between Cord Blood and Unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease.

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.

Successful treatment strategy in corporating mogamulizumab and cord blood transplantation in aggressive adult T-cell leukemia-lymphoma: a case report.

Adult T-cell leukemia-lymphoma (ATL) is a rare type of mature T cell lymphoma caused by human T-lymphotropic virus type 1 (HTLV-1) with dismal outcome with conventional chemotherapy. A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be effective for CCR4-positive ATL. However, MOG administration before allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported to be associated with an increased risk of severe acute graft-versus-host disease (aGVHD) after allo-HSCT due to reduction of donor-derived regulatory T cells (Tregs). We herein present a patient with ATL who underwent allo-HSCT after MOG administration without developing severe GVHD while referring to serum MOG concentration. The clinical course of our case suggests that it might be possible to determine the appropriate timing of allo-HSCT with monitoring of residual MOG level while avoiding the detrimental effect of MOG on post-transplant clinical outcome without increasing the risk of relapse/progression.

GVHD prophylaxis by tacrolimus and mini-MTX in single-unit CBT: a single institute experience.

Tacrolimus (TAC) combined with short-term methotrexate (MTX) is widely used to prevent graft-versus-host disease (GVHD) in cord blood transplantation (CBT). As short-term MTX aggravates mucositis and delays engraftment, we reduced the dose of MTX, as previously reported in the non-CBT setting. Here, we retrospectively analyze outcomes of 20 patients who received CBT from April 2017 to December 2018. All patients received TAC with mini-MTX as GVHD prophylaxis. Mini-MTX was administered at a dose of 5 mg/m2 of MTX on days 1, 3 and 6 after CBT. Median age was 54.5 years. Median follow-up time in surviving patients was 396 days. The primary disease was acute leukemia (n = 12) or malignant lymphoma (n = 8). Three patients and 17 patients received myeloablative and reduced-intensity conditioning, respectively. Rate and median time to engraftment of neutrophils were 90.0% and 20.5 days, respectively. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35.0% and 5.0%, respectively. At one year after CBT, the overall survival rate was 80.5%, cumulative incidence of relapse/progression was 15.0%, and non-relapse mortality rate was 5.0%. In conclusion, TAC with mini-MTX may be a promising GVHD prophylaxis regimen in single-unit CBT.

Pure intravascular recurrence of CD5-positive diffuse large B-cell lymphoma primarily arising from the nasal cavities.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) and intravascular large B-cell lymphoma (IVL) are recognized as rare subsets of large B-cell lymphoma with poor prognosis. These two categories have similar clinicopathological features suggesting that they might overlap. CASE PRESENTATION: We present a case of a 72-year-old man with submental tumors. Positron emission tomography/computed tomography (PET/CT) showed tumors in the nasal and paranasal region and multiple submental and jugular swollen lymph nodes with abnormal uptake of 18F-fluorodeoxyglucose (FDG). Histology of biopsy from nasal tumors showed diffuse infiltration of large lymphoid cells, which showed positive expressions for CD20, CD79a, CD5 and negative for CD3 on immunohistochemistry. Thus, a CD5-positive DLBCL was diagnosed. After administration of 8 cycles of R-THPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone), complete remission was achieved. Eight months after the first chemotherapy dose, local recurrence occurred. After salvage chemotherapy, nasal and paranasal tumors and lymph node swelling disappeared on PET/CT images, although the patient suffered from respiratory disturbance. A random skin biopsy revealed IVL, which was consistent with intravascular recurrence of CD5-positive DLBCL. Bone marrow smears showed hemophagocytosis. CONCLUSION: We present a rare case of primary CD5-positive DLBCL that relapsed as pure IVL after chemotherapy. Our case suggests that CD5-positive DLBCL is closely related to IVL.

Sequential Onset of Varicella-Zoster Virus Encephalomeningitis and Progressive Multifocal Leukoencephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Recipient.

Here, we describe a case of sequential varicella-zoster virus encephalomeningitis and progressive multifocal leukoencephalopathy following an allogeneic hematopoietic stem cell transplant procedure. A 37-year-old male patient presented with fever, incomplete paralysis of bilateral legs, and bullous eruptions 8 months after allogeneic transplant. Polymerase chain reaction assays of cerebrospinal fluid samples for varicella-zoster virus were positive. Bullous eruptions and incomplete paralysis of bilateral legs improved after administration of acyclovir. However, higher brain dysfunction was present and getting worse. We detected no herpes simplex virus, varicella-zoster virus, Cytomegalovirus, human herpes virus 6, Epstein-Barr virus, or JC virus in cerebrospinal fluid samples with polymerase chain reaction assays. Pathologic findings and polymerase chain reaction assays with brain biopsy samples revealed that the patient had progressive multifocal leukoencephalopathy. This is the first report of a case showing dual central nervous system infections due to varicella-zoster virus and JC virus after allogeneic stem cell transplant.

Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia.

One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year-old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan.

Changes from imatinib mesylate to second generation tyrosine kinase inhibitors improve renal impairment with imatinib mesylate in chronic myelogenous leukemia.

Understanding adverse events in long-term tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) is important. We investigated changes in renal function during TKI therapy for CML. We retrospectively analyzed levels of serum creatinine (sCrn) and values of estimated glomerular filtration rate (eGFR) from June 2001 to March 2015. Sixty patients initially treated with imatinib were enrolled in this study. Continuous variables of sCrn and eGFR were compared by paired student's t test. Median age or duration of treatment with imatinib was 49 years (range 19-81) or 101 months (range 8-165), respectively. Mean levels of sCrn or mean values of eGFR had increased or decreased 1 year later from start of imatinib throughout observation with statistical significance (p < 0.05), respectively. In 38 patients, the TKI used was changed from imatinib to a second-generation TKI (nilotinib: 32; dasatinib: 6) for various reasons. We observed statistically significant (p < 0.05) amelioration in mean levels of sCrn and values of eGFR after only 1 month following the changes to second-generation TKIs. These results suggest that imatinib has adverse effects on renal function and that changes from imatinib to a second-generation TKI should be considered as a therapeutic option in cases of renal impairment due to imatinib.

Clinical usefulness of WT1 mRNA expression in bone marrow detected by a new WT1 mRNA assay kit for monitoring acute myeloid leukemia: a comparison with expression of WT1 mRNA in peripheral blood.

We have previously shown the clinical usefulness of Wilms' tumor 1 gene (WT1) mRNA expression in peripheral blood (PB) as a minimal residual disease (MRD) monitoring marker in 191 acute myeloid leukemia (AML) patients using the WT1 mRNA assay kit "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "former kit"). In contrast, the usefulness of WT1 mRNA expression in bone marrow (BM) has been investigated in only a limited number of subjects using former kit. Following that previous study, a next-generation kit, WT1 mRNA assay kit II "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "new kit") has been newly developed. In the present study, we aimed to evaluate the performance of the new kit and to investigate the clinical usefulness of WT1 mRNA expression in BM. The PB and BM were collected on the same day from 164 blood disease patients, including 118 AML patients. WT1 mRNA expression was determined using the new and former kits and the values obtained were compared. The performance of new kit was shown to be equivalent to that of former kit. As reported in PB, WT1 mRNA expression in BM was found to be a useful marker for monitoring disease status as well as for a diagnosis of early stage relapse in AML patients.

Comparison of survival of adolescents and young adults with hematologic malignancies in Osaka, Japan.

The survival gap between adolescents and young adults (AYAs) with hematological malignancies persists in many countries. To determine to what extent it does in Japan, we investigated survival and treatment regimens in 211 Japanese AYAs (15-29 years) in the Osaka Cancer Registry diagnosed during 2001-2005 with hematological malignancies, and compared adolescents (15-19 years) with young adults (20-29 years). AYAs with acute lymphoblastic leukemia (ALL) had a poor 5-year survival (44%), particularly young adults (29% vs. 64% in adolescents, p = 0.01). Additional investigation for patients with ALL revealed that only 19% of young adults were treated with pediatric treatment regimens compared with 45% of adolescents (p = 0.05). Our data indicate that we need to focus on young adults with ALL and to consider establishing appropriate cancer care system and guidelines for them in Japan.

Significant improvement following combination treatment with mefloquine and mirtazapine in a patient with progressive multifocal leukoencephalopathy after allogeneic peripheral blood stem cell transplantation.

We report a case of a 40-year-old female who developed progressive multifocal leukoencephalopathy (PML), which is associated with JC virus reactivation, after allogeneic hematopoietic cell transplantation. As she had been suffering from graft-versus-host disease and lung damage after pneumocystis pneumonia, the administration of calcineurin inhibitor and steroid could not be discontinued. However, she showed a favorable improvement in clinical symptoms and imaging findings after treatment with the anti-malarial drug, mefloquine and a serotonin receptor blocker, mirtazapine. Continuation of the treatment for eight months finally led to the clearance of the JC virus from her cerebrospinal fluid. She currently shows no neurological disturbance and has resumed her daily activities. PML due to the severe immunosuppressive condition has been reported as a fatal complication after allo-SCT. Our case suggests that combination treatment with mefloquine and mirtazapine may be of great value for the treatment for PML patients in the post allo-SCT setting, although it is difficult to say whether the combination treatment alone led to improvement. Further clinical study is needed to clarify the efficacy of these drugs for the treatment of PML.

Successful treatment of duodenal myeloid sarcoma with allogeneic bone marrow transplantation and additional radiotherapy.

Myeloid sarcoma (MS) is a tumor consisting of myeloid blasts that occurs at an anatomical site other than the bone marrow. We report the case of a 38-year-old man with duodenal MS who underwent an allogeneic bone marrow transplant in a non-complete remission (CR) state. After the transplant, residual disease was suspected on a fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan, and additional radiotherapy resulted in CR, which has been maintained for 21 months. FDG-PET/CT scanning is useful for evaluating residual myeloid sarcoma during the peritransplant period.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders after allogeneic peripheral blood stem cell transplantation for Hodgkin-like adult T-cell leukemia/lymphoma.

A 56-year-old woman with Hodgkin-like adult T-cell leukemia/lymphoma was treated with allogeneic peripheral blood stem cell transplantation on 17 April 2009. She manifested a moderate fever on day 41. CT scanning and other examinations detected slightly swollen lymph nodes, and pathological findings of right axillary lymph nodes revealed an Epstein-Barr virus-associated post-transplant lymphoproliferative disorder. She was successfully treated with rituximab.

Antifungal activity of micafungin in serum.

We have evaluated the antifungal activity of micafungin in serum by using the disk diffusion method with serum-free and serum-added micafungin standard curves. Serum samples from micafungin-treated patients have been shown to exhibit adequate antifungal activity, which was in proportion to both the applied dose and the actual concentration of micafungin measured by high-performance liquid chromatography. The antifungal activity of micafungin in serum was also confirmed with the broth microdilution method.

Adiponectin binds to chemokines via the globular head and modulates interactions between chemokines and heparan sulfates.

OBJECTIVE: Adiponectin, a fat cell-derived protein, has been attracting considerable attention because of its antidiabetic and antiatherogenic activities. The aim of the present study is to identify molecules physiologically associating with adiponectin and to understand how the protein displays diverse biological activities. MATERIALS AND METHODS: We used an expression cloning method combined with enzyme-linked immunosorbent assay to clone adiponectin-binding proteins from the MS-5 complementary DNA library. RESULTS: We successfully isolated two chemokines, stromal cell-derived factor-1 (SDF-1) and CCF18, and verified that adiponectin bound to them via its globular head. Adiponectin bound with various chemokines in vitro, such as macrophage-inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemoattractant protein-1 (MCP-1), suggesting that the protein had a feature commonly to bind to the chemokine family. The middle part of chemokines, dispensable for interacting with their receptors, was found to be important for the adiponectin binding. Although the interaction of adiponectin to SDF-1 affected neither the SDF-1-CXCR4 binding nor the SDF-1 signaling in Jurkat cells, adiponectin and heparin mutually interfered in their association to SDF-1 and MCP-1 in vitro, implying that their association might influence the distribution of adiponectin and SDF-1 in inflammatory sites. Indeed, both adiponectin and SDF-1 was positively immunostained in vascular walls in guts from acute graft-vs-host disease patients. In addition, peripheral blood of adiponectin-deficient mice contained more hematopoietic progenitors than that of wild-type mice. CONCLUSION: Adiponectin may be involved in regulation of inflammation via binding to specific chemokines. Additionally, the interaction possibly enables adiponectin to gather and play its role in inflammatory sites.

Identification of amino-terminal region of adiponectin as a physiologically functional domain.

Adiponectin is an abundant adipose-specific protein, which acts as an anti-diabetic, anti-atherogenic, and anti-inflammatory adipokine. Although recent advances in the field of adiponectin have been made by the identification of adiponectin receptors and by the understanding about relationship between its multimerization and functions, detailed molecular background remains unclear. Our established anti-human adiponectin antibodies, ANOC 9103 and ANOC 9104, blocked some adiponectin functions such as the growth inhibition of B-lymphocytes on stromal cells and the inhibition of acetylated LDL uptake in macrophages, suggesting that they may recognize important functional regions of adiponectin. As a result of epitope mapping based on the ability to bind to the deleted adiponectin mutants, we identified that these antibodies recognize amino-terminal region of adiponectin before the beginning of the collagen-like domain. Notably, a peptide fragment (DQETTTQGPGVLLPLPKGACTGWMA) corresponding to amino acid residues 17-41 of human adiponectin could bind to restricted types of cells and block adiponectin-induced cyclooxygenase-2 gene expression and prostaglandin E2 production in MS-5 stromal cells. Moreover, the deletion of its amino-terminal region reduced the abilities to inhibit not only collagen-induced platelet aggregation but also diet-induced hepatic steatosis. These data indicate that amino-terminal region of adiponectin is a physiologically functional domain and that a novel receptor, which recognizes amino-terminal region of adiponectin, may exist on some types of cells. Further investigations will contribute to the understanding of molecular mechanisms about adiponectin functions as well as to the designing of novel strategies for the treatment of patients with insulin-resistance, vascular dysfunction, and chronic inflammation.

Differential effects of a novel IFN-zeta/limitin and IFN-alpha on signals for Daxx induction and Crk phosphorylation that couple with growth control of megakaryocytes.

OBJECTIVE: Although a novel IFN-zeta/limitin uses IFN-alpha/beta receptor, it lacks some common activities of type I IFNs. We compared effects on megakaryocyte proliferation and differentiation as well as signals for their biological activities. MATERIALS AND METHODS: Recombinant IFN-zeta/limitin and IFN-alpha titrated with a cytopathic effect dye binding assay, were used in this study. Colony assays and serum-free suspension cultures for megakaryocytes were performed to compare their growth inhibitory effects. To analyze signals, megakaryocytes cultured in serum-free suspension cultures were stimulated and Western blotted with the indicated antibody. RESULTS: Both IFN-zeta/limitin and IFN-alpha suppressed the proliferation of megakaryocyte progenitors without influencing their differentiation. However, much higher concentrations of IFN-zeta/limitin were required for the growth inhibition than IFN-alpha. The growth inhibition by IFN-zeta/limitin and IFN-alpha was significantly reduced when either Tyk2 or STAT1 was disrupted. In addition, the antisense oligonucleotides against Crk and Daxx, downstream molecules of Tyk2, greatly rescued the IFN-zeta/limitin- and IFN-alpha-induced reduction of megakaryocyte colony numbers. In cultured megakaryocytes, IFN-zeta/limitin induced the expression of SOCS-1 as strongly as IFN-alpha. However, IFN-zeta/limitin induced weaker phosphorylation of Crk and lower induction of Daxx than IFN-alpha. CONCLUSIONS: Weaker signals for Crk and Daxx may participate in less megakaryocyte suppressive activity of IFN-zeta/limitin and may distinguish IFN-zeta/limitin from IFN-alpha in megakaryocytes. Our results extend the understanding about thrombocytopenia in patients with IFN-alpha treatment as well as the possibility for the clinical application of human homologue of IFN-zeta/limitin or an engineered cytokine with useful features of the IFN-zeta/limitin structure.