Central Nervous System Peripheral T Cell Lymphoma Manifesting as Lymphomatosis Cerebri That Was Misdiagnosed as Neuro-Behçet’s Disease: A Case Report

Background: Lymphomatosis cerebri (LC) is a unique form of primary central nerves lymphoma (PCNSL), which presents as diffuse infiltration of lymphoma cells characteristically in the white matter rather than tumor formation. However, the involvement of central nervous system (CNS) is unclear because of the lack of contrast enhancement. Case Presentation: We treated a 53-year-old woman with LC and brain lesions resembling neuro-Behcet’s disease. She had a past history of acute uveitis and current symptoms of somnolence and gait disturbances progressing for one month. Cranial magnetic resonance imaging (MRI) revealed high signal lesions in the brain stem. Based on her past history and present clinical findings, she was clinically diagnosed with neuro-Behcet’s disease, which was treated with 1 g of methylprednisolone (mPSL) pulse therapy. Repeated mPSL pulse therapy resulted in a minor response, but the cerebral lesions persisted. After a short remission of several months, signal changes of the brain stem lesion recurred and her consciousness level worsened at 4 months after diagnosis. Upon admission to our hospital, positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography revealed abnormal uptake in the systemic lymph nodes (LNs), including the bilateral inguinal LNs. A diagnosis based on a biopsy of the left inguinal LNs was primary central nervous system lymphoma with inguinal LN lesions, manifesting as LC from malignant peripheral T cell lymphoma, not otherwise specified. Four courses of high-dose methotrexate (3.5 g/m2) therapy lead to temporary recovery of consciousness, but there was no improvement in other neurological findings. All nodal lesions tentatively regressed. Serum soluble interleukin-2 receptor (sIL-2R) (normal range: 121–613 U/mL) was constitutively decreased from 8,520 U/mL before chemotherapy to 740 U/mL after chemotherapy. We observed cerebral micro-bleeds in the center of LC lesions during chemotherapy, but no surgical intervention was required. Two months later, LC recurred in the brain, which was fatal. Conclusions: Neuro-Behçet’s disease is difficult to distinguish from LC when other clinical findings, including human leukocyte antigen disparity, serum sIL-2R, or cerebrospinal IL-6, are lacking. LC should be differentiated from CNS lymphoma before corticosteroid therapy

Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma

Background: Human multiple myeloma (MM) is an incurable hematological malignancy for which novel therapeutic agents are needed. Calmodulin (CaM) antagonists have been reported to induce apoptosis and inhibit tumor cell invasion and metastasis in various tumor models. However, the antitumor effects of CaM antagonists on MM are poorly understood. In this study, we investigated the antitumor effects of naphthalenesulfonamide derivative selective CaM antagonists W-7 and W-13 on MM cell lines both in vitro and in vivo.Methods: The proliferative ability was analyzed by the WST-8 assay. Cell cycle was evaluated by flow cytometry after staining of cells with PI. Apoptosis was quantified by flow cytometry after double-staining of cells by Annexin-V/PI. Molecular changes of cell cycle and apoptosis were determined by Western blot. Intracellular calcium levels and mitochondrial membrane potentials were determined using Fluo-4/AM dye and JC-10 dye, respectively. Moreover, we examined the in vivo anti-MM effects of CaM antagonists using a murine xenograft model of the human MM cell line.Results: Treatment with W-7 and W-13 resulted in the dose-dependent inhibition of cell proliferation in various MM cell lines. W-7 and W-13 induced G1 phase cell cycle arrest by downregulating cyclins and upregulating p21cip1. In addition, W-7 and W-13 induced apoptosis via caspase activation; this occurred partly through the elevation of intracellular calcium levels and mitochondrial membrane potential depolarization and through inhibition of the STAT3 phosphorylation and subsequent downregulation of Mcl-1 protein. In tumor xenograft mouse models, tumor growth rates in CaM antagonist-treated groups were significantly reduced compared with those in the vehicle-treated groups.Conclusions: Our results demonstrate that CaM antagonists induce cell cycle arrest, induce apoptosis via caspase activation, and inhibit tumor growth in a murine MM model and raise the possibility that inhibition of CaM might be a useful therapeutic strategy for the treatment of MM

Graft-versus-host diseases characterized by effusion: A case of steroid-refractory graft-versus-host disease

Background: Although the biology of steroid-refractory acute GVHD is still unknown, the pathogenesis of steroid-refractory acute GVHD is recognized to be associated with aberrant cytokine milieu. Case presentation: We treated a 41-year-old Japanese male representing a characteristic clinical manifestation among unspecific cases of heterogeneous steroid-refractory acute GVHD. The patient underwent allogeneic bone marrow transplantation due to relapsed neurolymphomatosis. He achieved neutrophil engraftment on day 21 with mild engraftment fever. Acute GVHD occurred on day 56 after transplantation with systemic skin eruptions and precedent body weight gain. Corneal ulceration and gut GVHD symptoms followed the skin lesions sequentially. A biopsy of skin and gut mucosa revealed pathological GVHD. We recognized that the patient presented anasarca symptoms due to acute GVHD. We treated the patient with 1.0 mg/kg corticosteroids (prednisolone) starting on day 68, but his edema worsened. He did not respond to 2.0 mg/kg prednisolone from day 80. He required artificial ventilation on day 80 due to the bilateral massive pleural effusion and died of respiratory failure on day 99 after transplantation. A measurement of serum cytokines before corticosteroid therapy, IL-6 (61.5 pg/mL; normal range: <4.0), VEGF (51 pg/mL; <38.3), IFNγ (0.2 IU/mL; <0.1), and TNF-α (10.5 pg/mL; 0.6–2.8) were elevated. Th2 cytokines, IL-4 (7.2 pg/mL; <6.0) and IL-10 (6.0 pg/mL; <5.0) were also elevated. Conclusions: Our case was prominently characterized by anasarca manifested as follows: systemic edema, massive ascites and pleural effusion. We speculated that acute/chronic GVHD with anasarca has an immunological propensity for proinflammatory and the Th2 cytokine milieu. We advocate that immunological modification by biologic agents such as tocilizumab would be promising theoretically for the treatment of such type of GVHD. Keywords: Graft-versus-host disease, Corticosteroid, Anasarc

Complete mimicry: a case of alveolar rhabdomyosarcoma masquerading as acute leukemia

Abstract Background A small number of rhabdomyosarcoma (RMS) cases involve the bone marrow. A leukemic presentation of RMS has been reported in a few case series, although almost all cases of leukemic RMS are not completely mimicking leukemia. We encountered a case with RMS cell infiltration of the bone marrow that resembled floating hematological cells. Case presentation We encountered a rare case of a 15-year-old boy with a 2-week history of left femoral pain. Upon admission, he was afebrile with no other symptoms. No apparent cause of femoral pain was detected on an initial examination. Laboratory findings revealed normal white blood cell (WBC) count and hemoglobin concentration, with a platelet count of 10.3 × 104/μL. WBCs included 2.0% metamyelocytes, 4.5% myelocytes, and 0.5% blasts. Lactate dehydrogenase concentration was 1299 U/L, creatine kinase was 437 U/L, and C-reactive protein was 1.25 mg/dL. Bone marrow aspiration demonstrated hypercellular marrow (nucleated cell count 1.84 × 104/μL) and 89.0% of blast-like cells of all nucleated cells. The proliferating cells were negative for myeloperoxidase and esterase, and strongly positive for CD56. Positron emission tomography exhibited extensive accumulation of 18F–fludeoxyglucose with a SUVmax of 7.09. Magnetic resonance imaging revealed T1-low intensity, gadolinium-enhanced, diffuse, and irregular lesions on his pelvis and bilateral femurs. These laboratory and imaging findings suggested hematological malignancy with diffuse bone involvement, suggestive of acute leukemia. However, the pathological diagnosis of bone marrow and basal penile muscle biopsy was alveolar RMS. Karyotype analysis of bone marrow cells revealed the characteristic translocation of t(2;13)(q35;q14). The final diagnosis was alveolar RMS with massive involvement of the bone marrow and the primary site in the perineal muscles. The tumor cells both of the primary site and bone marrow were positive for myogenin. Conclusions A literature review found a misdiagnosed case of completely mimicking leukemic RMS as natural-killer (NK)-cell leukemia. Such a misdiagnosis can have critical consequences. We experienced a rare case of alveolar RMS with symmetrical diffuse bone marrow involvement completely masquerading as acute leukemia. The results of a surface marker study showing that the tumor cells had a near NK-cell phenotype were misleading