Development of diffuse large B-cell lymphoma from duodenal type follicular lymphoma: a retrospective study of 23 cases.

The incidence and clinical characteristics of histological transformation (HT) from duodenal type follicular lymphoma (DFL) are unclear. A retrospective analysis was conducted to identify the incidence and clinical features of HT from DFL in 23 cases with DFL. The median follow-up duration was 4.6 years (range, 0.8-20 years). HT to diffuse large B-cell lymphoma was observed in 2 of 23 cases during follow-up (8.7%). One of two cases transformed at 21 months later with increased serum lactate dehydrogenase (LDH; 1655 U/L) and abdominal lymphadenopathy. Partial response was achieved after R-THP (pirarubicin)-COP therapy, but the disease progressed. The other case transformed at 8.3 years with an increase of serum LDH (4022 U/L), abdominal lymphadenopathy, and bone marrow involvement. The disease was refractory to DA-EPOCH-R and a high-dose methotrexate/cytarabine regimen. The patient received allogenic peripheral blood stem cell transplantation and finally achieved complete response. Both cases developed HT at nodal or other intestinal lesions with no progression of the primary duodenal lesion. No significant factors for the occurrence of HT were identified. Although the incidence is low, HT could occur in DFL with aggressive clinical manifestations.

Prognostic implications of TdT expression in acute myeloid leukemia with an intermediate-risk karyotype.

Terminal deoxynucleotidyl transferase (TdT) is expressed on precursor lymphoblastic neoplasms and some acute myeloid leukemia (AML) cells. The clinical impact of TdT expression on AML outcomes remains unclear. Here, we conducted a retrospective analysis to identify prognostic implications of TdT expression in AML with an intermediate-risk karyotype. Forty-eight cases of intermediate-risk AML were enrolled. TdT positivity was defined as expression on ≥ 10% of the gated cells. Of 48 cases, 12 (25%) were positive for TdT [median expression rate of TdT 0.9% (range 0-86.9%)]. No significant differences in patient characteristics or complete remission rate were observed between TdT-positive and TdT-negative cases. The probability of overall survival (OS) and event-free survival (EFS) at 1 year was not significantly different between TdT-positive and TdT-negative cases (OS: 58.3% vs. 65.2%, p = 0.32; EFS: 33.3% vs. 57.1%, p = 0.06). Relapse-free survival (RFS) probability at 1 year was significantly lower for TdT-positive than TdT-negative cases (10% vs. 71.3%, p = 0.002). Multivariate analyses revealed that TdT positivity was an independent significant adverse factor for RFS [hazard ratio: 3.309, 95% confidence interval: 1.334-8.209, p = 0.009]. Our results suggest that TdT expression is associated with increased risk of relapse in patients with intermediate-risk AML.

[Concurrent subcutaneous panniculitis-like T-cell lymphoma and myelodysplastic syndrome with fibrosis].

A 66-year-old male presented with fever and erythema at our hospital, and leukoerythroblastosis, anemia, thrombocytopenia, and multiple low-density lesions in the moderately enlarged spleen were detected. Skin tissue revealed CD8+ T cells with the expression of cytotoxic molecule markers involving fat lobules, and subcutaneous panniculitis T-cell lymphoma (SPTCL) was diagnosed. The bone marrow displayed no infiltration of lymphoid tumor cells, but hyperplasia of granulocytes and megakaryocytes with grade 2 stromal fibrosis. In addition, the bone marrow exhibited diffuse 18F-fluorodeoxyglucose (FDG) accumulation on FDG positron-emission tomography/computed tomography (FDG-PET/CT). Although chemotherapy improved SPTCL, the patient died from leukocytosis with leukoerythroblastosis. We obtained negative results for the JAK2 V617F mutation, and CD34+ cells were elevated in the bone marrow compared with the levels at initial examination. The final diagnosis was concurrent myelodysplastic syndrome (MDS) with fibrosis and SPTCL. This report highlights that it is essential to consider MDS or other myeloproliferative neoplasms (MPN) as possible complications when malignant lymphoma complicates myelofibrosis in the absence of bone marrow infiltration of lymphoma cells. Perhaps, the assessment of clonal markers of MPN and FDG accumulation patterns in the bone marrow by FDG-PET/CT could enable differentiation.

[Ibrutinib therapy for a blastoid variant mantle cell lymphoma patient with early extranodal relapse after autologous stem cell transplantation].

A 65-year-old man with multiple lymphadenopathy presented to our hospital and was diagnosed with StageIVA blastoid-variant mantle cell lymphoma (MCL), with a Ki-67 index of 93%. Partial response was achieved after four courses of CHASER (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab) chemotherapy, and complete response was achieved after autologous stem cell transplantation (ASCT). Six months after ASCT, the MCL relapsed with occurrence of tumors one on the left upper arm and one in the cerebrum, which were proved to be resistant to the conventional chemotherapy and progressed rapidly. These tumors disappeared with scarring following the local irradiation (45 Gy). However, the unirradiated regions became enlarged. The bulky abdominal lesion was treated with local irradiation (41 Gy) combined with 560 mg of ibrutinib but still resulted in progressive disease 1 month after initiating the ibrutinib treatment. Finally, the patient died 5 months post-relapse. The prognosis of patients with blastoid-variant MCL with high Ki-67 index is extremely poor. Furthermore, the risk of central nervous system (CNS) involvement is very high. Therefore, ibrutinib maintenance therapy post ASCT might be a treatment option to prevent CNS involvement. Further efforts might be needed to improve the outcomes of blastoid-variant MCL with a high Ki-67 index.

[Successful treatment of myelodysplastic syndrome-associated autoinflammatory lymphedema with azacytidine].

An 84-year-old woman presented pancytopenia. She was diagnosed with myelodysplastic syndromes (MDS) with excess blasts-1, however, she declined treatment with azacitidine (AZA). Ten months later, bilaterally symmetrical, non-pitting edema appeared on the lower legs. A skin biopsy of the lower leg revealed lymphedema. The appearance and location of the lymphedema suggested an immunologic etiology; however, tests for autoimmune diseases yielded negative results. Therefore, a relationship between MDS and lymphedema was, therefore, speculated. Consequently, treatment with AZA was started, which led to marked improvement in both the lymphedema and pancytopenia. Based on the skin tissue pathology and the improvement in MDS after treatment with AZA, MDS-related autoinflammatory lymphedema was diagnosed.

[Successful diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein using MYD88 L265P mutation analysis].

A 76-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. M protein of the immunoglobulin G (IgG) type was detected using immunoelectrophoresis. A bone marrow biopsy revealed infiltration of small mature lymphocytes, lymphoplasmacytoid cells with Dutcher bodies, grape cells, and Russell bodies. The MYD88 L265P mutation was detected in the abnormal peripheral lymphocytes, and a diagnosis of lymphoplasmacytoid lymphoma was established. MYD88 L265P mutation analysis is useful for making a diagnosis of non-IgM lymphoplasmacytoid lymphoma because it enables the differentiation from other low-grade B-cell malignancies.

Cancer-associated retinopathy after surgery for breast cancer: a case report and review of the literature.

We herein report a 50-year-old Japanese woman with breast cancer who complained of blurred vision and central scotoma in her left eye on the 12th day after surgery. Subsequently, the sudden-onset binocular visual disorder progressed, and she was diagnosed with cancer-associated retinopathy (CAR) based on the clinical findings. Although her visual acuity temporarily improved following the start of adjuvant chemotherapy, reductions in her visual acuity progressed once again. After two courses of steroid pulse therapy initiated from the 59th day following the onset of CAR, although her visual field was still constricted, her binocular visual acuity improved from finger movement to 0.8 2 months later. The shorter the period from onset to treatment, the better the prognosis of the visual function. However, a diagnosis is often delayed because the incidence of this disease is very rare. Therefore, it is important to suspect CAR whenever a sudden visual disorder develops in cancer patients. Furthermore, treatment is believed to be effective even if steroid therapy is started up to 2 months from onset.

Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate.

Lanthanum carbonate (LaC) is used to prevent hyperphosphatemia in dialysis patients. It is commonly believed that there is little LaC absorption from the intestines. However, La deposition in the gastric mucosa, which we coined "gastric lanthanosis", was recently reported. We describe here the clinicopathological features of and a possible mechanism for gastric lanthanosis. This study included 23 patients with definite gastric lanthanosis. We extracted characteristic clinicopathological features of gastric lanthanosis by computed tomography (CT) imaging and endoscopic, histologic, electron-microscopic, and element analysis examinations. The Helicobacter pylori infection rate in the lanthanosis group was much lower than that among the general population. The clinicopathological features characteristic of gastric lanthanosis were mucosal high-density linear appearance by CT, reflective bright-white spots (BWS) by gastroscopy, eosinophilic histiocytes occasionally phagocytizing foreign materials by histology, and numerous electron-dense particles in the histiocytes. The particles had burr-like skeletons resembling La crystals. Gastric lanthanosis is an under-reported, but not a rare lesion. It is characterized by endoscopic BWS and histologic eosinophilic histiocytes in dialysis patients treated with LaC. The proposed mechanism for gastric lanthanosis is that LaC is dissolved by gastric juice, crystallized within the mucosa and is phagocytized by histiocytes.

Chronic Myopathy Associated With Anti-Signal Recognition Particle Antibodies Can Be Misdiagnosed As Facioscapulohumeral Muscular Dystrophy.

OBJECTIVES: To report cases of chronic autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (anti-SRP myopathy) initially misdiagnosed as muscular dystrophy, in particular, facioscapulohumeral muscular dystrophy (FSHD). METHODS: Medical records of patients with anti-SRP myopathy in our institution were retrospectively reviewed. RESULTS: All 6 patients were initially diagnosed with muscular dystrophy because of the long-term clinical course and lack of inflammation on biopsy; 5 were diagnosed with FSHD based on a winged scapula. However, the following features suggested an alternative diagnosis, leading to anti-SRP antibody measurement: (1) lack of family history, (2) lack of facial involvement and asymmetry, (3) prominent dysphagia, and (4) profuse spontaneous activities on needle electromyography. All patients showed improvement with immunomodulating therapy. CONCLUSIONS: Anti-SRP antibody measurement should be considered in patients diagnosed with FSHD if they present with diagnostic hallmarks of anti-SRP myopathy listed above, to avoid oversight of this potentially treatable disorder.

Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3.

An inhibitor of 3T3-L1 adipocyte differentiation was isolated from Streptomyces sp. TK08330 and identified by spectroscopy as the 18-membered macrolide borrelidin. Treatment with 1.0 µM borrelidin suppressed intracellular lipid accumulation by 80% and inhibited the expression of adipocyte-specific genes. Borrelidin suppressed the mRNA expression of two master regulators of adipocyte differentiation, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein (C/EBPα). Studies on well-known upstream regulators of PPARγ revealed that borrelidin down-regulated C/EBPδ mRNA expression but did not affect expression of C/EBPß. Borrelidin increased mRNA expression of negative regulators of differentiation such as GATA-binding protein (GATA) 3, Krüppel-like factor (KLF) 3 and KLF7, as well as positive regulators, KLF4, KLF6 and KLF15, at early stages of differentiation. To elucidate a primary mediator of borrelidin differentiation inhibitory activity, small interfering RNA (siRNA) transfection experiments were performed. The mRNA expression of PPARγ, which was down-regulated by borrelidin, was not changed by KLF3 and KLF7 siRNA treatment. In contrast, expression of PPARγ in GATA-3 siRNA-treated cells was not significantly different from that of control siRNA-treated cells. Borrelidin significantly inhibited lipid accumulation in control siRNA-treated cells, and treatment with GATA-3 siRNA slightly reduced the inhibitory effect of borrelidin. These results indicate that borrelidin inhibited adipocyte differentiation partially via GATA-3.

Cineromycin B isolated from Streptomyces cinerochromogenes inhibits adipocyte differentiation of 3T3-L1 cells via Krüppel-like factors 2 and 3.

AIMS: 3T3-L1 cells are preadipocytes and often used as a model for cellular differentiation to adipocytes; however, the mechanism of this differentiation is not completely understood even in these model cells. In this study, we sought to identify a unique anti-adipogenesis agent from microorganisms and to examine its mechanism of action to gain knowledge and create a tool and/or seed compound for anti-obesity drug discovery research. MAIN METHOD: Screening for anti-adipogenesis agents from microorganisms was performed using a 3T3-L1 cell differentiation system, and an active compound was isolated. The inhibitory mechanism of the compound was investigated by measuring the expression of key regulators using quantitative real-time PCR and Western blot analysis. KEY FINDINGS: The compound with anti-adipogenic activity in 3T3-L1 cells was identified as cineromycin B. Cineromycin B at 50 µg/mL suppressed intracellular lipid accumulation and the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα), which are master regulators of adipocyte differentiation. Further investigations showed that cineromycin B increased significantly the mRNA expression of two negative regulators of adipocyte differentiation, Krüppel-like factor (KLF) 2 and KLF3, at an early stage of the differentiation. The results of siRNA transfection experiments indicated that cineromycin B is a unique adipocyte differentiation inhibitor, acting mainly via upregulation of KLF2 and KLF3, and these KLFs may play a role in the early stage of differentiation. SIGNIFICANCE: Cineromycin B inhibited adipocyte differentiation in 3T3-L1 cells mainly via upregulation of KLF2 and KLF3 mRNA expression at an early stage of the differentiation.

Semi-quantitative analyses of antibodies to N-methyl-d-aspartate type glutamate receptor subunits (GluN2B & GluN1) in the clinical course of Rasmussen syndrome.

OBJECTIVE: In Rasmussen syndrome (RS), in addition to the predominant involvement of cytotoxic T cells, heterogeneous autoantibodies against neural molecules are also found, but their function has not been elucidated. We examined antibodies to N-methyl-d-aspartate (NMDA) type glutamate receptor (GluR) subunits (GluN2B & GluN1) semi-quantitatively in cerebrospinal fluid (CSF) samples from RS patients, and evaluated their changes over time and their roles in immunopathogenesis. METHODS: Autoantibodies against N-terminal and C-terminal of GluN2B and GluN1 were examined in 40 CSF samples collected from 18 RS patients 5 to 180 months after the onset of RS. Epileptic patients without infectious etiology or progressive clinical course served as disease controls (n=23). Synthesized peptides encoding the extracellular and intracellular domains of human GluN2B and GluN1 subunits were used as antigens in ELISA. We defined the cut-off for these antibodies as mean +2 standard deviations (optimal density) of the disease controls. MRI were evaluated according to the MRI staging proposed by Bien et al. (2002b, Neurology 58, 250). RESULTS: CSF levels of antibodies against N-terminal and C-terminal of GluN2B were higher in RS patients than in disease controls (p<0.01). Likewise, CSF levels of antibodies against N-terminal and C-terminal of GluN1 were also higher in RS patients than in disease controls (p<0.01). All four antibodies tested were below cut-off levels in almost all CSF samples collected within one year from epilepsy onset. The proportions of CSF samples with these antibodies above cut-off levels were highest from 12 to 23 months after epilepsy onset, and declined after 24 months. CSF levels of these antibodies were higher when seizure occurred daily than when seizure occurred less frequently (p<0.01), and were higher at MRI stage 3 than at MRI stages 0, 2 and 4 (p<0.05), except for anti-GluN1-CT antibody at stage 2. CONCLUSIONS: Broad epitope recognition spectrum and delayed production of autoantibodies to NMDA type GluR in CSF of RS patients suggest that the autoantibodies are produced against NMDA type GluR antigens derived from cytotoxic T cell-mediated neuronal damages. These antibodies may impact the pathophysiology of RS in the most active stage, and could be a marker for active inflammation in the clinical course of RS. Further studies including passive transfer of the antibodies to mice may reveal the pivotal roles of the antibodies in RS.

Effect of enamel surface modification by novel aqueous phosphate-type fluoride surfactants.

Three novel aqueous fluoride surfactants (F4, F6, and F8) and a positive control (10F2S-3I) were applied to bovine enamel and the surface free energy was calculated by measuring the surface contact angles of three liquids: distilled water, α-bromonaphthalene and diiodomethane. The specimens were stored in water for 90 days, and then immersed in acetic acid/sodium acetate. The modified specimens recorded higher contact angles and lower surface free energy immediately after treatment than the control (p<0.05). Less calcium dissolved from the modified enamel surfaces than the control, with the F8-modified specimen registering significantly lower values than those of the F4, F6 and 10F2S-3I groups (p<0.05). These results suggest that the novel aqueous phosphate-type fluoride surfactant F8 is the most effective anti-cariogenic surface modifier.

α-amylase crystalloid granuloma of the parotid gland: case report and review of the literature.

We report a case of α-amylase crystalloid granuloma of the parotid gland in a 65-year-old Japanese woman. Histopathologically, the lesion comprised cystlike dilatation of the ducts and foreign body granulomas, with deposits of numerous crystalloid structures. The crystalloids were eosinophilic and varied in size and shape. Immunohistochemically, the crystalloids were positive for α-amylase. Immunoelectron microscopy showed the crystalloids to be cuboidal or rectangular in shape with irregularly shaped central spaces. We discuss this rare condition and review the literature on α-amylase crystalloids.

[Limb-girdle muscular dystrophy type 2M with adult-onset loss of ambulation. A case report].

We report a 29-year-old man with limb-girdle muscular dystrophy type 2M (LGMD2M) caused by a compound heterozygous mutation of 3-kb insertion in the 3'-untranslated region and c.1073A > C (p.Q358P) mutation in exon 9 in FKTN. He had been diagnosed since childhood as having Becker muscular dystrophy based on limb-girdle muscle weakness and calf muscle hypertrophy. Loss of ambulation occurred at age 26 years and cardiomyopathy was noted one year later. Muscle biopsy at age 29 revealed dystrophic changes with loss of immunoreactivity to alpha-dystroglycan (alpha-DG), which prompted us to analyze FKTN and subsequent establishment of the diagnosis of LGMD2M. Brain MRI revealed hypoplasia of the right cerebellar hemisphere and tonsil. Dysplastic part was present in the lower medial part of the hypoplastic hemisphare, which was bordered by a deep cleft. Previously reported LGMD2M patients had mild or minimal muscle weakness in addition to dilated cardiomyopathy. In contrast, our patient had more severe skeletal muscle weakness and loss of ambulation. Treatment with 3-blockers or angiotensin II converting enzyme blockers has been reported to be efficacious for cardiomyopathy in patients with muscular dystrophy. The precise diagnosis should be established early in patients with muscular dystrophy complicated with cardiomyopathy.

[Monthly low-dose immunoglobulin infusion as a maintenance therapy for multifocal motor neuropathy may reduce allergic adverse effects: a case report].

A 41-year-old man with multiple motor neuropathy developed weakness of the left hand at the age of 35 years. The weakness gradually progressed to his right hand. High-dose intravenous immunoglobulin (IVIg) therapy (0.4 g/kg for 5 consecutive days) improved the muscle weakness in the hands but led to the development of generalized severe pompholyx that spread to the skin over the entire body. Because muscle weakness of the hands worsened several months after IVIg therapy, we attempted another course of IVIg therapy. However, antiallergic agents and oral corticosteroids did not suppress the pompholyx induced by the high-dose IVIg. Hence, the treatment was switched to low-dose immunoglobulin therapy (0.4 g/kg for one day) once every month. After more than 8 months of low-dose therapy, only mild form of pompholyx remained and the muscle strength was maintained without further deterioration.