Extranodal natural killer/T-cell lymphoma coexisting with peripheral T-cell lymphoma, not otherwise specified.

We report the case of a 52-year-old male who presented to our hospital with cervical lymphadenopathy. Lymph node biopsy revealed small atypical lymphoid cells positive for CD3 and CD5 and negative for CD56 and Epstein-Barr virus (EBV)-encoded small RNA (EBER) by in situ hybridization. CD4-positive cells and CD8-positive cells were mixed in almost equal numbers. He was diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The patient received one cycle of chemotherapy, resulting in severe sepsis. While undergoing treatment in the intensive care unit with an antimicrobial agent and prednisone, ascitic fluid appeared. Abdominal aspiration revealed neutrophil-predominant ascites and microbiological studies revealed Candida albicans. However, ascites did not improve when treated with micafungin for Candida peritonitis. Abdominal aspiration was re-performed, and atypical lymphoid cells that were positive for CD3 and CD56 were detected. EBV-DNA levels in whole blood were significantly elevated. Atypical lymphoid cells were positive for EBER by in situ hybridization and Southern blot analysis showed EBV terminal repeat monoclonal patterns. Bone marrow examination revealed the same atypical lymphoid cells. Therefore, the patient was diagnosed with extranodal natural killer/T-cell lymphoma (ENKTL) with bone marrow involvement 3 months after the diagnosis of PTCL-NOS. Complications associated with PTCL-NOS and ENKTL are rare. PTCL-NOS, chemotherapy, sepsis, and prednisone might have led to immunodeficiency and reactivation of EBV, which might be one of the pathophysiologies for developing ENKTL. Our case indicates that measuring EBV-DNA in the blood is a simple and prompt examination to detect complications of EBV-associated lymphoma.

[Myelodysplastic syndrome with der (1;7)(q10;p10) complicated with eosinophilia and organizing pneumonia].

The unbalanced translocation der (1;7)(q10;p10) is a characteristic cytogenetic abnormality observed in myelodysplastic syndrome (MDS). A 63-year-old man presented to our hospital with fever and lung disease. The chromosomal analysis of bone marrow cells showed 46, XY, +1, der (1;7)(q10;p10) in all four metaphases. The patient was diagnosed with MDS. Bronchoscope examination revealed organizing pneumonia. The patient's eosinophil count rose to 39% after 30 days. His fever and dyspnea worsened, and a skin rash (systemic erythema) appeared simultaneously. Therefore, the patient was commenced on azacitidine and corticosteroids. Although treatment with both drugs could control disease progression transiently, the WT-1 value and the percentage of myeloblasts in the patient's bone marrow increased. Therefore, the patient received hematopoietic stem cell transplantation from his haplo-identical donor daughter. Some reports have demonstrated that patients with MDS with der (1;7)(q10;p10) have better prognosis than those with other abnormalities, such as -7/7q-. However, reported cases with severe complications show very poor prognosis. MDS with der (1;7)(q10;p10) complicated by eosinophilia and organizing pneumonia have not been reported, and its prognosis is expected to be very poor. Our case suggests that such cases might quickly require hematopoietic stem cell transplantation before the disease worsens.

Primary Effusion Lymphoma-like Lymphoma Mimicking Tuberculous Pleural Effusion: Three Case Reports and a Literature Review.

Primary effusion lymphoma-like lymphoma (PEL-LL) is a rare lymphoma, localized in the body cavity without detectable tumor masses. Tuberculous pleural effusion is a form of extra pulmonary tuberculous. We herein report three cases of PEL-LL in patients with a history of pulmonary tuberculosis. Despite the presentation with lymphocyte predominance and high levels of adenosine deaminase, a notable characteristic of tuberculous pleural effusion, the patients were ultimately diagnosed with PEL-LL. Pleural fluid laboratory tests yield similar results for PEL-LL and tuberculous pleural effusion; therefore, cytological and immunophenotyping examinations are useful for their differential diagnosis and the determination of treatment.

Spontaneous regression of dasatinib-related primary effusion lymphoma-like lymphoma.

Primary effusion lymphoma-like lymphoma (PEL-LL) shows a unique clinical presentation, characterized by lymphomatous effusions in the body cavities. PEL-LL may be associated with hepatitis C virus infections and fluid overload states; and owing to its rarity, no standard therapies have been established. We report a case of a 55-year-old woman who developed PEL-LL during treatment with dasatinib, for chronic myeloid leukemia (CML). She presented to our hospital with dyspnea lasting for approximately a month and showed pericardial and bilateral pleural effusions. The pericardial effusion was exudative, and cytopathological and immunophenotypic examinations showed numerous CD 20-positive, large atypical lymphoid cells, which were also positive for the Epstein-Barr virus gene. No evidence of lymphadenopathy or bone marrow infiltration was found. We diagnosed PEL-LL, immediately discontinued dasatinib, and performed continuous drainage of the pericardial effusions. Complete response was achieved, and remission was maintained for 15 months. Two months after discontinuation of dasatinib, she was administered imatinib and a deep molecular response for the CML was maintained. PEL-LL occurring during dasatinib treatment is rare. We compared the results of previous reports with this case, and found that early diagnosis of PEL-LL, discontinuation of dasatinib, and sufficient drainage can improve the prognosis of PEL-LL.

An Unbalanced Diet Limited to the Consumption of Boiled Vegetables Led to the Onset of Scurvy.

Scurvy is a rare disease caused by a vitamin C deficiency. Vitamin C is a water-soluble vitamin found in vegetables and fruits, but it is lost after boiling. A 59-year-old man presented with gingival pain after having a tooth extracted five years previously. Following the procedure, his diet comprised boiled vegetables to prevent pain. He then experienced bilateral lower leg pain, and computed tomography revealed intramuscular bleeding. His serum vitamin C level was below the detectable limit. His symptoms immediately improved with vitamin C administration. This case emphasized that consuming only boiled vegetables can lead to the onset of scurvy.

[Aseptic meningitis as paraneoplastic syndrome related to chronic myeloid leukemia in chronic phase].

Chronic myeloid leukemia (CML) is a clonal hemopoietic stem cell disorder characterized by reciprocal translocation between the long arms of chromosomes 9 and 22 that produces the fusion BCR-ABL1 gene. Major manifestations in CML patients are increased white cell count and splenomegaly. In this case, the patient presented with aseptic meningitis and showed symptoms, such as disorientation, double vision, and neurogenic bladder disorder. Pulse steroid and antibiotic treatment was ineffective for these symptoms; however, the combination therapy with these drugs and dasatinib was very effective. Moreover, our patient had myelopathy that could have been induced by dasatinib after the treatment was started. To our knowledge, this is the first report of meningitis of the paraneoplastic syndrome associated with CML.

Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea During Treatment: A Case Report and Literature Review.

A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (123I-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients.

Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.

BACKGROUND: Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required. OBJECTIVE: We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever. METHODS: Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d). RESULTS: Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07). CONCLUSION: ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.

[Successful treatment with enzyme replacement therapy for pelvic fragile fracture in an elderly case of type I Gaucher's disease].

A 76-year-old male with lower-limb weakness was admitted to our hospital where thrombocytopenia and anemia were noticed. CT showed massive splenomegaly and multiple nodules inside the spleen. Bone marrow examination showed an increase of macrophages with large cytoplasm. Suspected of splenic lymphoma, the patient underwent splenectomy. Spleen specimens were histologically analyzed and suggested the probability of Gaucher's disease (GD). Leukocyte glucocerebrosidase (GBA) enzyme activity had decreased to 1.25 nmol/mg, and mutation analysis of GBA revealed two missense variants, p.D448H (D409H), p.L483P (L444P), which confirmed the diagnosis of type I GD. Fourteen months after splenectomy, he developed right buttock pain, and pelvic magnetic resonance imaging showed a fragile right pubic and pelvic fracture. We initiated injection of imiglucerase as enzyme replacement therapy (ERT) and administered bisphosphonate. His symptoms gradually improved without surgical treatment. In addition, thrombocytopenia and anemia also improved, and angiotensin-converting enzyme levels decreased. Type I GD should be considered a differential diagnosis of giant splenomegaly and thrombocytopenia, even in the elderly. ERT or substrate reduction therapy should be administrated to GD patients, while paying attention to the development of bone lesions.

High-dose Dexamethasone Therapy as the Initial Treatment for Idiopathic Thrombocytopenic Purpura: Protocol for a Multicenter, Open-label, Single Arm Trial.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.

Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL.

The Japan Adult Leukemia Study Group (JALSG) Ph+ALL202 study reported a high complete remission (CR) rate for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients treated with imatinib-combined chemotherapy. However, the long-term treatment efficacy remains uncertain. Here, we report a final analysis of the JALSG Ph+ALL202 study. The outcomes were compared with those of the JALSG ALL93 and ALL97 studies, which were conducted in the pre-imatinib era. Ninety-nine newly diagnosed Ph+ALL patients were enrolled in Ph+ALL202 (median age, 45 years; median follow-up, 4.5 years). CR was achieved in 96/99 (97%) patients. Fifty-nine of these 96 patients (61%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first CR (CR1). The 5-year overall and disease-free survival (DFS) rates were 50 and 43%, respectively, which were significantly higher compared to those in the pre-imatinib era (15 and 19%, respectively). Multivariate analysis revealed that imatinib administration, allo-HSCT in CR1, and a white blood cell count < 30 × 109/L were favorable independent prognostic factors for long-term DFS. Improved odds of receiving allo-HSCT and a lower relapse rate leaded to good long-term outcomes. The 3-year DFS tended to be higher in PCR-negative than that in PCR-positive patients (29 vs. 14%) in the non-HSCT patients, and this tendency was also seen in the allo-HSCT patients (59 vs. 50%). The higher rate of CR upon imatinib use may have contributed to these improvements.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease.

Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT.

Deep skin infection of Scedosporium apiospermum in a patient with refractory idiopathic thrombocytopenic purpura.

Infection of Scedosporium apiospermum is very rare but is now emerging as an important cause of both localized and disseminated infections in immunocompromised patients. A 62-year-old woman, who had undergone steroid therapy for refractory idiopathic thrombocytopenic purpura and had a history of diffuse large B cell lymphoma, developed a deep skin ulcer complicated with lymphangitis. After culture study demonstrated the presence of S. apiospermum, voriconazole (VRCZ) was administered and prompt improvement was observed. Because it is difficult to distinguish S. apiospermum from Aspergillus by histopathology and S. apiospermum is resistant to amphotericin B, VRCZ should be selected as the first choice of antifungal agent when mold is considered to be the causative organism.

Successful treatment of KIT D816V-positive, imatinib-resistant systemic mastocytosis with interferon-alpha.

We describe a case of systemic mastocytosis associated with myelodysplastic syndrome. The bone marrow showed multifocal clusters of mast cells and myeloid dysplasia. Sequencing of the KIT DNA revealed a point mutation at codon 816 including a substitution of valine for aspartic acid (D816V). The patient's tumor did not respond to imatinib; however, interferon-alpha reduced the bone marrow mast cells and serum total tryptase. The patient remains alive at one year after the diagnosis without disease progression.

Histiocytic sarcoma: identification of its histiocytic origin using immunohistochemistry.

We describe a 56-year-old woman with histiocytic sarcoma involving the bone marrow. The neoplastic cells proliferated diffusely and showed occasional erythrophagocytosis. Immunohistochemically, the neoplastic cells were positive for CD68, lysozyme, CD4 and CD163, but negative for B- and T-cell markers, S100 protein and epithelial markers. The patient received multi-agent chemotherapy and is living at 22 months after diagnosis without recurrence. Histiocytic sarcoma is an exceedingly rare hematopoietic neoplasm and the prognosis is poor due to its rapid progression, widespread disease and poor response to therapy. It is important to recognize this rare neoplasm and to confirm the diagnosis using specific immunohistochemical markers.

Induction of urokinase-type plasminogen activator, interleukin-8 and early growth response-1 by STI571 through activating mitogen activated protein kinase in human small cell lung cancer cells.

We previously demonstrated the simultaneous induction of urokinase-type plasminogen activator and interleukin-8, a CXC chemokine, in doxorubicin-treated human NCI-H69 small cell lung cancer cells in which extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase might be involved. NCI-H69 cells expressed one of the receptor tyrosine kinases, c-Kit, and STI571 inhibited the cell growth and stem cell factor-induced phosphorylation of c-Kit. We therefore investigated the effects of STI571 on the expression of urokinase-type plasminogen activator and interleukin-8 in NCI-H69 cells. Microarray analysis revealed the gene induction of not only urokinase-type plasminogen activator and interleukin-8, but also early growth response-1 in STI571-treated cells. Treatment with STI571 resulted in the induction of phosphorylation of all three mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and stress-activated protein kinase/c-jun N-terminal protein kinase. U0126, an inhibitor against extracellular signal-regulated kinase 1/2, however, only inhibited the STI571-induced interleukin-8 accumulation. Urokinase-type plasminogen activator and interleukin-8 are important biological factors in tumor cell regulation; STI571 may therefore influence many aspects of tumor cell biology through inducing urokinase-type plasminogen activator and interleukin-8, in which the induction of early growth response-1 expression and extracellular signal-regulated kinase 1/2 phosphorylation might be involved.

Amurubicinol-induced eotaxin-3 expression in human NCI-H69 small cell lung carcinoma cells.

We previously demonstrated the doxorubicin-induced expression of urokinase-type plasminogen activator (uPA), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Amurubicin hydrochloride (AMR), a novel derivative drug of doxorubicin, was recently introduced to clinical practice for treatment of lung cancer in Japan. Therefore, we investigated the effects of AMR on the expression of uPA and chemokines in NCI-H69 cells. AMR and its active form, amurubicinol hydrochloride (AMROH), both induced the expression of uPA, IL-8 and MCP-1 in H69 cells in a dose-dependent manner. When the cultured supernatant obtained from AMR-treated H69 cells was subcutaneously injected into rabbits, migration of a significant number of eosinophils was observed around the injected site. Antigen levels of eotaxin-3, a major migration-factor of eosinophils, were increased in AMROH-treated cells in parallel with the mRNA levels. The induction was observed below the clinically achievable concentration of AMR or AMROH. Thus, the simultaneous induction of uPA, IL-8, MCP-1 and eotaxin-3 may play a role in the pharmacological action of AMR through induction of the interaction between proinflammatory cells and lung carcinoma cells.

Induction of CXC and CC chemokines by all-trans retinoic acid in acute promyelocytic leukemia cells.

We previously reported the induction of interleukin-8 (IL-8), one of the CXC chemokines, by all-trans retinoic acid (ATRA) in PL-21 and NB4 human myeloid leukemia cells, which may be implicated in APL differentiation syndrome that is a relatively frequent complication in patients with acute promyelocytic leukemia (APL) during treatment with ATRA. We, therefore, further investigated the effects of ATRA on the expression of chemokine family in NB4 cells and APL cells prepared from two APL patients. The RNase protection assay using a multi-probe template set for human chemokines revealed that ATRA induced gene expressions of a number of CC chemokines, such as monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in NB4 cells. Their antigen levels were also increased in the cultured media. APL cells prepared from two APL patients showed gene expression of chemokines, such as IL-8, MCP-1, MIP-1alpha, and MIP-1beta when stimulated with ATRA in vitro. Furthermore, serum levels of IL-8, MIP-1beta and RANTES were increased during the course of ATRA treatment in both APL patients who developed APL differentiation syndrome. These chemokines are all chemoattractants of particular inflammatory cell types, including neutrophils, monocytes and lymphocytes; therefore, the simultaneous induction of these chemokines after stimulation with ATRA may exacerbate the hyper-inflammation observed in ATRA-induced APL differentiation syndrome.