Thymic Extranodal Marginal Zone Lymphoma of Mucosa-associated Lymphoid Tissue with 8q24 Abnormality.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the thymus is reported to have characteristic features that distinguish it from MALT lymphoma of other organs; it is proposed to be a distinct clinicopathological subgroup of MALT lymphoma. We herein present a case of thymic MALT lymphoma accompanied by Sjögren's syndrome, involving the first report of a thymic MALT lymphoma patient carrying a chromosomal abnormality of 8q24. No c-myc gene translocation or c-Myc protein overexpression was observed, suggesting that c-myc was not involved in lymphomagenesis or progression. Although we did not examine the mechanisms by which the lymphoma developed, this chromosomal structural change in 8q24 may be associated with the pathogenesis in our case.

Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version.

TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca including pleural effusion and ascites, fever, renal insufficiency, and organomegaly including hepatosplenomegaly and lymphadenopathy. Its onset may be acute or sub-acute, but its etiology is undetermined. Although several clinical and pathological characteristics of TAFRO syndrome resemble those of multicentric Castleman disease (MCD), other specific features can differentiate between them. Some TAFRO syndrome patients have been successfully treated with glucocorticoids and/or immunosuppressants, including cyclosporin A, tocilizumab and rituximab, whereas others are refractory to treatment, and eventually succumb to the disease. Early and reliable diagnoses and early treatments with appropriate agents are essential to enhancing patient survival. The present article reports the 2015 updated diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, as formulated by Japanese research teams. These criteria and classification have been applied and retrospectively validated on clinicopathologic data of 28 patients with this and similar conditions (e.g. MCD with serositis and thrombocytopenia).

[Efficacy of serum immunoglobulin free light chain and 18F-FDG PET/CT for therapeutic evaluation in a case with multiple plasmacytoma of bone].

Solitary/multiple plasmacytoma of bone, a rare disease as compared to multiple myeloma, is characterized by monoclonal proliferation of plasma cells in local legion (s) of bone, with no bone marrow abnormalities. Monoclonal gammagloblinemia is often absent in these conditions, and useful examinations allowing evaluation of responses to treatment are as yet lacking. Recently, 18F-FDG PET/CT (PET/CT) was reported to be useful for detecting bone lesions. PET/CT is also valuable for predicting the outcomes of patients with solitary plasmacytoma, when applied in combination with the serum free light chain (sFLC) κ/λ ratio. We present a 62-year-old male with multiple plasmacytoma of bone (MPB), in whom PET/CT and the sFLC κ/λ ratio were useful for evaluating the response to treatment. The patient was diagnosed with MPB, with PET/CT showing multiple abnormal tracer uptakes in the scapula, spine, and ribs. The sFLC ratio was markedly elevated, with the κ chain level being especially high. We administered bortezomib and dexamethasone, after which the abnormal uptakes on PET/CT disappeared. The sFLC ratio and the FLC value also normalized, and have remained stable for more than one year, to date, since treatment. In our case, PET/CT and the sFLC κ/λ ratio were found to be extremely useful for monitoring treatment responses.

Thrombocytopenia with reticulin fibrosis accompanied by fever, anasarca and hepatosplenomegaly : a clinical report of five cases.

We report five cases that presented with high fever, anasarca, hepatosplenomegaly and severe thrombocytopenia with reticulin fibrosis of the bone marrow. The constellation of symptoms is not compatible with any known disease, and we had difficulty in diagnosis and treatment. The age distribution was from 47 to 56 years, and two men and three women were affected. Two patients needed hemodialysis because of renal dysfunction and oliguria with massive pleural effusion. Laboratory examinations showed normal immunoglobulin levels and no monoclonal protein. None of them showed diagnostic autoantibodies for any autoimmune diseases. Histological examination of the liver in three patients and spleen in two showed non-specific findings. Lymphadenopathy was tiny and lymph node biopsy was carried out in only one case. Histologically, paracortical hyperplasia with vascular proliferation and atrophic germinal centers resembling hyaline-vascular-type Castleman's disease or POEMS syndrome were detected. Without a definitive diagnosis, treatment was started with cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP) regimen in one patient, semi-pulse therapy with methyl-predonisolone in three and cyclosporin A in three. Two patients achieved complete remission, two were steroid-dependent and the remaining one died of multiple organ failure. These findings suggest that this disease may be a novel clinical entity belonging to systemic inflammatory disorder with a background of immunological abnormality or a unique variant of multicentric Castleman's disease. [J Clin Exp Hematop 53(1): 63-68, 2013].

IL-6-positive classical Hodgkin's lymphoma co-occurring with plasma cell type of Castleman's disease: report of a case.

We present a case of classical Hodgkin's lymphoma (HL) co-occurring with histological features of Castleman's disease (CD). A 25-year-old man presented with left supraclavicular and axillary lymph node swelling and mediastinal mass. Using an initial biopsy specimen from left axillary lymph node, a tentative diagnosis of multicentric CD of plasma cell type was made. The serum level of interleukin-6 (IL-6) was elevated. The patient was treated with immunosuppressive therapy containing tocilizumab (TCZ). Shrinkage of mediastinal mass and axillary lymph nodes was seen; however, swelling of his left axillary lymph nodes reemerged, even after therapy with TCZ. A second left axillary lymph node biopsy was performed and a diagnosis of nodular sclerosis of classical HL without histologic features of CD was made. The initial biopsy specimen was re-examined, and scattered CD30+ Hodgkin/Reed-Sternberg cells were found in the interfollicular area. Interestingly, Hodgkin/Reed-Sternberg cells and surrounding reactive cells in both lymph nodes were stained with anti-IL-6 antibody. We emphasize that biopsy specimens with HL involvement may also have histologic features reminiscent of those seen in CD. To our knowledge, this is the first report to provide a detailed description of this pathology, including a survey of IL-6 and clinical course upon treatment with TCZ.

Features of Japanese patients with myelodysplastic syndrome in an aging population of Sado Island.

Myelodysplastic syndrome (MDS) is relatively common in the elderly, and aging of populations is progressing in developed nations, notably so in Japan. The major age group in Japan and Sado Island are distributed between 30 and 60 and between 50 and 80, respectively. The aim of this study was to analyze the features of MDS in the population of Sado Island to anticipate the characteristics of the disease in the near future. One-hundred and fifty-three patients (71 male, 82 female, 19-94 years old, median 73 years old) with de novo MDS between 1985 and 2005 were retrospectively evaluated. All patients were reclassified according to WHO-2001 criteria. The predictive power of the international prognostic scoring system and the WHO classification-based prognostic scoring system were evaluated. The major causes of death were leukemic transformation (38%) in refractory anemia with an excess of blasts and infection (48%) for total MDS. Age was another independent prognostic factor. Elderly patients exhibited a significantly poorer prognosis mainly due to infections such as pneumonia. Although novel remedies for MDS and hyperferremia have recently been developed, prevention of infection remains important in MDS, particularly for older patients.

[Efficacy of chemotherapy combined with bevacizumab for metastatic colorectal cancer].

Bevacizumab (BV) is widely used for patients with metastatic colorectal cancer. We investigated the efficacy and safety of chemotherapy combined with BV for metastatic colorectal cancer. From July 2007 to October 2008, 59 patients were treated by chemotherapy with BV in our hospital. Of the 47 patients who received BV in first-line therapy, 3 cases (6%) with complete response (CR), 25 cases(53%) with partial response (PR), and 17 cases (36%) with stable disease (SD) were observed. The overall response rate and tumor control rate were 60% and 96%, respectively. The median progression-free survival (PFS) was 11. 9 months, and median overall survival (OS) was 23. 6 months. There were 12 patients treated first with BV in second-line therapy. Of the 12 patients, 1 case (8%) with CR, 3 cases (25%) with PR, and 4 (33%) with SD were observed. The overall response rate and tumor control rate were 33% and 67%, respectively. The median PFS was 6.0 months and median OS was not reached. With regard to the grade 3 to 4 adverse events by NCI-CTCAE ver3.0, neutropenia was observed in more than half of the patients (56%), but a few of patients had gastrointestinal toxicities, peripheral neuropathy and infections in non-hematologic toxicities. BV-associated adverse events were hypertension, proteinuria, venous thrombosis, wound healing complication, gastrointestinal perforation and bleeding, each of which were few and not serious. Six of the patients experienced PD after first-line therapy treated with BV continuously in second-line therapy. Four of six were surviving without disease progression at the last follow-up, which suggests the effectiveness of continuation of BV. Our study showed the efficacy and safety of BV for metastatic colorectal cancer.

Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation.

Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.

[Effective combination chemotherapy with rituximab for acute lymphoblastic leukemia with bone relapse after bone marrow transplantation].

A 26-year-old woman with acute lymphoblastic leukemia (ALL) relapsed three times after HLA-matched related bone marrow transplantation. Initially, ALL relapsed in the central nervous system (CNS) 1 year after transplantation. Then, ALL relapsed as a single bone tumor involving the CNS and pelvis 4 years after transplantation. Finally, multiple bone tumors in the pelvis and lumbar bones were found as well as spread to the bone marrow 5 years after transplantation. Bone marrow aspiration also showed ALL relapse. Flow cytometry analyses detected CD20-positive cells in the bone tumor. Though the initial bone tumor was resistant to hyper CVAD, radiation was effective and this patient achieved complete remission. At that time, the total radiation dose had already reached the upper limit. After the third relapse, bone marrow achieved complete remission with the administration of pirarubicin, vincristine, prednisolone, and L-asparaginase (arranged DVP-L), though this combination chemotherapy itself was not effective in multiple bone tumors. Thereafter, arranged DVP-L plus rituximab was administered, which resulted in significant tumor reduction. Biweekly rituximab administration as maintenance therapy has completely prevented the regrowth of bone tumors. Rituximab for relapsed CD20-positive ALL patients after stem cell transplantation could be beneficial.

Successful treatment of adult T-cell leukemia with unrelated cord blood transplantation.

This study reports the first well-documented case of adult T-cell leukemia (ATL) successfully treated with unrelated cord blood transplantation (UCBT). A 49-year-old woman was diagnosed with acute-type of ATL. Chemotherapy induced complete remission, but the human T-cell leukemia virus type 1 (HTLV-1) proviral load was detected in mononuclear cells of her peripheral blood. The patient received UCBT with a conditioning regimen consisting of total body irradiation, cytarabine, and cyclophosphamide. She remains in remission 30 months after UCBT and the HTLV-1 proviral load has fallen to undetectable levels. This result suggests that UCBT should be a therapeutic option for ATL patients who do not have suitable donors and those who urgently require treatment.

High-dose cyclophosphamide as an effective therapy for a patient with refractory multiple myeloma relapsing after autologous stem cell transplantation.

Alkylating agents are often used to treat patients with multiple myeloma (MM). However, it is not common for high-dose cyclophosphamide (CPM) therapy to be used as a treatment for MM. Herein, we report a case of refractory MM associated with hypercalcemia. We decided to give her high-dose CPM. After this treatment, the serum calcium level decreased and the tumor mass in the iliac bone was reduced. This therapy is potentially useful for patients with refractory MM.

Cutaneous lymphoblastic lymphoma of putative plasmacytoid dendritic cell-precursor origin: two cases.

Although the neoplasm of relatively mature type plasmacytoid dendritic cells (pDC) was recently reported, that of pDC-precursor has not yet been defined. We experienced two elderly male Japanese patients with reddish skin tumors. The histology of the tumors in both patients showed terminal deoxinucleotidyl transferase (TdT)-positive lymphoblastic lymphoma (LBL). The pathological cells did not express T, B or NK markers, and no rearranged bands were shown for immunoglobulin (Ig)-JH, T cell receptor (TCR)-C beta, J gamma, J delta1, and c-myc. In addition, no Epstein-Barr virus (EBV)-derived DNA was detected in either case. The cells were (CD45, CD43, CD74, CD10, and HLA-DR)-positive in both cases, and one of the cases showed (CD4, CD36, CD54, CD58 and CD86)-positive plasmacytoid lymphoblasts, which appeared to be compatible with intermediate cells between human bone marrow lymphoid precursors and mature lymphoid DC. The cutaneous LBL in the two cases may, therefore, have been of pDC-precursor origin.

CD56+, NKp46+ cell line (MZ93) expressing T-cell and myeloid antigens.

The MZ93 cell line, established from a patient with CML, expressed CD4, CD7, CD13, CD25, CD33, CD34, CD56 and NKp46. The additional karyotype abnormality of the Ph-positive leukemia cells in vivo, 6p+, was also observed in MZ93. The early passages of MZ93 expressed CD3 in the cytoplasm, but the late passages did not. The cells did not express mature NK-markers as expected. The messenger RNAs of CD2 and NKp46 were detected and those of CD3varepsilon and CD3zeta were absent in the cells. Therefore, the cell line has the immunophenotype likely to NK and/or T cell precursor.