Elotuzumab Enhances CD16-Independent NK Cell-Mediated Cytotoxicity against Myeloma Cells by Upregulating Several NK Cell-Enhancing Genes.

Multiple myeloma (MM) is an intractable hematological malignancy caused by abnormalities in plasma cells. Combination therapy using antibodies and natural killer (NK) effectors, which are innate immune cells with safe and potent antitumor activity, is a promising approach for cancer immunotherapy and can enhance antitumor effects. Elotuzumab (Elo) is an immune-stimulatory antibody that targets the signaling lymphocytic activation molecule family 7 (SLAMF7) expressed on the surface of MM and NK cells. We confirmed that Elo strongly promoted NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against SLAMF7-positive MM cells in a CD16-dependent NK cell line, and also activated expanded NK cells derived from peripheral blood mononuclear cells of healthy donors and patients with MM in the present study. However, the antitumor effects and genes involved in the direct promotion of NK cell-mediated activation using Elo in CD16-independent NK cells are not clearly known. In this study, we demonstrated that Elo pretreatment significantly enhanced CD16-independent NK cell-mediated cytotoxicity in both SLAMF7-positive MM.1S and SLAMF7-negative K562, U266, and RPMI 8226 tumor cells. Upon direct simulation of CD16-independent NK cells with Elo, increased levels of CD107a degranulation and IFN-γ secretion were observed along with the upregulation of granzyme B, TNF-α, and IL-1α gene expression. The enhanced NK cell function could also be attributed to the increased expression of the transcription factors T-BET and EOMES. Furthermore, the augmentation of the antitumor effects of CD16-independent NK cells upon pretreatment with Elo enhanced the expression of CRTAM, TNFRSF9, EAT-2, and FOXP3 genes and reduced the expression of HSPA6. Our results suggest that Elo directly promotes the cytotoxic function of CD16-independent NK cells against target cells, which is associated with the upregulation of the expression of several NK cell-enhancing genes.

[Successful treatment of acute promyelocytic leukemia with all-trans retinoic acid on hemodialysis for acute renal failure].

All-trans retinoic acid (ATRA) is used as standard induction therapy for acute promyelocytic leukemia (APL), but it is contraindicated for patients on hemodialysis. We present a case of a patient with APL on hemodialysis, intubated, and with marked disseminated intravascular coagulation (DIC) who was successfully treated with ATRA. A 49-year-old man was transferred to our hospital and admitted into the intensive care unit due to renal dysfunction, DIC, and pneumonia. Promyelocytes were noted in the peripheral blood, and he was diagnosed with APL after bone-marrow examination. Because of renal dysfunction, only Ara-C was used but with a reduced dose. The patient's condition improved, and he was extubated and withdrawn from dialysis on the 5th day of hospitalization. The patient suffered from APL syndrome during induction therapy, which necessitated ATRA withdrawal and steroid administration. Remission was achieved after induction therapy, and the patient is currently on maintenance therapy. There are few cases of patients with APL on hemodialysis who were treated with ATRA; hence, it is necessary to review the treatment plan for these patients.

Successful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports.

We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.

Erythematosus plaques with macrophage infiltration as an initial manifestation of macrophage activation syndrome in a patient with systemic lupus erythematosus.

The diagnosis of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) may be challenging as it can mimic the clinical features of the underlying disease or be confused with an infectious complication. In this report, a Japanese woman in her forties had diverse clinical features of MAS at initial presentation of SLE, where erythematosus plaques with histiocytic infiltrates focally surrounding degenerated collagen might be the earliest indicator of MAS.

Peroxiredoxin 2 expression is increased in neutrophils of patients with refractory cytopenia with multilineage dysplasia.

Myelodysplastic syndromes (MDS) are heterogeneous clonal disorders characterized by cytopenias that arise due to ineffective haematopoiesis and morphological dysplasia and carry an increased risk of incident acute myeloid leukaemia. The pathogenesis of marrow dysfunction in MDS is multifactorial and consistent with a multistep model and may lead to heterogeneity of MDS. We investigated the proteome profile of circulating neutrophils purified from patients with refractory cytopenia with multilineage dysplasia (RCMD) to identify proteins that have a role in the pathogenesis. Using 2-dimensional difference gel electrophoresis and protein identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we found that peroxiredoxin 2 (PRDX2), a member of the peroxiredoxin family that regulates reactive oxygen species, was markedly upregulated in neutrophils of RCMD patients compared to healthy donors. Increased PRDX2 expression in the neutrophils of RCMD patients was confirmed using quantitative reverse transcription polymerase chain reaction, immunoblotting and immunocytochemical analysis. In addition, white blood cell and neutrophil counts in RCMD patients correlated inversely with the PRDX2 expression of. Oxidative stress is a known factor involved in the pathogenesis of MDS, and PRDX2 is associated with tumourigenesis of several solid tumours. Accordingly, our results suggest that PRDX2 may perform an important function in the pathogeneis of RCMD.

Long-term remission of primary bone marrow diffuse large B-cell lymphoma treated with high-dose chemotherapy rescued by in vivo rituximab-purged autologous stem cells.

Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is a rare type of extranodal lymphoma with poor prognosis. Here, we report a case of primary bone marrow DLBCL successfully treated with high-dose chemotherapy and rescued by in vivo rituximab-purged autologous stem cells. A 39-year-old woman visited our hospital because of anemia. Bone marrow examination revealed a large B-cell lymphoma invasion. An (18)F-fluorodeoxyglucose positron emission tomography scan revealed disseminated bone marrow uptake without evidence of dissemination at other sites. These findings led to a diagnosis of primary bone marrow DLBCL. Our patient underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy and achieved complete remission. Subsequently, she received high-dose chemotherapy with an in vivo rituximab-purged autologous stem cell transplant. Seven years have passed since the transplantation, and she remains in remission. This suggests that transplantation of an in vivo rituximab-purged autograft is a promising strategy for primary bone marrow DLBCL.

[Usefulness of (18)F-FDG PET/CT for detecting lesions in patients with POEMS syndrome].

Many patients with POEMS syndrome have osteosclerotic plasmacytoma. Radiation therapy is useful for patients who have localized lesions, although chemotherapy is necessary for patients who have widespread lesions. Thus, evaluation of these lesions is important to determine the therapeutic strategy. We evaluated the activities of lesions in two patients with POEMS syndrome by (18)F-FDG positron emission tomography (PET)/computed tomography (CT) scan. In the first patient, PET/CT scan revealed osteosclerotic lesions, which were not detected by Ga-scintigraphy or plain X-ray. It also detected residual disease activity and relapse. In the second patient, lymph node involvement was suggested by (18)F-FDG uptake, and plasmacytoma was confirmed by subsequent biopsy. In the extramedullary lesions of this case, FDG uptake was as marked as in myeloma, whereas bone lesion was only detectable by CT scan. In POEMS syndrome, the PET and CT are complementary, and the combined PET/CT scan is considered to be very useful for evaluation of involved lesions.

[Angioimmunoblastic T-cell lymphoma with marked polyclonal plasmacytosis in peripheral blood and bone marrow mimicking plasma cell leukemia].

A 70-year-old man was admitted to our hospital with fever, generalized lymphadenopathy and hypoxia in October 2009. Blood examination demonstrated leukocytosis, anemia, thrombocytopenia and hyper γ-globulinemia. Peripheral blood and bone marrow smear showed marked plasma cell proliferation mimicking plasma cell leukemia. However, flow cytometric analysis showed that plasma cells were of polyclonal origin and M-protein was not detected by immunofixation of serum protein. Elevations of soluble interleukin 2 receptor and serum IL-6 were observed. A heavy Epstein-Barr viral load was detected in serum by real-time PCR. Biopsy was obtained from the right inguinal lymph node. The pathological diagnosis was angioimmunoblastic T-cell lymphoma (AITL) and rearrangement of the T-cell receptor Cß1 gene was detected. The patient was treated with CHOP therapy, and all clinical manifestations, including fever, lymphadenopathy, anemia, thrombocytopenia, hyper γ-globulinemia, plasmacytosis and hypoxia, were improved. Only a few reported cases have demonstrated AITL with marked polyclonal plasmacytosis. Although pathological mechanisms of plasmacytosis in AITL patients have not been fully elucidated, it is suggested that IL-6 and IL-10 were involved in its pathogenesis in the present case.

[Factors affecting the response of thalidomide therapy for patients with multiple myeloma].

Factors that affect the response of multiple myeloma patients to thalidomide were evaluated in 40 patients who were not eligible for chemotherapy (untreated: 14, relapse/refractory: 26). The complete response (CR) rate was 2.5%; partial response (PR) 50.0%; minimal response (MR) 25.0%; no change (NC) 12.5%; and progressive disease 10.0%. The response to thalidomide could be evaluated after four weeks of treatment. Significantly higher responses were associated with untreated patients, patients with combined use of thalidomide plus dexamethasone, and patients with kappa light chain. Patients who responded well to thalidomide showed a significantly higher progression-free survival (PFS) rate. In patients with kappa light chain, PFS and overall survival rates were significantly higher than those with lambda light chain. Frequent adverse reactions were numbness (47.5%), constipation (32.5%), and eruption (30.0%). In patients previously treated with vincristine, numbness occurred in a significantly higher percentage of patients.

Pyothorax-associated lymphoma: a case showing transition from T-cell-rich polymorphic lesion to diffuse large B-cell lymphoma.

Pyothorax-associated lymphoma was found in a man who had a history of collapse therapy for pulmonary tuberculosis about 50 years ago. An autopsy specimen revealed histology of diffuse large B-cell lymphoma with latency III Epstein-Barr virus (EBV) infection. However, an open biopsy 2 years and 7 months before death showed a polymorphic appearance with abundant T-lymphocytes. Most of the EBV-infected atypical lymphocytes did not express either B- or T-cell markers as far as examined in the paraffin-embedded biopsy specimen, and rearrangements of immunoglobulin and T-cell receptors were not found. It seemed difficult to diagnose a B-cell lymphoma at the time of biopsy. However, retrospectively considered, if a phenotype of EBV-infected atypical lymphocytes is uncertain in cases showing polymorphic appearance, it might be better to consider the future evolution to overt B-cell lymphoma. Since pyothorax-associated lymphoma shows latency III infection of EBV, at least the immunohistochemistry of EBNA-2 and LMP-1 seems helpful for the diagnosis to prove which cells are infected by EBV.