Mikio Danbara

Analysis of the oligosaccharide chain of human serum immunoglobulin G in patients with localized or metastatic cancer

A quantitative imbalance between matrix metalloproteinases produced by cancer cells and tissue inhibitors of metalloproteinases produced by fibroblasts and other types of cells has been demonstrated to be a causative factor in invasion and metastasis of cancer cells. On the other hand, it is reported that sugar chains of adhesion molecules such as integrins and CD44 also influence the metastasis of cancer cells. Here, alterations of serum IgG oligosaccharide chain structure were investigated during tumor progression using the new method of fluorophore-assisted carbohydrate electrophoresis (FACE). The structure of serum IgG oligosaccharide chains from 22 cancer patients (11 localized cancer, 11 metastatic cancer) and 10 healthy controls was evaluated by FACE. It was clearly demonstrated that serum IgG oligosaccharide chains without galactose (agalactosyl IgG oligosaccharide) significantly increased with tumor progression of lung and gastric cancers. It is concluded that a marked increase of agalactosyl IgG oligosaccharide in these cancer patients is associated with carcinogenesis and metastasis. Therefore, the analysis of serum IgG oligosaccharide chain structure by FACE may be useful for evaluating diagnosis and prognosis in patients with these carcinomas.

Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection.

Background and aim: De novo hepatitis B virus (HBV)‐related hepatitis is a well‐known fatal complication following chemo‐immunosuppressive therapy in patients with past HBV infection (HB surface antigen and serum HBV DNA negative, but HB core antibody and/or HB surface antibody positive). This research was conducted to evaluate the incidence of and clinical features associated with re‐appearance of serum HBV DNA following chemo‐immunosuppressive therapy in Japanese patients with past HBV infection.

Lymphoproliferative Disorders after Immunosuppressive Therapy for Aplastic Anemia: A Case Report and Literature Review

A 61-year-old Japanese man was referred to our hospital in 2002 due to severe pancytopenia. Bone marrow and peripheral blood findings indicated he had severe aplastic anemia (AA). A whole-body CT scan and Ga scintigraphy revealed no abnormal findings. Antithymocyte globulin and cyclosporine A (CyA) were administered and he got transfusion independently. In September 2004, he complained of abdominal fullness and a skin eruption in the lower abdomen. An abdominal CT revealed a spleen mass and lymphoadenopathy of the pancreas head. Splenectomy was done, and he was diagnosed with a diffuse large B cell lymphoma (DLBCL) of the spleen and skin. His karyotype was associated with t(14; 18). CyA was stopped, all lesions disappeared, and then his AA relapsed. In January 2007, antithymocyte globulin/CyA was readministered. In May 2007, he complained of acute swelling in his right thigh. A biopsy from the tumor revealed DLBCL. CyA was stopped again, yet the lymphoma did not regress. He was given R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone), followed by 5 cycles of R-VP (rituximab, vincristine, prednisolone) and radiation therapy, resulting in a partial remission. We report DLBCL after immunosuppressive therapy for AA. Although this is a rare complication, it should be considered before beginning immunosuppressive therapy.

Immature platelet fraction measurement is influenced by platelet size and is a useful parameter for discrimination of macrothrombocytopenia.

Abstract Background Reticulated platelets (RPs) as measured using flow cytometry are useful parameters of thrombopoiesis; however, difficulties remain with standardization between laboratories. On the other hand, immature platelet fraction (IPF) measurement, as determined using an automated hematology analyzer, is simple, reproducible, and displays a good correlation with RP, although specific factors may affect its value. We previously noticed that a small proportion of patients exhibit extremely high IPF values that do not correlate with flow cytometrically measured RP. Objectives We investigated the mechanism of the aberrant increase in IPF values of different types of macrothrombocytopenia. Patients/methods IPF, RP, and other platelet indexes were analyzed using samples from 15 congenital macrothrombocytopenic patients from 12 families, 150 immune thrombocytopenic patients, and 27 normal individuals. We further monitored the change in IPF values and morphology during platelet agglutination. Results IPF values were about five times higher in MYH9 disorders (IPF 48.6 ± 1.9%) and about twice as high in other macrothrombocytopenias (IPF 18.4 ± 2.1%) than in immune thrombocytopenic patients with similar platelet counts (IPF 9.2 ± 0.3%). We then examined changes in IPF values during ethylenediaminetetraacetic acid- and macroglobulinemia-induced platelet agglutination. The IPF value significantly increased in a time-dependent manner along with the formation of platelet clumps and was strongly influenced by a few tiny platelet aggregates. Conclusions These results suggested that IPF values are influenced by platelet size. Furthermore, IPF could be a useful and convenient parameter for screening of macrothrombocytopenia, which presents with a disproportionately high IPF value.

Development of Pyothorax-Associated Pleural Lymphoma in Relation to Focal Cytokinemic Condition and Epstein-Barr Virus Infection

We report an initial case of pyothorax-associated pleural lymphoma (PAPL) in which the level of interleukin 6 (IL-6) was remarkably high in the pleural fluid contaminated with tumor cells; at the same time Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected in the lymphoma cells by in situ hybridization. These findings suggest the possibility that EBV-transformed B cells proliferated in the focal cytokinemic condition caused by long-standing chronic inflammation of the pleura and give us a clue to the lymphoma genesis of PAPL.

Biological Characteristics of Chronic Eosinophilic Leukemia Cells with a t(2;5)(p23;q35) Translocation

We studied the biological features of eosinophils in a patient with chronic eosinophilic leukemia and a unique t(2:5)(p23;q35) translocation. Microscopic and cytochemical studies revealed no particular abnormalities, although more than 90% of the peripheral eosinophils had a density lighter than 1.080 g/ml. Clonogenic assay disclosed that myeloid progenitor cells possessed the translocation, although in vitro eosinophilopoiesis seemed normal, and there were also hematopoietic cells with a normal karyotype. In a surface marker study, EG1 was positive on 34.0% of the eosinophils, while EG2 positivity was only 0.5%. Eosinophilopoietic growth factors and adhesion molecules were virtually absent with the exception of GM-CSF and CD11b. Functional studies showed that chemotaxis for C5a was normal, although that for IL-2 or FMLP was attenuated. In addition, leukotriene C4 production was decreased while O2- production was intact. These findings indicated that our patients eosinophils were not in an activated state despite their extreme hypodensity, and suggested that the leukemic eosinophils had slight defects of cellular function. These characteristics may have saved the patient from the multiple organ damage which occurs in typical hypereosinophilic syndrome.

Flow Cytometric Detection of Small Cell Lung Cancer Cells with Aberrant CD45 Expression in Micrometastatic Bone Marrow

A lot of hematologists are often faced with the difficulty of diagnosing bone marrow micrometastasis of carcinoma cells. We employed a new flow cytometric immunophenotyping by a combination of CD45 with three neuroendocrine markers: CD56, microtubule-associated protein-2 and synaptophysin, and successfully detected micrometastatic tumor cells in the bone marrow of a 61-year-old male patient with small cell lung cancer (SCLC), whose marrow smears never showed a distinct morphology of metastasis. It was noteworthy that these SCLC cells accompanied the aberrant expression of CD45, leukocyte common antigen known as a specific marker for hematolymphoid neoplasms, which was not detected in the tumor of primary lesion. We describe this rare case to arouse an attention that tumors of non-hematolymphoid origin can exhibit exceptional CD45-positvity in metastatic sites.

A case of giardiasis expressing severe systemic symptoms and marked hypereosinophilia.

An 88-year-old Japanese woman was referred to our hospital due to a one-month history of face edema, aphagia, shortness of breath, and skin rush over almost her entire skin. She had no abdominal symptoms. Her peripheral blood count showed a white blood cell (WBC) count of 27.1x10(9)/L with 82.1% eosinophils. Serum non-specific Immunoglobulin E was within a normal range. Soluble interleukin-2 receptor was elevated to 4200U/mL. At first, her eosinophil count was so high that we suspected she had an eosinophilic leukemia or hypereosinophilic syndrome. After admission, cysts of Giardia duodenalis (G. duodenalis) were detected in the patients feces by microscopic analysis, then she was diagnosed with giardiasis, and 750mg per day of metronidazole was administered for seven days. Her WBC count decreased to 6.0x10(9)/L with 10% eosinophils, and her systemic symptoms improved. At that time her serum IL-5 was within a normal range. A few months later, the patient again complained of skin rush, and G. duodenalis was once again found in her feces. Her serum IL-5 was elevated to 751pg/mL. Metronidazole was administered for two weeks, and her eosinophil count decreased. G. duodenalis is a protozoan parasite, and it is one of the most common waterborne transmission gastrointestinal parasites in the world. G. duodenalis rarely causes hypereosinophilia. To our knowledge, this is the first case report of giardiasis with extreme hypereosinophilia and severe systemic symptoms.

Incidence and clinical significance of aberrant T-cell marker expression on diffuse large B-cell lymphoma cells.

Introduction: Aberrant expression of T-cell markers is occasionally observed in B-cell lymphomas. We conducted a retrospective study to establish its incidence and to determine its relationship with clinical features of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods: We reviewed DLBCL patients diagnosed between January 2002 and April 2009. Patients fulfilled the following criteria: (1) age >18 years, (2) HIV negative, (3) B-cell lymphoma confirmed by restricted expression of surface immunoglobulin light chains by flow cytometry (FCM). Aberrant T-cell marker expression (ATCME) was defined as positivity for CD2, CD3, CD4, CD7, and/or CD8 on DLBCL cells by FCM. Phenotyping was also performed by immunohistochemistry (IHC). Patients were grouped according to positive or negative ATCME and their clinical features including survival were compared. Results: Of 150 patients, 11 (7.3%) showed ATCME; CD2 and CD7 were most often expressed. ATCME was less often detected and the signal was weaker using IHC. There were no statistically significant differences in clinical features between the two groups. Conclusions: FCM may be useful to detect ATCME in a small amount of lymphoma cells. The mechanism responsible for ATCME, and whether it contributes in any way to the pathogenesis of B-cell neoplastic transformation, requires clarification.

Lenalidomide-induced acute lung injury in case of multiple myeloma.

OBJECTIVE Lenalidomide is now widely used for the treatment of multiple myeloma in virtue of its potent anti-tumor activity and low toxicity. Very few reports stressed the association of this drug with serious pulmonary toxicity. Here we present the case of multiple myeloma who underwent acute respiratory failure caused by non-specific interstitial pneumonia after few days of treatment with lenalidomide. CASE SUMMARY A 50-year-old man diagnosed as multiple myeloma of IgA κ type, International Staging System III received a combination therapy of lenalidomide (15 mg, Day 1 - 21) with dexamethasone (40 mg, Day 1, 8, 15, 22). After 4 days on chemotherapy, he experienced worsened dyspnea and was urgently hospitalized because of acute respiratory failure. Because serial imaging procedures and thorough laboratory workup strongly suggested that his lung injury was caused by drug-induced interstitial pneumonia, lenalidomide, which was the most suspicious drug, was discontinued immediately, and the glucocorticoid pulse was performed. He showed an excellent response to the therapy. Interstitial pneumonia on the CT scan was resolved dramatically at 12 days after the start of the glucocorticoid pulse. CONCLUSION We are convinced that our case is so instructive as to arouse attention to clinicians that lenalidomide has an extremely rare but potential adverse effect.