A case of refractory multiple myeloma with proliferation of large granular lymphocytes by lenalidomide treatment and its association with clinical efficacy.

A 72-year-old Japanese male was diagnosed as having monoclonal gammopathy of undetermined significance and was followed up without therapy. Three years later, the patient progressed to symptomatic multiple myeloma. Melphalan + prednisolone was administered as first-line chemotherapy for ~6 years. Since the patient was judged to exhibit refractory multiple myeloma, he subsequently received radiation therapy on the lumbar spine. The patient was enrolled in a clinical trial and received lenalidomide + lowdose dexamethasone (Rd) therapy. The patient achieved very good partial remission following four cycles of Rd. At this time, large granular lymphocytes (LGLs) increased to 25-40% of peripheral blood leukocytes, however, the LGLs were present in the blood (~8%) prior to lenalidomide treatment. By flow cytometry of surface antigens, it was revealed that the LGLs were positive for cluster of differnetiation (CD)2, 7, 8, 16, 56, and 57, and human leukocyte antigen-D related, however, were negative for CD3, 4 and 5, suggesting that these LGLs predominantly exhibited an natural killer (NK) cell phenotype. T-cell receptor ß gene rearrangement was not detected by polymerase chain reaction. A 51Cr release assay was performed to investigate whether the NK cells actually possessed activity. A low level of M protein was sustained for ~15 months. This implied the enhancement of immune activation during lenalidomide treatment. The present case study suggested that LGL cells induced by lenalidomide may contribute to long-term restraint of myeloma cells. This immune system component may contribute to disease control.

Donor-derived 47, XXY in an unrelated cord blood transplant recipient.

A 65-year-old Japanese male with therapy-related myelodysplastic syndrome was admitted for unrelated cord blood transplantation. A cord blood unit from a male donor was obtained from the Japan Cord Blood Bank Network. The patient then received a conditioning regimen consisting of fludarabine, intravenous busulfan, and total body irradiation. Successful engraftment was obtained. The bone marrow examination on day 28 revealed trilineage engraftment, and chimerism analysis by variable number of tandem repeat polymerase chain reaction confirmed complete donor chimerism. At that time, conventional cytogenetics of the bone marrow aspirate showed 20 out of 20 metaphases with the 47, XXY karyotype characteristic of Klinefelter syndrome. Klinefelter syndrome is the most common genetic cause of human male infertility with a reported prevalence of 0.1-0.2% in the general population. In Japan Cord Blood Bank Network, there is no informed consent from parents about the possibility that post-unrelated cord blood transplantation patient evaluation may reveal donor-origin inherited diseases including cytogenetic abnormality. It is desirable to have opportunities in Japan discussing whether parents will be notified of the possibility that post-unrelated cord blood transplantation evaluation may reveal donor-derived illness incidentally.

Decreased serum levels of immunoglobulin A, immunoglobulin M and immunoglobulin G in a patient with primary biliary cirrhosis: A case report.

Primary biliary cirrhosis (PBC) is a cholestatic liver disease with an elevated serum immunoglobulin (Ig)M level. Patients with PBC may develop extrahepatic manifestations, including hypogammaglobulinemia. However, hypogammaglobulinemia seldom occurs, and the associated changes of lymphocytes remain unknown. Furthermore, the impact of Ig on the progression of PBC is still unclear. Here, we describe a case of hypogammaglobulinemia developed in a female patient with PBC. The patient was diagnosed with PBC at the age of 46 years and treated with ursodeoxycholic acid and bezafibrate. At the age of 50 years, the patient developed bronchitis, and laboratory test results indicated a marked decrease in serum levels of IgA, IgM and IgG. Then, the patient was diagnosed as having idiopathic hypogammaglobulinemia and treated with Ig replacement therapy; however, respiratory infections recurred frequently, leading to the patient's death at the age of 53 years. An autopsy revealed hyperplastic bone marrow with CD3, CD20 and IgG positive lymphocytes. However, no CD79a, CD138, IgA and IgM positive lymphocytes were observed. Moreover, the severity of PBC progressed even after the onset of hypogammaglobulinemia. In addition, CD3 positive cells were seen around chronic non-suppurative destructive cholangitis in the autopsy specimen of the liver. Thus, the present case demonstrated changes of lymphocytes in hypogammaglobulinemia developed in patients with PBC. Furthermore, the clinical course of the present case of PBC may indicate that the Ig-mediated mechanisms may be non-essential for the progression of PBC.

[Fatal zygomycosis caused by Mucor indicus after haplo-identical stem cell transplantation].

A 62-year-old woman with acute lymphoblastic leukemia in first complete remission was treated with unrelated cord blood transplantation, but exhibited primary graft failure. She then underwent HLA-haploidentical peripheral blood stem cell transplantation from her daughter. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days, intravenous busulfan 3.2 mg/kg/day for 2 days, and thymoglobulin 1 mg/kg/day for 2 days. Voriconazole was administered to prevent fungal infections. The patient achieved prompt hematopoietic recovery. Fever was observed 21 days after the second transplant, followed by sigmoid colon perforation and a liver space occupying lesion (SOL). A filamentous fungus was detected in a percutaneous biopsy of the liver SOL. In spite of changing the antifungal drug from voriconazole to liposomal amphotericin B, the patient died on day 41. The fungus was identified as Mucor indicus, a type of zygomycete. Although Mucor indicus inhabits soil, an infectious disease is extremely rare, and breakthrough infection after voriconazole prophylaxis had not been reported until now. It is mandatory to consider preventive antifungal treatment for drug-resistant fungal infectious diseases in patients after neutrophilic recovery with a strongly immunocompromised state after a HLA-haploidentical transplant.

Successful treatment of small cell variant anaplastic large cell lymphoma with allogeneic peripheral blood stem cell transplantation, and review of the literature.

The small cell variant of anaplastic large cell lymphoma (ALCL) presents in a nearly identical manner to the more common ALK(+) primary ALCL, with the exception that it is more frequently associated with leukemic involvement, and the prognosis has been reported to be poor. We report a 40-year-old Japanese male who was diagnosed with small cell variant ALCL with peripheral blood involvement stage IVB, age-adjusted international prognostic index 3. Conventional cytogenetics of the bone marrow aspirate specimen showed abnormal metaphases with the following karyotype: 47, XY, +X, t(2;5)(p23;q35). The patient was treated with acute lymphoblastic leukemia-oriented intensive chemotherapy. He underwent allogeneic peripheral blood stem cell transplantation from his HLA-DR1 locus mismatch sister. Prior to transplant, the patient had residual lymphadenopathy considered to be in partial remission. As of August 2012, the patient has achieved 18 months of continuous complete remission (CCR), with a Karnofsky score of 100 %. We have identified a total of seven cases of small cell variant ALCL treated with allogeneic hematopoietic stem cell transplantation (HSCT) in the literature. Of these, no relapse was reported, and four patients were CCR more than 1 year. Allogeneic HSCT appears to represent a promising treatment option for small cell variant ALCL.

A case of 8p11 myeloproliferative syndrome with BCR-FGFR1 gene fusion presenting with trilineage acute leukemia/lymphoma, successfully treated by cord blood transplantation.

The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11-12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11-12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date.

Unrelated cord blood transplantation for patients with adult T-cell leukemia/lymphoma: experience at a single institute.

We report the results of unrelated cord blood transplantation (UCBT) for patients with adult T-cell leukemia/lymphoma (ATLL) conducted in our single institute. Ten patients with ATLL (nine acute and one lymphoma-type) received UCBT during the period from August 2003 to July 2011. The median age at the time of diagnosis of ATLL was 51 years (range 37-64). The median period from diagnosis of ATLL to UCBT was 130 days (range 94-344). Conditioning regimens were myeloablative for six and reduced intensity for four. The median number of infused nucleated cells and CD34 positive cells were 2.52 × 10(7)/kg and 1.04 × 10(5)/kg, respectively. There was no engraftment failure. Three patients developed grade II acute graft versus host disease, and four developed grade III. The estimated 2-year overall survival was 40 % (95 % CI 12-67 %). Four of six chemosensitive patients prior to UCBT survived for 1035, 793, 712, and 531 days post-UCBT, respectively. There were no survivors among the four chemorefractory patients prior to UCBT. Our data indicates that UCBT is feasible and provides long-term survival in patients with chemosensitive ATLL.

[Amebic colitis and liver abscess complicated by high serum procalcitonin in acute myeloid leukemia].

We present a case of amebic colitis and liver abscess complicated by acute myeloid leukemia (AML) with high serum procalcitonin (PCT). A 61-year-old Japanese man seen at our hospital for severe diarrhea and high fever was found to have multiple ulcers in the transverse and sigmoid colon and rectum by colonoscopy and biopsies were conducted. Immature leukocytes with mild anemia and thrombocytopenia were seen in peripheral blood, necessitating bone marrow aspiration and biopsy that yielded a diagnosis of AML (FAB M4Eo). Serum C-reactive protein and PCT were extremely elevated. Blood cultures for bacteria and fungi were negative. Multiple low-density areas in the liver were found in abdominal computed tomography. Histological colon biopsy findings revealed amebic colitis, strongly suggesting amebic liver abscess. Metronidazole treatment was initiated for amebiasis and subsequent standard chemotherapy for AML was followed after fever was lowered. Hematological and cytogenetic CR was maintained with good clinical condition. Few case reports have been published in Japan to date on amebic colitis and liver abscess complicated by AML and no reports have been made on PCT elevation caused by amebiasis. In conclusion, differential diagnosis of amebiasis is necessary in addition to that of bacterial or fungal infection in serum PCT elevation.

Invasive pneumococcal disease in a traveler who returned from the Philippines: a case report and in vivo study of the isolate.

A 54-year-old Japanese man without underlying disease developed pneumococcal bacteremia and meningitis after traveling to the Philippines. The isolate demonstrated high affinity to the lung and invasiveness in vivo. The international travelers can import indigenous high virulent strains even if the bacterium is commonly isolated in the home country.

[Case of acute kidney injury related to intravenous zoledronic acid in a patient with multiple myeloma].

We report the first case of acute kidney injury related to intravenous zoledronic acid (ZA)in a patient with multiple myeloma in Japan. A 37-year-old male was diagnosed as having multiple myeloma (MM) of the Bence Jones lambda type. He showed a good response to two courses of vincristine, adriamycin and dexamethasone (VAD) therapy, and remarkable reduction was seen in plasma cells in bone marrow from 38.4% to 6.8% and 24-hour urine protein from 18.5 g/dL to 2.8 g/dL. At that time, serum Cr(s-Cr) of 0.7 mg/dL and calcium of 9.3 mg/dL were in the normal range. ZA was administered intravenously at the dose of 4 mg for the first time. Subsequently, he developed a fever of up to 39.4 degrees C and used NSAIDs and cefepime. Four days later, s-Cr increasd rapidly to 7.3 mg/ dL and he received hemodialysis (HD) therapy. Four weeks later, renal biopsy was performed and demonstrated cast nephropathy (CN) and acute tubular necrosis. Seven months later, renal function had improved. ZA may be an identifiable precipitating factor of CN. We recommend that ZA should be used with caution, especially hypovolemia and NSAIDs, in patients with MM and renal insufficiency.

Characterization of the light chain-restricted clonal B cells in peripheral blood of HCV-positive patients.

To investigate the association between hepatitis C virus (HCV) and B cell proliferation, we searched for the clonal B cells by flow cytometric analysis of the surface immunoglobulin kappa (kappa):lambda (lambda) light chain ratios of the circulating B (CD19+) cells in 240 HCV-positive patients and 150 negative controls with liver diseases. Clonal B cells with light chain restriction (kappa:lambda ratio >3:1 or <1:2) were analyzed for CD5 expression and the presence of monoclonal immunoglobulin heavy-chain (IGH) gene rearrangements and the t(14;18) chromosomal translocation. Clonal B cells were detected in 7 cases with HCV (2.9%), but was never detected in the controls (p < 0.05). Of the 7 cases, all had monoclonal IGH gene rearrangements and one had the t(14;18) chromosomal translocation. These HCV-related clonal B cells are not uniform in the intensity of CD5 expression and showed no increase in the frequencies of CD5+ population compared with non-clonal B cells. No "chronic lymphocytic leukemia-phenotype" cells were found. The loss of clonality was observed in 2 cases treated with interferon and in one case treated with splenectomy. The longitudinal study is required to determine whether these circulating clonal B cells progress to lymphoproliferative disorders in future or not.

Periostin and bone marrow fibrosis.

Periostin is a secreted protein that shares structural homology with the insect axon guidance protein fasciclin 1. Periostin is expressed predominantly in collagen-rich fibrous connective tissues that are subjected to constant mechanical stresses. We have shown previously that periostin is a novel component of subepithelial fibrosis in bronchial asthma. Here, we investigated the relationship between periostin and bone marrow (BM) fibrosis. Periostin was expressed in the stroma and stromal cells of BM fibrosis specimens and to a great extent its expression levels correlated closely to the grade of fibrosis, as estimated by silver staining. However, in the present study, we found no relationship between plasma periostin levels and the extent of BM fibrosis. We also demonstrated that periostin is secreted by human BM hTERT stromal cells and that its secretion is enhanced by TGF-beta, a cytokine produced by clonal proliferation of megakaryocytes and/or monocytes. These results indicate that periostin is a component of BM fibrosis and that it may play a role in the disease progression.

Promyelocytic crisis of chronic myelogenous leukaemia during imatinib mesylate treatment.

An untreated 66-year-old woman with chronic myelogenous leukaemia (CML) in the chronic phase was initially given imatinib mesylate, rapidly achieving a good cytogenetic response with treatment. However, acute promyelocytic leukaemia complicated by a disseminated intravascular coagulation occurred 9 months after beginning imatinib treatment. Promyelocytic crisis of CML was diagnosed by demonstration of both BCR/ABL and PML/RAR alpha chimeric genes in leukaemic cells by karyotypic and fluorescence in situ hybridization analysis. Clonal evolution with addition of the PML/RAR alpha translocation may have arisen in the early chronic phase of CML, with expansion of this clone during imatinib treatment. Promyelocytic crisis of CML is rare; furthermore, we know of no previous report of promyelocytic crisis occurring during treatment with imatinib.

Simultaneous hepatic relapse of non-Hodgkin's lymphoma and hepatocellular carcinoma in a patient with hepatitis C virus-related cirrhosis.

We report a 66-year-old man with hepatitis C virus (HCV)-related cirrhosis and simultaneous hepatic relapse of non-Hodgkin's lymphoma (NHL) and of hepatocellular carcinoma (HCC). Although the liver is frequently involved by NHL, hepatic colocalization of NHL and HCC is rarely detected by imaging techniques. HCV has been suggested to be lymphotrophic as well as hepatotrophic, and therefore has attracted speculation about a causative role in some cases of lymphoma. The patient had a past history of cutaneous diffuse large B cell lymphoma (DLBCL) in concurrence with HCC 32 months previously. Complete remission (CR) had been maintained for both diseases until February 2004, when ultrasonography and computed tomography (CT) showed multiple liver tumors. Two of these, appearing hyperattenuating in the arterial phase of contrast-enhanced CT, were diagnosed histopathologically as HCC, and treated with radiofrequency ablation. The other tumors, hypoattenuating in the portal phase CT, were diagnosed histopathologically as DLBCL, and treated with cyclophosphamide, tetrahydropyranyl-Adriamycin, vincristine and prednisolone (THP-COP) in combination with rituximab. CR was achieved for both DLBCL and HCC. Given the previously demonstrated immune system tropism and perturbation by HCV, the virus might have contributed to the occurrence of the NHL as well as the HCC.

Immunological evaluation of vaccination of peptides derived from epithelial cancer-related antigens in two patients with hematological malignancy.

Recent advances in tumor immunology have resulted in identification of many epithelial cancer-related antigens and peptides applicable to specific immunotherapy. We and others have reported that several epithelial cancer-related antigens are also expressed in hematological malignancies. Two patients with hematological malignancy (multiple myeloma and chronic lymphocytic leukemia) were vaccinated with peptides derived from epithelial cancer-related antigens to evaluate the immune responses to peptides under a personalized peptide vaccination regimen. There was no adverse event except for local skin reaction at the injection site. The peptide vaccination augmented both peptide-specific CTLs cytotoxic to hematological malignant cells in post-vaccination peripheral blood mononuclear cells and peptide-specific IgG in post-vaccination sera. A transient but obvious decrease of malignant cells was observed at the early phase of the vaccination in both cases. Vaccines consisting of peptides derived from epithelial cancer antigens safely increased anti-tumor cell activity in patients with hematological malignancies. These results may provide a scientific rationale in use of epithelial cancer-related antigens for specific immunotherapy to patients with hematological malignancies.

Blastoid variant of mantle cell lymphoma with lactic acidosis: a case report.

Approximately 20% of mantle cell lymphomas (MCL) present with the blastoid variant associated with poor prognosis. Lactic acidosis complicated with hematologic malignancies is seen infrequently and is associated with a poor outcome. Here we report the case of a patient with the blastoid variant of MCL complicated by lactic acidosis and who achieved complete remission through chemotherapy combined with rituximab therapy. A 77-year-old man presented with peripheral blood lymphoma cells, huge splenomegaly, abdominal and mediastinal lymphadenopathy, and pleural effusion. A bone marrow smear showed an increase in large, abnormal lymphoid cells with oval or round nuclei, distinct nucleoli, and abundant basophilic cytoplasm with vacuolization. Splenic sections also showed massive and diffuse infiltration by these cells. Flow cytometry analysis showed these cells to be positive for CD5, CD19, CD20, and kappa chain and negative for CD10 and CD23. A blastoid variant of MCL was diagnosed from the results of histologic, immunohistochemical (cyclin D1), and cytogenetic (chimeric bcl-1/IgH fusion gene) analyses. The patient recovered from the 2 episodes of severe lactic acidosis for which he had been given chemotherapy, and he achieved complete remission after subsequent chemotherapy combined with rituximab treatment.

B-Flow contrast US with Levovist in hepatic tumors: preliminary results.

Usefulness of Levovist contrast ultrasonography by the B-Flow method was evaluated in cases of hepatic tumor. Subjects included 14 patients with moderately differentiated hepatocellular carcinoma and 4 patients with hepatic hemangioma. Each patients had a single tumor mass. Images showed strong staining in 11 of the 14 nodes in the hepatocellular carcinomas and all 4 hemangiomas. Staining was seen only in lesions located within 4 cm of the probe. Thus B-Flow ultrasonography using Levovist was proved useful for evaluating vascularity of superficially located.

Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma.

The F-box protein Skp2 positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has suggested an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. In this study, we performed immunohistochemical analysis on the cell-cycle-associated proteins, Skp2, p27, and Ki-67, in 27 patients with de novo diffuse large B-cell lymphoma (DLBCL), evaluating the correlation between the clinical characteristics and expression levels of these proteins. The patients were classified into two groups according to the positivity for Skp2 expression: a high Skp2 expression group (>60% positive for Skp2 in lymphoma cells) and a low Skp2 expression group (< or = 60%). A high level of Skp2 expression significantly correlated with advanced clinical stage (P = 0.029), although the increase did not correlate with age, gender, LDH levels, presence of extranodal disease, or performance status and resulted in no correlation with the International Prognostic Index-based risk grading. However, it was noteworthy that the high Skp2 expression group demonstrated a significantly worse prognosis than the low Skp2 expression group (P = 0.0007). The expression level of Skp2 correlated with that of Ki-67 but not necessarily with that of p27. The p27 expression level did not correlate patients' prognosis. Taken together, it was suggested that Skp2 was a valuable and independent marker predicting the outcome in DLBCL.