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Regarding viral infection of intestinal mucosa, there have been only a few studies on limited diseases, targeting a few herpes family viruses. In this study, we analyzed 12 kinds of DNA viruses including 8 species of herpes family viruses in the gastrointestinal mucosa of patients with hematologic malignancies, inflammatory bowel diseases, collagen diseases, or other miscellaneous forms of gastroenteritis using the multiplex virus PCR assay, which we recently developed. The virus PCR assay yielded positive results in 63 of 102 patients; Epstein-Barr virus (EBV) was the most frequently detected, followed by cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, parvovirus B19, and herpes simplex virus type 1. The frequencies of viral detection in the 4 diseases were similar involving these 6 viruses. Regarding CMV colitis, the multiplex virus PCR assay was superior to the immunohistopathologic method in detecting CMV. All viruses were more efficiently detected in the mucosa than in the blood in individual patients. These results suggest that CMV, EBV, and HHV-6 were commonly detected in the gastrointestinal mucosa of patients with these 4 diseases, and our multiplex virus PCR assay was useful for the early diagnosis of gastrointestinal virus infection, especially CMV colitis.

Giant cell arteritis (GCA), a type of systemic arteritis, is rare in Japan. We herein report a case of acute myeloid leukemia (AML) complicated by GCA that manifested during chemotherapy for AML. A 77-year-old woman with severe back pain was diagnosed with AML. She achieved complete remission with the resolution of her back pain following induction chemotherapy. However, she developed a headache and fever after consolidation chemotherapy. A diagnosis of GCA was made based on a biopsy of the temporal artery and arterial imaging. GCA should therefore be included in the differential diagnosis in AML patients complicated with a headache and fever of unknown origin.

T-cell prolymphocytic leukemia, small cell variant (T-PLL-s), is a rare lymphoid neoplasm associated with a poor prognosis. We encountered a case of T-PLL-s with a characteristic phenotype. A 67-year-old female was referred to our hospital because of lymphocytosis in August 2013. Hepatosplenomegaly, lymphadenopathy, and skin lesions were absent. Hematologic examination revealed a white blood cell count of 17.9 × 10(9)/L with 81.2% mature lymphocytes, which were small with a high nuclear/cytoplasmic ratio, lacking a nucleolus and cytoplasmic granules. Anemia and thrombocytopenia were not observed. Flow cytometric analysis showed that these lymphocytes were positive for CD2, cyCD3, CD4, CD5, CD7, CD21, and CD38 (partially), but negative for smCD3, smTCR-αβ and -γδ, cyTCR-β, CD1a, CD8, CD25, HLA-DR, and terminal deoxynucleotidyl transferase. Polymerase-chain reaction analysis of cells from both the peripheral blood and the bone marrow demonstrated monoclonal rearrangement of TCR-γ. A possible rearranged band of the TCR-β gene was observed by Southern blot analysis. The karyotype of the marrow cells was 46, XX. A diagnosis of T-PLL-s, possibly at the stage of cytoplasmic CD3 expression in the ontogenesis of T-cells, was made. The patient has been asymptomatic, and the white blood cell count has gradually increased during one-year observation, being 69.0 × 10(9)/L with 89.7% lymphocytes in August 2014.

A diagnosis of acute promyelocytic leukemia (APL) is usually made when normal hematopoietic cells are substituted by APL cells. We encountered a unique APL patient who presented with persistent hypoplastic features of APL. An 84-year-old man presented with leukopenia (2.2 × 10(9)/L) and anemia (Hb 12.5 g/dL). Five months later, the bone marrow (BM) was hypoplastic with a normal proportion of blasts and promyelocytes (5.2%), although the latter cells were hypergranular. The karyotype of BM cells was 46, XY, t(15;17)(q22;q12), t(9;11)(q13;p13). Two months later, the BM remained hypoplastic with 8.5% hypergranular promyelocytes, some of which contained faggot of Auer rods. RT-PCR examination yielded the PML-RARα transcript, and its sequencing revealed the breakpoint of PML to be bcr2. The patient was treated with all-trans retinoic acid under a diagnosis of APL with improvement of the bicytopenia. FISH analysis of BM cells yielded a negative result regarding t(15;17), although RT-PCR was positive for PML-RARα mRNA. Six months later, APL recurred with the same karyotypic abnormalities and therapeutic resistance, and the patient died of pneumonia. A persistent hypoplastic state of APL may be a rare event, and the association of t(15;17) and t(9;11) is novel.

Scedosporium prolificans (S. prolificans) is a type of mold, which rarely affects immunocompromised people. We treated a 71-year-old woman with acute myeloid leukemia (AML-M5a) with low-dose cytarabine, acralubicin, and filgrastim as the induction therapy. On day 7 after the initiation of chemotherapy, she became febrile and agranulocytic, and developed anal pain ; therefore, we discontinued the chemotherapy on day 8. Broad-spectrum antibiotics, micafungin, and then liposomal amphotericin B were ineffective. The serum concentration of β-D-glucan was 525 pg/mL. She died of multiple organ failure on day 17. S. prolificans was detected from the blood culture on day 13. Physicians should consider Scedosporium spp. infection when principal antifungal agents are ineffective and fungal infection is strongly suspected.

A 30-year-old woman developed severe liver dysfunction 1 year after bone marrow transplantation (BMT) from an HLA-identical sibling donor for B lymphoblastic leukemia (B-ALL) during the tapering of cyclosporin A. The histologic picture resembled autoimmune hepatitis (AIH), although neither autoantibody nor hypergammaglobulinemia was detected. She entered hepatic coma, and underwent living donor liver transplantation from the same donor on day 421 after BMT. She is well 18 months after the procedure, showing normal liver function and hematopoiesis. AIH-like hepatic graft-versus-host disease (GVHD) has not been documented. This patient is the second case of living donor liver transplantation for hepatic GVHD from the same donor.

A 47-year-old woman with marked thrombocytosis of 1,650 × 10(9)/L was diagnosed with chronic eosinophilic pneumonia (CEP) based on imaging of the lung and abundant eosinophils in bronchoalveolar lavage fluid. Known gene abnormalities that cause eosinophilia were not detected in bone marrow cells. Treatment with oral prednisolone at 20 mg/day relieved the CEP and resolved the laboratory abnormalities, including eosinophilia and thrombocytosis. Serum concentrations of interleukin (IL)-5 and IL-6 were elevated to 9.6 and 14.0 pg/mL, respectively. The megakaryocyte-potentiating activity of IL-6 and possibly, that of IL-1β, which is known to be secreted by activated eosinophils, may have caused the marked thrombocytosis in this patient.

The isolation and characterization of living human epithelial stem cells is difficult because distinguishing cell surface markers have not been identified with certainty. Side population keratinocytes (SP-KCs) that efflux Hoechst 33342 fluorescent dye, analogous to bone marrow-derived side population (SP) hematopoietic stem cells, have been identified in human skin, but their potential to function as keratinocyte stem cells (KSCs) in vivo is not known. On the other hand, human keratinocyte populations that express elevated levels of beta1 and alpha6 integrins and are distinct from SP-KCs, which express low levels of integrins, may be enriched for KSCs based on reported results of in vitro cell culture assays. When in vitro assays were used to measure total cell output of human SP-KCs and integrin-bright keratinocytes, we could not document their superior long-term proliferative activity versus unfractionated keratinocytes. To further assess the KSC characteristics in SP-KCs and integrin-bright keratinocytes, we used an in vivo competitive repopulation assay in which bioengineered human epidermis containing competing keratinocyte populations with different human major histocompatibility (MHC) class I antigens were grafted onto immunocompromised mice, and the intrinsic MHC class I antigens are used to quantify expansion of competing populations. In these in vivo studies, human SP-KCs showed little competitive expansion in vivo and were not enriched for KSCs. In contrast, keratinocytes expressing elevated levels of alpha6 integrin and low levels of CD71 (alpha6-bright/CD71-dim) expanded over 200-fold during the 33-week in vivo study. These results definitively demonstrate that human alpha6-bright/CD71-dim keratinocytes are enriched with KSCs, whereas SP-KCs are not.

We report here the successful treatment of cold agglutinin-associated refractory hemolysis with bortezomib in a patient with Waldenstrom’s macroglobulinemia (WM). A 78-year-old man was referred to our hospital with cold hemagglutinemia of unknown cause. Laboratory examination revealed a hemoglobin concentration of 6.9 g/dL, serum IgM concentration of 1904 mg/dL, and a titer of cold hemagglutinin of over ×8192. Serum immunoelectrophoresis demonstrated monoclonal protein of the IgM-κ type. A bone marrow aspirate showed many lymphoplasmacytic cells, which were positive for CD19, CD20, CD38, and cytoplasmic μ and κ light chains. A diagnosis of WM-associated cold hemagglutinemia was made. Because of red blood cell transfusion-dependency, we treated him with intravenous fludarabine, oral melphalan–prednisolone, cyclophosphamide, and melphalan, and two courses of R-CHOP in sequence with a marked decrease of serum IgM (928 mg). We then started weekly bortezomib plus dexamethasone (BD) therapy, as he was still transfusion-dependent. Soon after the initiation of BD, he achieved transfusion independence, with a further decrease in serum levels of IgM and marked improvement of anemia. Interestingly, his marrow abnormal lymphocytes were later found not to carry the MYD88 L265P mutation. The successful treatment with bortezomib for WM lacking this mutation is discussed.

Recurrent acyclovir (ACV)-resistant (ACV-r) herpes simplex virus type 1 (HSV-1) infections occurred in a patient with Wiskott-Aldrich syndrome, an X-linked recessive immunodeficiency syndrome composed of three clinical characteristics of immunodeficiency, thrombocytopenia, and an eczematous dermatitis. The patient had severe and recurrent ACV-r herpes simplex and was treated with vidarabine in a satisfactory manner from 1993 to 1997. During the 4-year observation period, two ACV-sensitive (ACV-s) HSV-1 isolates and five ACV-r HSV-1 isolates were recovered. The nucleotide sequence of the thymidine kinase (TK) gene from these sequential ACV-r isolates was compared with the ACV-s isolates. A single nucleotide deletion of cytosine (C) from homopolymer stretch of four C residues between nucleotide 1061 and 1064 of the open reading frame was found in all ACV-r isolates. No other differences were observed in the TK nucleotide sequence between ACV-s and ACV-r isolates. The TK nucleotide sequences of the two ACV-s isolates were identical to each other and those of the five ACV-r isolates were identical to one another. These results suggest that the ACV-r HSV-1 might have derived from the ACV-s strain in the patient body and that TK-associated ACV-r HSV-1 can reactivate from latency.

We report a patient with aggressive systemic mastocytosis (SM), who exhibited eosinophilia and unusual destructive bone lesions. A 43-year-old female was referred to our hospital because of a vertebral compression fracture, multiple lytic bone lesions, and eosinophilia in February 2011. A diagnosis of aggressive SM was made on the basis of abnormal mast cells in the bone marrow, high serum tryptase levels, and multiple lytic bone lesions including vertebral compression fractures. Polymerase chain reaction and subsequent sequencing of its products to identify mutations of c-kit yielded negative results and imatinib mesylate failed to improve the SM of the patient. She was then treated with interferon-α, with considerable improvement of the disease, although severe myelosuppression prevented the continued administration of a sufficient dose of this agent. In August 2011, the patient suddenly developed paraplegia of the lower extremities. Magnetic resonance imaging demonstrated epidural mass lesions at the levels from Th9 to Th11, compressing the spinal cord. Emergent laminectomy and subsequent irradiation of the tumors were performed without improvement of the paraplegia. Histopathologic examination of the epidural tumors, from samples obtained intraoperatively, confirmed the diagnosis of SM. She was further treated with dasatinib and then cladribine without obvious improvement, although the latter reduced the eosinophilia to some extent ; however, she died of sepsis in September 2011.

A 47-year-old man was diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in October 2005. He could not receive treatment with imatinib mesylate due to his economic circumstances. He was consequently treated with hydroxyurea with partial hematological remission until June 2008. Although imatinib mesylate was started thereafter, the adherence to this treatment was poor because of his occupational circumstances. In September 2009, imatinib mesylate was switched to nilotinib, with a subsequent phase of acceleration of the disease, presumably due to his poor adherence to the treatment. Dasatinib was started in September 2010, with transient hematological response and final blastic crisis of the disease in January 2011, regardless of improved adherence. Blast cells showed immature monocytic morphology and were positive for α-naphtylbutyrate esterase staining. They also expressed surface CD14 and CD64 antigens. A diagnosis of rare monocytic crisis of CML was made. He was treated with low-dose nilotinib following cytoreduction with MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy. Severe leucopenia without circulating leukemic cells continued for about 2 months with sustained hepatosplenomegaly, and he died of pneumonia in March 2012. Necropsy showed severe bone marrow hypoplasia with focal infiltration of mature leukemic cells and similar infiltration in the liver.

A 19-year-old girl with T-lymphoblastic lymphoma (T-LBL) was referred to our hospital because of refractory disease. After complete remission was achieved by the JALSG ALL-97 protocol, she received a bone marrow transplantation (BMT) from an unrelated, HLA-matched donor with myeloablative conditioning. Four months after BMT, T-LBL relapsed and donor lymphocyte infusion was ineffective. After partial remission was achieved with l-asparaginase therapy, she received 2 antigen-mismatched cord blood transplantation with non-myeloablative conditioning; however, sustained engraftment of cord blood stem cells has failed. This was associated with the reappearance of the blood cells from the first donor and the disappearance of leukemic cells from both the peripheral blood and bone marrow. Computed tomography showed no enlarged lymph nodes. The patient and the cord blood donor shared two minor histocompatibility antigens (mHAgs), while these mHAgs were not detected in the blood cells of the first donor. TCR analysis disclosed expanded oligoclonal Vbeta2T cells in the peripheral blood at relapse, and these cells secreted IFN-gamma in response to stimulation by the patient's leukemic cells. Moreover, these cells exhibited cytotoxicity against both leukemic cells and cord blood mononuclear cells. These results strongly suggest that Vbeta2T cells, derived from the first donor, may have been cytotoxic lymphocytes against both leukemic cells and cord blood stem cells.

A 30-year-old woman developed severe liver dysfunction 1 year after bone marrow transplantation (BMT) from an HLA-identical sibling donor for B lymphoblastic leukemia (B-ALL) during the tapering of cyclosporin A. The histologic picture resembled autoimmune hepatitis (AIH), although neither autoantibody nor hypergammaglobulinemia was detected. She entered hepatic coma, and underwent living donor liver transplantation from the same donor on day 421 after BMT. She is well 18 months after the procedure, showing normal liver function and hematopoiesis. AIH-like hepatic graft-versus-host disease (GVHD) has not been documented. This patient is the second case of living donor liver transplantation for hepatic GVHD from the same donor.