Cryptosporidiosis in a transplant recipient with severe intractable diarrhea : Detection of Cryptosporidium oocysts by intestinal biopsies

Disseminated Cryptosporidium infection results in manifestations similar to those of graft‐versus‐host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation

Busulfan for lymphoma with CNS involvement

The prognosis of relapsed or refractory lymphoma with central nervous system (CNS) involvement remains poor because of the lack of anticancer drugs with sufficient CNS penetration. [Case 1] A 65-year-old man was diagnosed with Stage IV mantle cell lymphoma. After two courses of chemotherapy and autologous hematopoietic stem cell (HSC) collection, urinary retention with fever developed. Cerebrospinal fluid analysis revealed leptomeningeal involvement, which was refractory to high-dose methotrexate therapy. Autologous peripheral blood stem cell transplantation (ASCT) was performed, followed by intravenous busulfan (ivBU), cyclophosphamide, and etoposide ; thereafter, no relapse has been detected for over six years. [Case 2] A 40-year-old woman with right lower hemiplegia was diagnosed with primary CNS lymphoma. Although four courses of high-dose methotrexate therapy were administered, the cerebral tumor increased in size. HSCs were collected after methotrexate therapy, and ASCT was performed in addition to conditioning using ivBU, cyclophosphamide, and etoposide, followed by whole-brain and local boost irradiation. She achieved complete remission, but relapsed two years after ASCT. High-dose ivBU-containing conditioning regimens with ASCT may be useful for refractory B-cell lymphoma with CNS involvement

ドウケイ コツズイ イショク ガ チョコウ シタ サイジュウショウ サイセイ フリョウセイ ヒンケツ ノ 1レイ

Aplastic anemia is a bone marrow failure caused by severely curtailed hematopoietic stem cells （HSCs） and dysregulation of ambient immune cells. Immumo-suppressive conditioning followed by allogeneic HSC transplantation is currently a mainstay in treatment for patients at a younger age or those refractory to conventional immunosuppressive remedies. Syngeneic HSC transplantation appears to be promising, but has been very rarely performed ; therefore, its impact on a long-term outcome as well as the best preparative measures for HSC engraftment and immune amelioration are still largely unknown. Here, we reported a successful and beneficial syngeneic HSC transplantation for a refractory case with very severe aplastic anemia. A 30-year-old female presented high fever after tooth extraction, and was diagnosed with very severe aplastic anemia. Cyclosporine and anti-thymocyte globulin were initiated, but showed no hematological effects. After obtaining an informed consent, she underwent bone marrow transplantation from a genetically identical twin following an non-myeloablative conditioning regimen consisted of cyclophosphamide （750mg/m２, 4 days）, fludarabine phosphate （25mg/m２, 4 days）. Cyclosporine was given for acute GvHD prophylaxis. Her neutrophils recovered over 500/μl on 12 days after the transplantation, and her blood counts have been maintained in a normal range over 7 years thereafter. Although a fate of HSCs from a genetically identical twin and an immune response of ambient cells in the bone marrow in recipients remains largely unknown, from the present case and previously reported cases, we dare to recommend immunoablative conditioning and acute GvHD prophylaxis in syngeneic HSC transplantation for a refractory case with aplastic anemia for better engraftment and sustained onward recovery of hematopoiesis

臍帯血移植が奏効した肝脾型T細胞リンパ腫

Cord blood for transplant is collected from the umbilical cord and donated cord blood is tested, frozen and stored for future use. Cord blood stem cell transplantation（CBT）do not have to be as closely matched as bone marrow or peripheral blood stem cell transplantations, therefore we are able to perform CBT for refractory patients at optimal timing. Here, we report a ３３ years old woman with refractory hepatosplenic T-cell lymphoma（HSTL）who achieved complete response ; CR after unrelated CBT. She complained of fever and abdominal pain, she was diagnosed with HSTL. She was refractory to several chemotherapy regimens, we planned to allogenic transplantation for her. However, she had no HLA-matched sibling donors and we were not able to find favorable unrelated donors from Japan Marrow Donor Program. Therefore, we decided to perform CBT for her. We used fludarabine（１８０mg/m2）, busulfan（１２．８mg/kg）and melphalan（８０mg/m2） as conditioning regimens and we chose tacrolimus and MMF for graft versus host disease（GVHD） prophylaxis. On day ２２ after transplantation, her neutrophil count engrafted, she suffered from acute GVHD（skin, gastrointestinal tract, grade２）, she was improved by medical treatment. She achieved CR her disease status maintained over two years after CBT. HSTL is often refractory to chemotherapy, the clinical efficacy of hematopoietic stem cell transplantation may be expected. Our case suggests that CBT may be effective and feasible option for refractory HSTL who has no favorable HLA-matched donors

同種移植後のHBV再活性化の後方視的検討

Reactivation of hepatitis B has been recognized as a careful adverse event after chemotherapies or immunosuppressive therapies because chronic hepatitis B leads to carcinoma and/or liver cirrhosis. Allogenic hematopoietic stem cell transplantation（allo-HSCT）against hematological diseases induces severe immunosuppression including reconstitution of naïve donor immunity against HBV-infected hepatocytes and we therefore need to follow-up HBV testing for a long term. In order to establish how to follow-up HBV-infected patients with receiving allo-HSCT, we retrospectively studied HBV serological markers and HBV-DNA in the HBV-infected patients, who received allo-HSCT and followed-up more than １ year in our single center. We detected ７ HBV-infected and allo-HSCT-received patients, and HBV reactivation was occurred in ３ patients with detecting HBV-DNA. No patients were died due to HBV reactivation. The HBV reactivation period after receiving allo-HSCT was １６，２０，７９ months, respectively. All the ３ patients received nucleoside analogues（NUCs）; however, the appearance of viral mutation was occurred in one patient who received lamivudine and already detected HBs-Ag before allo-HSCT. The HBV reactivation was controlled with addition of adefovir. Others were due to discontinuation of entecavir, which reason was poor medication-adherence after stopping immunosuppressive therapies. These two patients received tenofovir alafenamide in addition or retreated with entecavir, respectively, leading to disappearing of HBV-DNA. HBs-Ab were disappeared in ３１ months after allo-HSCT in one patient, and then the Ab was detected after occurring HBV reactivation, suggesting reconstitution of donor immunity. Taken together, our findings suggest that we need to follow-up immune-reconstitution and regularly evaluate HBV serological markers and HBV-DNA, in addition to maintain medication-adherence

Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase

Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM

TAK1 inhibition in myeloma

Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 in order to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSC) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSC. TAK1 inhibition effectively impaired MM cell adhesion to BMSC to disrupt the support of MM cell growth and survival by BMSC. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM

CD20陰性DLBCL

A ６８-year-old woman presented with sustained fever for more than １ month and admitted due to hematemesis and systemic edema. Computed tomography scan revealed swelling of the cervical, paraaortic lymph nodes. Blood test results showed severe anemia, elevation of white blood cell count, elevation of liver enzyme and coagulopathy with high C-reactive protein. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells with necrosis and hemorrhage, which are positive for CD７９α, CD３０, MUM‐１, and bcl‐６ and negative for CD２０, CD５, CD１０, ALK, CD３８, CD１３８, and EBER. Gene rearrangement of immunoglobulin heavy chain was detected in tumor cells. Bone marrow aspiration showed tumor involvement. The patient was diagnosed with de novo CD２０‐negative diffuse large B-cell lymphoma（DLBCL）stage IV B. Reduced CHOP therapy was performed under artificial respiration due to pulmonary edema and takotsubo cardiomyopathy. Although her general condition and high CRP levels temporarily improved, she died ４７ days after admission due to rapid relapse. De novo CD２０‐negative DLBCL was rare and presented with high CRP levels and rapid progression, and was thought to be clinically different from the existing DLBCL. It is imperative to elucidate molecular pathophysiology and establish new treatment strategy for de novo CD２０‐negative DLBCL