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

Multiple myeloma with high adenosine deaminase expression

A 50-year-old man with immunoglobulin A type multiple myeloma (MM) was referred to our hospital after bortezomib therapy. He had high alkaline phosphatase and lactate dehydrogenase levels. Computed tomography showed osteolytic and osteoblastic bone lesions. Response to salvage chemotherapy was temporary, and he developed a right pleural effusion with high adenosine deaminase (ADA) levels. He died from bleeding associated with a pelvic bone fracture 9 months later. ADA mRNA expression and ADA secretion of the MM cells from the patient were higher than those from myeloma cell lines tested. Clinical relevance of high ADA expression in MM cells is warranted

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

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis

HTVL‐1キャリアへの免疫抑制療法中に発症したATLL

A ６４-year-old woman presented with lower leg edema, fever, and bilateral joint pain, involving the wrists, fingers, and knees, in April ２０１X. Serological test results were negative for rheumatoid factor, antinuclear antibody, and anti-cyclic citrullinated peptide antibody. A diagnosis of remitting seronegative symmetrical synovitis with pitting edema syndrome, a type of seronegative rheumatoid arthritis, was made and prednisolone was administered. The joint pain was refractory to prednisolone therapy. In February, ２０１X＋２, the patient presented with right cervical lymphadenopathy. The CT scan revealed swelling of the cervical, axillary, and inguinal lymph nodes bilaterally and rapidly enlarged. In April, １８F-fluorodeoxyglucose PET/CT scan showed an abnormal collection in the enlarged lymph nodes. The patient subsequently developed hoarseness with dyspnea and attended our department. Blood test results showed high levels of lactate dehydrogenase （５４７U/L） and soluble interleukin‐２ receptor （３４２００ IU/L） and were positive for anti-human T-cell leukemia virus type１ （HTLV‐１） antibody. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells positive for CD３, CD４, and CD２５ and negative for CD７. Monoclonal integration of HTLV‐１ proviral DNA was detected in the lymph node. A diagnosis of adult T-cell leukemia/lymphoma （ATLL）, lymphoma type was made. The pain involving multiple joints was attributed to HTLV‐１associated arthropathy. Immunosuppressive therapy for HTLV‐１ carrier status may have played a role in the development of ATLL

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

インターフェロン-γと協調したパノビノスタットによる骨髄腫細胞のPD-L1発現誘導

Immunotherapy is revolutionizing the treatment paradigm for multiple myeloma (MM). Interferon (IFN)-γ is essential for immune responses, whereas immune checkpoint molecules, such as programmed cell death-1 ligand-1 (PD-L1), mitigate the beneficial anti-tumor immune responses. As HDAC inhibitors alter the immunogenicity and anti-tumor immune responses, we here explored the regulation of PD-L1 expression in MM cells by the clinically available HDAC inhibitor panobinostat in the presence of IFN-γ. IFN-γ activated the STAT1-IRF1 pathway to upregulate PD-L1 expression in MM cells, and panobinostat was able to upregulate their PD-L1 expression without activating the STAT1-IRF1 pathway. Of note, panobinostat enhanced IFN-γR1 expression, which substantially increased the total and phosphorylated levels of STAT1 protein but reduced IRF1 protein levels through proteasomal degradation in the presence of IFN-γ. Panobinostat further enhanced the IFN-γ-mediated durable STAT1 activation in MM cells; STAT1 gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-γ in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-γ-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-γ. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat