Severe thrombocytopenia and maculopapular erythema-induced by regorafenib in a patient with advanced gastrointestinal stromal tumor

　A 28-year-old Japanese male was diagnosed with a gastrointestinal stromal tumor and multiple liver metastases at 23 years of age underwent gastrectomy and partial hepatectomy. At 27 year of age, multiple liver metastases and peritoneal dissemination were observed and the patient was switched to sunitinib. Approximately, one year later, the liver metastases worsened, and the patient was switched to regorafenib. Fatigue and palmar-plantar erythrodysesthesia syndrome occurred seven days after starting regorafenib, and thrombocytopenia occurred nine days later. Eleven days later, small erythema with fever and erythematous papules appeared throughout the body; therefore regorafenib was discontinued, and oral administration of steroids was initiated accordingly. After 17 days, platelets count decreased to 14,000/μL, prompting platelet transfusion. Maculopapular erythema was diagnosed based on the skin findings and histopathological examination. Oral and topical steroids were initiated and the maculopapular eruption gradually improved. A drug hypersensitivity reaction to regorafenib was diagnosed and treatment was discontinued, after which the patient entered a clinical trial for a new drug. We encountered a case of marked thrombocytopenia and maculopapular erythema during the early stages of regorafenib treatment. Regorafenib occasionally causes serious adverse events; therefore, careful observation and prompt treatment are necessary

Folliculotropic mycosis fungoides treated with electron beam therapy that evolved into fatal, tumor-stage mycosis fungoides and erythroderma with multiple ulcerations

　A 71-year-old woman diagnosed with mycosis fungoides with multiple erythematous plaques and follicular papules on the scalp, trunk, and thigh was referred to our institution. Folliculotropic mycosis fungoides was histologically diagnosed, and the erythematous papules and plaques regressed temporarily after total-skin electron beam therapy. The patient then developed tumors and erythroderma. The area of painful erosion spread, and her condition rapidly worsened. The patient died 3 years and 4 months after the first examination due to multiple organ failure caused by sepsis. The cause of rapid evolution into erythroderma remains elusive and requires further investigation in similar cases

Sphingosine-1-phosphate receptor 1 expression in angiosarcoma : Possible role in metastasis and a potential therapeutic target

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that has been implicated in the migration of lymphocytes and endothelial cells through S1P receptors. S1PR1 is strongly expressed in angiosarcoma, a malignant tumor of endothelial cell origin that has a high propensity for metastasis and poor prognosis; however, the pathological significance of S1PR1 expression is not clear. In this study, we investigated the effect of S1PR1 modulation on cell migration, and examined its potential role as a therapeutic target against metastatic dissemination of angiosarcoma. S1PR1 expression in the human angiosarcoma cell line MO-LAS was assessed by immunocytochemical examination and Western blotting. Effects of S1PR1- specific small interfering RNA (siRNA) and that of FTY720-P (a functional S1PR1-antagonist) on MO-LAS cell chemotactic migration towards sphingosine-1-phosphate (S1P) or 10% fetal bovine serum (FBS) were assessed by Transwell migration assay; wound healing assays for random cell migration were performed using a live cell analyzer. Immunostaining revealed high expression of S1PR1 on the MO-LAS cell membrane. Transwell and wound-healing assays showed that S1P enhanced chemotactic and random migration of MO-LAS cells, respectively. Inhibition of S1PR1 expression with siRNA significantly attenuated chemotaxis of cells towards S1P and 10% FBS. Further, FTY720-P strongly induced the internalization and degradation of S1PR1 even in the presence of serum containing S1P. It attenuated chemotactic cell migration of MO-LAS towards both S1P and serum, as well as the random motility of cells at nanomolar concentrations. These results suggest that the S1P/S1PR1 axis may be a potential therapeutic target for inhibition of angiosarcoma metastasis by controlling its cell motility

赤芽球癆を合併したT-cell large granular lymphocyte leukemia の一例

T-cell large granular lymphocyte leukemia は長期(6か月以上)にわたる末梢血中の著明な大顆粒リンパ球(large granular lymphocyte;以下,LGL)のモノクローナルな増加によって特徴づけられる疾患で,しばしば赤芽球癆を伴うことが知られている.今回,我々はHCV陽性肝硬変患者に赤芽球癆を合併したT-LGLの1例を経験した.末梢血および骨髄塗抹標本では細胞質内に微細なアズール顆粒を有し,核異型を示すリンパ球の増加がみられ,末梢血および骨髄のフローサイトメトリーおよび骨髄吸引クロット標本の免疫組織化学で,CD3,CD8,CD57陽性リンパ球の増加が確認された.骨髄細胞のPCRではTCRβの再構成を認めず,TCRγおよびTCRδの再構成がみられた.またプレドニゾロン治療にてCD57陽性リンパ球の減少および赤芽球造血の回復が確認されたことから,赤芽球癆を合併したγδT-LGLと診断した.最近,T-LGLにはSTAT3あるいはSTAT5bのSHドメインの遺伝子変異が高頻度にみられることが報告されているが,本症例においては,これらの遺伝子変異は確認できなかった.T-cell large granular lymphocytic leukemia (T-LGL) is characterized by marked increase of monoclonal large granular lymphocytes (LGL) in the peripheral blood over the long term (6 months or more). It has been reported about 20% cases of T-LGL cases are associated with pure red cell aplasia (PRCA). Here, we describe a case of T-LGL associated with PRCA. This case was characterized by increase in the number of CD3+,CD8+,CD57+, and granzyme B-positive lymphocytes with fine azurophilic cytoplasmic granules and nuclear atypia in peripheral blood and bone marrow. The patient was diagnosed havingγδT-LGL because T-cell receptor (TCR)γ and TCRδ gene but not TCRβ gene rearrangement was detected by the PCR of the bone marrow cells. Prednisolone administration decreased in number of the LGL cells, accompanying recover of erythropoiesis. Although somatic mutations in the Src homology 2 domain of STAT3 or STAT5b gene are reported in 70% percent of the T-LGL with PRCA, such STAT mutations could not be detected in this case

Severe thrombocytopenia and maculopapular erythema-induced by regorafenib in a patient with advanced gastrointestinal stromal tumor

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Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease

Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NF kappa B pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT