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Anti-platelet agents or anticoagulants are administered for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) to prevent thrombotic events (TEs). However, there is a discrepancy between current guidelines and clinical practice in thromboprophylaxis and the varied incidence of TEs depending on patient cohort. Therefore, a consensus on the optimal thromboprophylactic strategy is needed. To determine an appropriate strategy for the prevention of TEs in MM patients receiving IMiDs, we performed a retrospective single-institution analysis. In total, 95 MM patients (62% male, median age 65 years, range 30–85 years) from November 2008 to January 2018 were recruited, and 140 cases were analyzed in the medical-record-based study. Thromboprophylactic drugs were given to 69% of patients, anti-platelet agents to 66%, and anticoagulants to 3.0%. Seven TEs (5.0%) and six bleeding events (4.3%) were observed, but no patients died from thrombohemorrhage. The median follow-up period was 184 days (range 21–2224), and the cumulative TE incidence was 1.7% at 3 months, 7.0% at 1 year, and 12.5% at 3 years. Multivariate analysis determined that age > 70 years (p = 0.012) and BMI

Mediastinal gray zone lymphoma (MGZL) is a provisional entity with intermediate features between classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma. Outcomes for patients with MGZL are reportedly poorer than those for patients with cHL or primary mediastinal large B-cell lymphoma. Additionally, no standard management guidelines for patients with MGZL are available, primarily due to its recent identification, rarity, and challenges in diagnosis. Although recent several studies have suggested dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and rituximab) may improve outcomes in patients with MGZL, numerous patients still suffer from relapsed/refractory MGZL, and the optimal management for such patients remains uncertain. Here, we report the first case of successful treatment of refractory MGZL by tandem high-dose chemotherapy supported by autologous stem cell transplantations (auto-SCTs) and consolidative radiotherapy (RT). To date, the patient remains in CR 33 months after the completion of RT, with no significant complications. This case suggests that tandem auto-SCTs may be a promising therapeutic option for relapsed/refractory MGZL.

A 60-year-old man with chronic hepatitis C was referred to our hospital with significantly elevated total protein and serum IgM (9,500 mg/dl) levels identified via a routine checkup. Blood examination revealed increased serum IgM-monoclonal protein and serum-soluble IL-2 receptor (sIL2R) levels. Computed tomography and fluorodeoxyglucose positron emission tomography revealed pulmonary masses, abnormal soft tissue masses surrounding the bilateral kidneys, and thickened mucous membrane of the bladder with high fluorodeoxyglucose uptake. Pathological examination of the pulmonary mass revealed infiltration of medium-sized lymphocytes and plasma cells. Immunohistochemical analysis revealed tumor cells positive for CD138 and IgM, with a low positive rate of Ki-67 expression. Notably, the tumor cell-surrounding lymphocytes were positive for CD20. Although the patient was initially regarded as having Waldenström's macroglobulinemia owing to the significantly increased serum IgM levels, based on positive IgH-MALT1 translocation and negative MYD88 L265P mutation findings, he was further diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Complete remission was achieved following six cycles of rituximab + CHOP therapy. This study data suggest that analysis of the MYD88 L265P mutation in tumor cells is suitable for accurately diagnosing hematopoietic malignancies with increased IgM monoclonal protein.

Dose intensity (DI) of chemotherapy affects prognosis of diffuse large B cell lymphoma (DLBCL). Myelotoxicity is the major dose-limiting toxicity (DLT) of most cytotoxic agents for hematological malignancies, whereas DLT of vincristine (VCR) is mainly neurological toxicity. Although VCR is a key drug and its combination with other cytotoxic agents needs consideration, studies focused on relative DI (RDI) of VCR have not been done before. We retrospectively analyzed 86 cases of DLBCL that received six or more cycles of cyclophosphamide (CPM), doxorubicin (DXR), VCR, prednisolone, and rituximab [R-CHOP] and calculated RDI of each cytotoxic agent to analyze its influence on treatment outcome. The median RDI of CPM, doxorubicin, and VCR was 80.0, 81.7, and 78.4 %, respectively (p = 0.002). The average RDI (ARDI) of these three agents was 80.0 %. The overall survival was significantly worse in the low ARDI (85 %) than in the high ARDI (85 %) group (2-year survival rate 67.2 vs 93.4 %, p = 0.011). The survival rate with low RDI VCR (85 %) was lower than that with high RDI VCR (85 %), even when the remaining two agents had high ARDI (2-year survival rate 74.3 vs 95.8 %, p = 0.047). In conclusion, VCR dose tended to be reduced compared with CPM and DXR in R-CHOP. Lower ARDI of cytotoxic agents and lower RDI of VCR could lead to poor prognosis in the treatment of DLBCL with R-CHOP. We thought these observations should be confirmed in a prospective study.

Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony–stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers (≥2.0 × 106 CD34+ cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P = .71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection.

Background : Anagrelide is a widely used therapeutic agent for patients with essential thrombocythemia. While other cytoreductive agents, such as hydroxyurea, influence multi-lineage blood cells, anagrelide exerts less effect on the white and red blood cell lineages. Although the clinical efficacy of anagrelide has been reported, the exact mechanism of action is unclear. Recently, immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from human induced pluripotent stem (iPS) cells by the introduction of doxycycline-inducible lentiviral vectors harboring c-MYC, BMI1, and BCL-XL for the clinical application of artificially generated platelets. In this study, we aimed to elucidate the molecular mechanism of anagrelide on the inhibition of platelet production using imMKCLs as an ideal model for human megakaryogenesis and platelet formation. Materials and Methods : imMKCLs, established at Center for iPS Cell Research and Application, Kyoto University, Japan, were cultured in Iscove's modified Dulbecco's medium with thrombopoietin (TPO), stem cell factor (SCF), and doxycycline. The differentiation of imMKCLs and platelet generation were induced by doxycycline removal. The generation of mature platelets was observed approximately 7 days after the differentiation was initiated. Both undifferentiated and differentiated imMKCLs were treated with several different concentrations of anagrelide. The cell proliferation and number of generated platelets following anagrelide treatment were analyzed by BrdU cell proliferation assay and flow cytometry, respectively. To explore the molecular mechanism of anagrelide treatment in imMKCLs, we performed mRNA sequencing in imMKCLs treated with or without anagrelide followed by gene ontology (GO) analysis and gene set enrichment analysis (GSEA). The expression of genes related to megakaryogenesis and platelet formation was also analyzed utilizing quantitative real-time PCR. Results : Anagrelide exposure caused morphologically suppressive changes in the differentiation of imMKCLs. Anagrelide treatment also suppressed the mRNA expression of the megakaryocytic surface markers CD41 and CD61 in both undifferentiated (P < 0.01 and P < 0.001, respectively) and differentiated (P < 0.01 and P < 0.001, respectively) settings. The BrdU incorporation rate in differentiated imMKCLs decreased significantly following anagrelide treatment (P < 0.001, anagrelide 0 vs. 1 or 10 µM). The resultant generation of mature platelets (double positive for CD41 and CD42b) was significantly decreased by exposure to anagrelide, as analyzed by flow cytometry (P < 0.001). Regarding the molecular mechanism of anagrelide treatment on imMKCLs, GO analysis following RNA sequencing demonstrated that gene sets related to platelet activation and degranulation were significantly downregulated in both undifferentiated and differentiated conditions. Moreover, GSEA revealed that gene sets related to the cell cycle, such as mitosis and DNA replication, were decreased as well as platelet-specific genes. The mRNA expression levels of genes related to megakaryogenesis and platelet-formation, such as FLI1, TAL1, GATA1, and PF4, were significantly downregulated, especially in differentiated imMKCLs, by anagrelide treatment (P < 0.001, P = 0.013, P < 0.01, and P < 0.01, respectively). Conclusions : We successfully reproduced the platelet-lowering effect of anagrelide by using imMKCLs from human iPS cells that could generate functional platelets in culture. Our RNA sequencing results revealed that anagrelide specifically suppressed megakaryogenesis and platelet formation-related genes. Additional studies including an apoptosis assay and cell cycle analysis of imMKCLs following anagrelide exposure are ongoing to elucidate further molecular mechanisms of anagrelide treatment. Disclosures Takayama: Megakaryon co. Ltd.: Research Funding. Eto:Megakaryon co. Ltd.: Research Funding.

A mixed papillary adenocarcinoma and transitional cell carcinoma (MAcTcc) was discovered in the uterine cervix of a 38-year-old woman. A condylomatous papillary lesion was found in the uterine cervix during a colposcopic study and histopathological examination showed that the tumor was composed of two different neoplastic subtypes. One was an adenocarcinoma (AC) component showing papillary and tubular structure with endocervical and intestinal differentiation; the other was a transitional cell carcinoma (TCC) component showing papillary excrescence mimicking papillary TCC of urothelial origin. To characterize the tumor, an immunohistochemical study of cytokeratins (CK) was performed. The AC component showed immunoreactivities similar to conventional adenocarcinomas: positive immunoreactivity of low-molecular-weight cytokeratins 7, 8 and 19, and negative immunoreactivity of CK20 and high-molecular-weight cytokeratin (34betaE12). The lower epithelial layer of the TCC component showed different immunoreactivity, but the superficial epithelial layer had similar immunohistochemical findings to the AC component. These findings indicate that the TCC component had the cellular character of AC rather than that of TCC or squamous cell carcinomas. This is thought to be the first report of a MAcTcc of the uterine cervix.

子宮内膜症性気胸と子宮広間膜異常裂孔ヘルニアは共に稀な疾患であるが,両者を併発した1例を経験したので報告する.症例は45歳,女性,平成11年5月胸痛を主訴に初診,右気胸の診断にて入院.発症日は月経最終日であった.その後6月と8月に月経周期に一致した右気胸を確認し,子宮内膜症性気胸と診断した. Gn-RH誘導体(酢酸ナファレリン)の点鼻を開始し,その後気胸再発なく経過していた.平成12年1月突然の心窩部痛にて入院. CTにて子宮後方に拡張した腸管と腹水を認め, 12日絞扼性イレウスの診断で緊急手術を行った.子宮広間膜異常裂孔ヘルニア嵌頓による回腸壊死と判明,壊死小腸切除を行った.この経過中気胸再発はなかった.平成12年4月より希望によりホルモン療法を中止したところ, 7, 8, 9月に右気胸を繰り返し発症したため10月17日胸腔鏡下手術を行った.肺に病変を認めず横隔膜に小孔2個を認め横隔膜部分切除を行い,フィプリン糊による胸膜癒着療法を加えた.横隔膜病理検査にては,明らかな子宮内膜上皮は認められなかった.術後もホルモン療法を続けており術後2年間再発はなかったが平成14年10月,平成15年9月に2回再発を認めた.入院加療を要せず改善した.

母子間のRh (E) 式血液型不適合妊娠に対し, 母体の抗体除去目的で血漿交換を施行した1例を経験した. 症例は30歳, 女性. Rh式血液型はCCDee. 夫はccDEE. 今回第2子妊娠に際し, 妊娠の継続を強く希望したため, 妊娠11週6日より胎児-新生児溶血性貧血 (HDN: hemolytic disease of the fetus and the newborn) を予防する目的で血漿交換を施行した (出産まで計71回). IgG型抗E抗体の抗体価は初診時妊娠5週4日1024倍であった. 抗体価は血漿交換前128倍, 後64倍で推移したが, 32週4日より血漿交換前512倍, 後256倍と増加傾向を示した. 羊水穿刺は28週1日より約2週間ごとに行い, 36週1日まで計6回施行したが, ΔOD450は0.085から0.127の間であり, prediction zoneにplotし, いずれも抗体による溶血の可能性の少ない領域であるzone IIにあった. 妊娠中の超音波検査では, 胎盤の肥厚, 胎児の肝, 脾の腫大, 腹水, 胸水, 心拡大等異常は認めなかった. 36週6日, 経腟的に女児を分娩, 直接クームス陽性, ヘモグロビン7.0g/dlと貧血を認めた. 交換輸血目的のため当院小児科に入院して光線療法および1回の交換輸血を行い, 経過良好にて退院した.OD450と胎児超音波所見を目安に血漿交換療法を行ったが, 誕生女児には貧血, 高ビリルビン血症を認めた. HDNを予防するには, 場合によっては臍帯血検査やIgGサブクラスの測定も考慮する必要があると思われた.