Toru Mitsumori

Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan

Abnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most important transcription factors for the adaptation of cells to hypoxia, is frequently observed in numerous types of solid tumors. Dysregulation of HIF-1 induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-associated enzymes in cancer cells, which in turn leads to the promotion of tumor growth. In the present study, we examined the pathophysiologic role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that HIF-1 may be a molecular target for myeloma therapy. We identified constitutive expression of the hypoxia-inducible factor-1 α (HIF-1α)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1α expression through activation of the AKT and mitogen-activated protein kinase signaling pathways. Inhibition of HIF-1 function either by echinomycin, a specific HIF-1 inhibitor, or a siRNA against HIF-1α resulted in enhanced sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of HIF-1 drastically reduced both basal and IGF-1–induced expression of survivin, one of the most important anti-apoptotic proteins in myeloma cells. We conclude that HIF-1 inhibition may be an attractive therapeutic strategy for multiple myeloma. [Mol Cancer Ther 2009;8(8):2329–38]

Rituximab activates Syk and AKT in CD20-positive B cell lymphoma cells dependent on cell membrane cholesterol levels

The introduction of rituximab, an anti-CD20 monoclonal antibody, has dramatically improved the treatment outcomes of patients with B cell lymphoma. Nevertheless, the clinical response to rituximab varies, and a subpopulation of patients does not respond well to this antibody. Although several molecular events have been shown to be involved in the mechanism of action of rituximab, recent studies have demonstrated that intracellular signaling pathways and the direct effects of rituximab on cell membrane components are responsible for the antilymphoma action of this drug. In the present study, we demonstrated that rituximab activated Syk and Akt, molecules with antiapoptotic functions, in several CD20-positive lymphoma cell lines. Notably, rituximab activated Syk and Akt in all the tested primary lymphoma samples from six patients. Our results show that the cholesterol levels in lymphoma cell membranes have a crucial role in the regulation of Syk and Akt. The depletion of cholesterol from the cell membrane completely blocked rituximab-induced Syk and Akt activation. Simvastatin, an inhibitor of cholesterol synthesis, also abrogated rituximab-mediated Syk and Akt activation. Finally, we report that rituximab inhibited the apoptosis induced by chemotherapeutic drugs, which was observed solely in Akt-activated cells. This work demonstrates for the first time that rituximab paradoxically works to suppress apoptosis under certain conditions in a manner that is dependent on the cell membrane cholesterol level. Our observations provide novel insights and suggest that the cell membrane cholesterol level represents a new biomarker for predicting patient response to rituximab. Furthermore, the modulation of lipid rafts could provide a new strategy for enhancing the antilymphoma action of rituximab.

Extranodal NK/T-cell lymphoma, nasal type of the uterine cervix: A case report.

We report a rare case of extranodal NK/T‐cell lymphoma, nasal type of the uterine cervix that showed cytologic features mimicking cervical cancer. A 65‐year‐old woman presented with vaginal bleeding. Gynecological examination revealed a bulky tumor of the cervix. A conventional Papanicolaou‐stained cervical smear showed hypercellularity consisting of numerous variably sized cohesive clusters that mimicked epithelial tumors, with a necrotic and inflammatory background. A small number of individually scattered cells were also identified. These scattered cells showed pleomorphic, often cleaved, or horseshoe‐shaped nuclei and pale cytoplasm. Biopsy specimens revealed a diffuse growth of atypical cells with an angiocentric pattern. Extensive necrosis and infiltration of inflammatory cells were present. There were numerous mitotic figures. The tumor cells were positive for CD45RO, CD3ε, CD56, granzyme B, TIA‐1, CD7, and Epstein–Barr virus (EBV)‐encoded small RNA (EBER) by in situ hybridization, and negative for cytokeratin, chromogranin A, synaptophysin, CD4, CD5, CD8, CD20, and CD30. Based on these findings, this tumor was diagnosed as extranodal NK/T‐cell lymphoma, nasal type of the uterine cervix. Diagn. Cytopathol. 2016;44:430–433.

Localized Langerhans cell histiocytosis of the thymus with BRAF V600E mutation: a case report with immunohistochemical and genetic analyses ☆

We report a case of localized Langerhans cell histiocytosis characterized by clonal aggregation of Langerhans cells in the thymus and identified with molecular genetic study. A 43-year-old Japanese woman was found to have an anterior mediastinal mass by radiologic studies. Laparoscopy-assisted biopsy was subsequently performed. Histologically, we found subtle nodules scattered in the thymus consisting of aggregated Langerhans cells, which caused destruction of Hassall corpuscles. These Langerhans cells were immunohistochemically positive for S-100, CD1a, and CD207/langerin. Using allele-specific polymerase chain reaction and immunohistochemistry with mutation-specific antibody VE1, the BRAF V600E mutation was identified in aggregated Langerhans cells. At the medical follow-up, the thymic tumor had spontaneously regressed; however, identification of oncogenic BRAF mutation supports the neoplastic nature of the current case.

Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group

Objective: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. Methods: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. Results: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. Conclusion: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy.

Mogamulizumabによる肺浸潤治療後に，同種造血幹細胞移植を行った成人T細胞性白血病・リンパ腫

Adult T cell lymphoma-leukemia (ATL) is a highly aggressive disease and allogeneic hematopoietic transplantation (allo-HSCT) is the only therapeutic option for achieving a cure. However, some ATL patients cannot undergo HSCT. One of the important reasons for restricting HSCT in ATL is the high incidence of pulmonary complications associated with ATL including opportunistic infections, infiltration of ATL cells, and HTLV-1 associated bronchopneumonopathy. Herein, we report an ATL case with pulmonary infiltration of ATL cells successfully treated with allo-HSCT after improvement of pulmonary function with administration of the anti-CCR4 antibody mogamulizumab. To our knowledge, this is the first ATL case showing improvement of pulmonary invasion of ATL cells after treatment with mogamulizumab. In addition, this case suggests that mogamulizumab treatment might be useful as a bridge to allo-HSCT in ATL patients.

A CSF3R T618I Mutation in a Patient with Chronic Neutrophilic Leukemia and Severe Bleeding Complications

Chronic neutrophilic leukemia (CNL) is a rare form of myeloproliferative neoplasm characterized by the drastic elevation of mature neutrophils. One of the major causes of death among patients with CNL is severe bleeding; however, the difficulty of accurately diagnosing this disease has caused confusion in this field. Recently, somatic mutations of the CSF3R gene have been associated with CNL. This has led to the establishment of more accurate diagnostic criteria for CNL. We herein report a case study of a patient with CNL with a T618I point mutation on the CSF3R gene who showed severe bleeding.

Gastric invasion of multiple myeloma presenting as gastrointestinal bleeding

gastric body. The patient was treated with red blood cell transfusion and a proton-pump inhibitor. Two days after the initial observation, esophagogastroduodenoscopy was performed again. As shown in Fig. 1a, irregular thickened folds were found at the gastric corpus. The biopsy specimens revealed significant invasion of round cells in the submucosal area (Fig. 1b). Immunohistochemical studies revealed that these cells were positive for CD 138 (Fig. 1c) and κ chain (Fig. 1d), and negative for CD56, CD20 and CD79a. There was no evidence of deposition of amyloids in the stomach wall. Based on these findings, we diagnosed the patient with gastrointestinal invasion of MM. Although we continued the treatment with protonpump inhibitor, we were unable to control the gastrointestinal bleeding and she developed multi-organ failure. She died 3 weeks after admission. Gastrointestinal bleeding is a common complication of hematological malignancies, including MM. A variety of factors are involved in the gastrointestinal bleeding observed in MM patients [2]. First, paraneoprotein impairs the function of platelets and coagulation factors, leading to increased bleeding tendency. Treatments for MM may also increase the risk for bleeding, including from chemotherapy-induced thrombocytopenia, steroid-induced gastric ulcers, or the administration of aspirin or anticoagulants to prevent the thromboembolic complications associated with lenalidomide or thalidomide. Additionally, the deposition of amyloid protein in the gastrointestinal system can cause severe bleeding. In the present case, we found substantial involvement of myeloma cells in the gastric mucosa. Although the incidence is rare, previous case reports have indicated that gastrointestinal involvement of multiple myeloma, including severe gastrointestinal bleeding, may occur [2–5]. The prognosis of these patients is often extremely poor [2, 3]. A 62-year-old woman was hospitalized because of melena. She had been diagnosed with Bence Jones κ-type multiple myeloma (MM) 7 years prior. At the diagnosis of multiple myeloma, chromosome analysis of bone marrow cells revealed the karyotype abnormality 46, XX, t(7;8) (q32;q13) in one of 20 cells analyzed. Following the initial diagnosis of MM, she was treated with the combination of vincristine, doxorubicin, and dexamethasone, followed by high-dose melphalan chemotherapy with autologous stem cell transplantation (ASCT) [1]. She achieved only a partial response to these treatments, and was subsequently treated with thalidomide, and then bortezomib, for 3 years. During the clinical course, she developed multiple subcutaneous plasmacytomas. She underwent palliative radiation therapy, and treatment with lenalidomide was started with prophylactic anticoagulants. Three days before the hospitalization for melena, she experienced epigastric pain. At the time of hospitalization, the patient showed marked anemia (Hb 4.8 g/dL); however, her platelet counts were only modestly decreased (141 × 10/L; normal range 155– 345 × 10/L). Emergent esophagogastroduodenoscopy was performed, and massive bleeding was observed in the

Combined Coagulopathy can Induce both Hemorrhagic and Thrombotic Complications in Multiple Myeloma

Coagulation abnormalities are a rare but critical complication associated with plasma cell diseases. We herein present a case of multiple myeloma (MM) with complicated coagulopathy. Initially, the patient showed severe bleeding tendency due to concomitant acquired hemophilia A and acquired von Willebrand syndrome. Interestingly, the patient also exhibited hyperactivation of factor IX. During treatment for MM, the bleeding complications were ameliorated; however, the patient had central retinal vein occlusion. All of the coagulation abnormalities were completely resolved after the complete remission of MM. This case suggests that MM patients may have concomitant risks for both bleeding and thromboembolic complications.

Tumor Lysis Syndrome after the Administration of Ruxolitinib in a Patient with Post-polycythemia Vera Myelofibrosis

The development of tumor lysis syndrome (TLS) in association with treatment for myeloproliferative neoplasms (MPNs) is relatively rare. We herein present the case of a post-polycythemia vera (PV) myelofibrosis patient with massive splenomegaly who developed laboratory TLS after treatment with ruxolitinib, a potent JAK1/JAK2 inhibitor. She also exhibited a rapid reduction of spleen volume. Our present case suggests the potential risk of TLS development after ruxolitinib treatment, particularly in patients with massive splenomegaly.