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Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders.

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.

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. J. Med. Invest. 68 : 196-201, February, 2021.

A 33-year-old man was admitted to our hospital for fever and abdominal pain. A blood analysis revealed pancytopenia and increased serum pancreatic enzymes with disseminated intravascular coagulation. A detailed examination revealed acute pancreatitis, with diffuse swelling of the pancreas and diffuse beaded dilatation of the main pancreatic duct, which mimicked autoimmune pancreatitis complicated by acute myeloid leukemia. Systemic cytotoxic chemotherapy led to the remission of leukemia and pancreatitis. We hypothesized that the etiology of acute pancreatitis was invasion of leukemia cells. Acute pancreatitis is rare as a symptom of leukemia; however, we should consider the possibility of leukemia during the differential diagnosis of acute pancreatitis.

Receptor activator of NF-&kappa, B ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells, however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox&rsquo, s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.

Primary superior vena cava lymphoma originating from the endothelium of a large vein is very rare. A 70-year-old man was admitted to the hospital; computed tomography showed a tumor limited to the inside of the superior vena cava, completely occluding the vessel. A transjugular biopsy confirmed the diagnosis of diffuse large B-cell lymphoma, which was diffusely positive for CD30. Rituximab monotherapy followed by five courses of R-CHOP chemotherapy induced a complete remission. There was no recurrence after two years. The pathophysiology of lymphoma derived from large vessels may be different from intravascular large B-cell lymphoma, which usually involves small vessels.

Although a therapeutic outcome with extended survival has been improved in patients with multiple myeloma (MM) owing to implementation new anti-MM agents, MM eventually relapses and still remains incurable. MM-initiating cells or MM progenitors are generally accepted to contribute to disease relapse through their drug-resistant nature. In order to overcome this drug resistance, various forms of immunotherapies have been studied. One such approach is the application of γδT cells. Vγ9Vδ2γδT (Vδ2 γδT) cells are important effectors in the first-line defense and tumor surveillance, and can be activated and expanded from peripheral blood mononuclear cells (PBMCs) upon treatment with zoledronic acid (Zol) and IL-2. New generation IMiDs, namely lenalidomide (LEN) and pomalidomide (POM), not only exert direct anti-MM actions, but also activate immune cells surrounding MM cells. In the present study, we aimed to clarify the effects of new generation IMiDs, LEN and POM, on activation and expansion of Vδ2 γδT cells in combination with Zol and the cytotoxic effects of ex-vivo expanded Vδ2 γδT cells against MM progenitors. After PBMCs isolated from normal donors were incubated for one week with Zol at 1 microM and LEN at 1 microM in combination, Vδ2 γδT cells were robustly expanded to be a majority of CD3-positive T cells as observed with Zol at 1 microM and IL-2 at 100 U/ml in combination. The expanded Vδ2 γδT cells expressed intracellular IFN-γ but not Foxp3 along with increased surface expression of NKG2D and DNAM-1, molecules known to be associated with NK or cytotoxic T cell-mediated cytotoxic activity, indicating induction of Th1-like Vδ2 γδT cells. In the same way as LEN, POM at 0.01, 0.1 and 1 microM was able to expand Vδ2 γδT cells from PBMCs isolated from all 10 normal donors. The expansion efficiency was slightly better with POM over LEN in some donors. The expansion efficiency with Zol plus these IMiDs appeared to be weaker in PBMCs from a majority of patients with MM than those from normal donors, as previously reported with Zol plus IL-2. Intriguingly, these IMiDs further expanded upon treatment with Zol plus IL-2 Vδ2 γδT cells from PBMCs from some donors. However, these IMiDs alone only marginally expanded Vδ2 γδT cells in the absence of Zol, suggesting costimulation of antigen-primed Vδ2 γδT cells by these IMiDs. Thus, LEN or POM appears to be able to expand Th1-like Vδ2 γδT cells in the presence of Zolwithout exogenous addition of IL-2. Such expanded Th1-like Vδ2 γδT cells exerted potent cytotoxic activity against MM cells. Interestingly, the expanded Vδ2 γδT cells also markedly minimized the sizes of side populations in RPMI8226 and KMS-11 cells, and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice, suggesting targeting a drug-resistant clonogenic MM cells. Panobinostat, a pan-HDAC inhibitor, upregulated surface expression of NKG2D ligands, ULBPs and MICA/B, on MM cells, while impairing MM cells. Pretreatment with panobinostat may further potentiate the cytotoxic activity of Vδ2 γδT cells against MM cells. Combination with novel anti-MM agents warrants further study in terms of further enhancement of anti-MM effects with the ex-vivo expanded Th1-like Vδ2 γδT cells. The precise underlying mechanisms for ex-vivo expansion of Th1-like Vδ2 γδT cells should be clarified to make the best use of these new generation IMiDs with this unique and interesting phenomenon. Disclosures No relevant conflicts of interest to declare.