[Successful cord blood transplantation for refractory gamma-delta hepatosplenic T-cell lymphoma developed during treatment of Crohn's disease].

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

Downregulation of miR-26 promotes invasion and metastasis via targeting interleukin-22 in cutaneous T-cell lymphoma.

It has been reported that certain microRNAs (miRNA) are associated with the pathogenesis of lymphoma. We have previously demonstrated that histone deacetylase inhibitors restore tumor-suppressive miRNAs, such as miR-16, miR-29, miR-150, and miR-26, in advanced cutaneous T-cell lymphoma (CTCL). Among these, the function of miR-26 remains unclear. In this study, we aimed to reveal the function of miR-26 in CTCL oncogenesis. First, we confirmed that the miR-26 family was markedly dysregulated in CTCL cell lines and primary samples. In vivo analysis using miR-26a-transduced CTCL cells injected into immunodeficient NOG mice demonstrated the significant prolonged survival of the mice, suggesting that the miRNA had a tumor-suppressive function. We performed gene expression assays and identified 12 candidate miR-26 targets, namely RGS13, FAM71F1, OAF, SNX21, CDH2, PTPLB, IL22, DNAJB5, CASZ1, CACNA1C, MYH10, and CNR1. Among these, IL22 was the most likely candidate target because the IL-22-STAT3-CCL20-CCR6 cascade is associated with tumor invasion and metastasis of advanced CTCL. In vitro analysis of IL22 and IL22RA knockdown and miR-26 transduction demonstrated inhibited CTCL cell migration. In particular, IL22 knockdown induced cell apoptosis. Finally, we conducted in vivo inoculation analysis of mice injected with shIL22-transfected CTCL cells, and found no tumor invasion or metastasis in the inoculated mice, although the control mice showed multiple tumor invasions and metastases. These results, along with our previous data, demonstrated that miR-26 is a tumor suppressor that is associated with tumor invasion and the metastasis of advanced CTCL by regulating the IL-22-STAT3-CCL20 cascade. Therefore, a IL-22-targeting therapy could be a novel therapeutic strategy for advanced CTCL.

[Postmortem diagnosis of intravascular large B-cell lymphoma after atraumatic splenic rupture due to splenic infiltration].

Atraumatic splenic rupture (ASR) is a rare but fatal complication of malignant lymphoma. However, only one case of intravascular large B-cell lymphoma (IVLBCL)-related ASR (IVLBCL-ASR) has previously been reported, and the mechanism of IVLBCL-ASR is unknown. We present the case of a 78-year-old man who died unexpectedly and was diagnosed with IVLBCL-ASR pathologically by autopsy. A massive intraperitoneal hemorrhage and four lacerations on the splenic surface were discovered during the autopsy. CD20-positive lymphoma cells that infiltrated into small vessels were highly concentrated in the center of the spleen and were only slightly distributed in the lacerations on the splenic surface. Therefore, increased intrasplenic pressure due to lymphoma cell proliferation was identified as the cause of ASR. The patient had undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for tongue cancer evaluation 3 months earlier, and positive uptake was found in the right adrenal gland, where lymphoma cell infiltration was confirmed by the autopsy. Our findings suggest that clinicians should be aware that the advanced stage of IVLBCL can cause fatal ASR via increased intrasplenic pressure. Therefore, early diagnosis and early treatment intervention are desirable to prevent the onset of IVLBCL-ASR, and 18F-FDG PET/CT is useful for the early diagnosis of IVLBCL.

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.

Hypoxia-inducible hexokinase-2 enhances anti-apoptotic function via activating autophagy in multiple myeloma.

Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco-biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia-inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI-resistant myeloma cells. Here, a hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti-apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2-knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3-bromopyruvate (3-BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3-BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM.

Pre-treatment metabolic tumour volume and total lesion glycolysis are superior to conventional positron-emission tomography/computed tomography variables for outcome prediction in patients with newly diagnosed multiple myeloma in clinical practice.

Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are positron-emission tomography/computed tomography (PET/CT) variables for predicting multiple myeloma's (MM) outcome. We retrospectively investigated and compared the predictive value of MTV, TLG and high-risk PET/CT variables in clinical practice in 185 patients with newly diagnosed symptomatic MM. High-risk PET/CT findings were defined as the presence of at least one of the following: more than three focal lesions, maximum standardised uptake value (SUVmax ) >4·2 and extramedullary disease. MTV was defined as the volume of myeloma lesions visualised on PET/CT with SUV ≥ 2·5. TLG was calculated as the sum of the product of the average SUV and MTV of all lesions. The mortality prediction optimal cut-off values for MTV and TLG were 56·4 cm3 and 166·4 g, respectively. High-burden MTV (≥56·4 cm3 ), TLG (≥166·4 g) and high-risk PET/CT findings differed significantly in progression-free survival (PFS) and overall survival (OS). High-burden MTV and TLG findings also predicted survival outcomes in young patients (age <75 years) and patients with high-risk chromosomal abnormalities. High-burden MTV and TLG independently predicted both worse PFS and OS. Pre-treatment MTV and TLG independently predicted survival outcomes in clinical practice and may be more useful than high-risk PET/CT variables.

Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years.

This study aimed to clarify the comprehensive clinical, laboratory, pathological and imaging features of intravascular large B-cell lymphoma (IVLBCL) using data on 42 IVLBCL patients diagnosed at our hospital over the past 20 years. The majority of patients were diagnosed via random skin biopsy (29/42, 69·0%) followed by bone marrow biopsy alone (8/42, 19·0%). Characteristic features included persistent fever (41/42, 97·6%), decreased performance status (≥2) (100%), hypoxaemia (32/40, 80·0%), impaired consciousness (19/42, 45·2%), hypoalbuminemia (42/42, 100%) and extreme elevation of lactate dehydrogenase and soluble interleukin 2 receptor levels. Brain magnetic resonance imaging showed abnormal findings in 32/37 patients (86·4%). Hyperintense lesion in the pons was a peculiar finding that was unrelated to the neurological deficits. Positron emission tomography-computed tomography revealed a high incidence of bone marrow (26/34, 76·5%), spleen (19/34, 55·9%) and adrenal gland (9/34, 26·5%) involvement. Neurolymphomatosis was noted in 6 patients during the course of the disease. About 60% of IVLBCL patients in whom in vivo diagnosis was possible survived more than 5 years with combination chemotherapy. Our observations provide additional insight into the diagnosis of IVLBCL and indicate that early disease recognition via random skin biopsy combined with imaging, enables in vivo diagnosis of the disease and improved survival for many patients.

Pretreatment 18F-FDG PET/CT combined with quantification of clonal circulating plasma cells as a potential risk model in patients with newly diagnosed multiple myeloma.

PURPOSE: Both 18F-FDG PET/CT and clonal circulating plasma cell (CPC) quantification are emerging tools for multiple myeloma (MM) prognostication that have been validated in recent studies. This study investigated the value of PET/CT coupled with CPC quantification for MM prognostication that may contribute to future risk-adapted treatment. METHODS: We retrospectively analysed the prognostic relevance of a combination of pretreatment PET/CT findings and CPC levels in 163 consecutive patients with newly diagnosed, symptomatic MM receiving novel agents during induction therapies. RESULTS: High-risk PET/CT findings and elevated CPC levels were defined by the presence of >3 focal lesions with or without extramedullary disease and CPCs ≥0.10% of the total mononuclear cells evaluated, respectively. Subsequently, patients were divided into three groups: PET-CPC stage I included patients with no high-risk PET/CT findings and low CPC levels; stage III included patients with high-risk PET/CT findings and high CPC levels; and stage II included the remaining patients. The three groups of patients differed significantly in terms of both progression-free survival (PFS) and overall survival (OS) (median PFS: not reached [NR] and 36.4 and 15.9 months, and median OS: NR, NR, and 40.4 months for stages I, II, and III, respectively; P < 0.001 for both PFS and OS). This system discriminated both PFS and OS even among younger (age < 75 years) or older (≥ 75 years) patients, patients with Revised International Staging System stage II or III, and patients with or without high-risk cytogenetic characteristics. In the multivariate analysis, the PET-CPC staging system remained prognostic for both PFS and OS. CONCLUSIONS: The PET-CPC staging system predicted survival outcomes independently of established risk factors in patients with newly diagnosed MM. Pretreatment 18F-FDG PET/CT assessment combined with CPC quantification may improve the prognostication of MM and facilitate the development of novel risk-adapted approaches for MM.

Low hexokinase-2 expression-associated false-negative 18F-FDG PET/CT as a potential prognostic predictor in patients with multiple myeloma.

PURPOSE: False-negative 18F-FDG PET/CT, which is associated with low hexokinase-2 (HK2) expression in multiple myeloma (MM), is a new concept that is relevant for diagnosis and treatment response assessment. This study aimed to investigate the prognostic relevance of low HK2 expression-associated false-negative PET/CT in patients with MM. METHODS: Ninety consecutive patients, with newly diagnosed MM, receiving novel agents during induction therapy were enrolled in this retrospective study. Patients were divided into three groups according to the combination of the positivity of PET/CT and whole-body diffusion-weighted magnetic resonance imaging (DWMRI), namely, negative DWMRI, false-negative PET/CT, and positive PET/CT. RESULTS: False-negative PET/CT was observed in 12% patients who were older, had documented clinical history of smouldering MM, and showed lower HK2 expression levels than the positive PET/CT patients. False-negative PET/CT patients showed a clear trend of longer time to next treatment (TTNT) and progression-free survival (PFS) than the positive PET/CT patients (P = 0.035 and 0.071, respectively). Furthermore, TTNT and PFS of false-negative PET/CT patients were similar to those of patients without established high-risk PET/CT findings and significantly longer than those of high-risk PET/CT patients (P = 0.013 and 0.047, respectively). CONCLUSIONS: This study showed, for the first time, that low HK2 expression-associated false-negative PET/CT was associated with relatively better prognosis in patients with newly diagnosed MM, suggesting that this phenomenon may not undermine the established PET/CT-based prognostication. Furthermore, this phenomenon may be useful for identifying patients at lower risk of disease progression among those with myelomatous lesions on DWMRI.

Medullary Abnormalities in Appendicular Skeletons Detected With 18F-FDG PET/CT Predict an Unfavorable Prognosis in Newly Diagnosed Multiple Myeloma Patients With High-Risk Factors.

OBJECTIVE. The prognostic value of medullary abnormalities in the appendicular skeleton (AS) of patients with multiple myeloma (MM) has recently been suggested. However, functional evaluation of these abnormalities using PET/CT has not been investigated to date. This study aimed to explore the prevalence and prognostic relevance of AS medullary abnormalities depicted by PET/CT in patients with MM. MATERIALS AND METHODS. This retrospective study included 228 consecutive patients with newly diagnosed, symptomatic MM who were treated with novel agents. All patients underwent pretreatment 18F-FDG PET/CT. RESULTS. There were 157 (68.9%) patients with zero AS focal lesions, 33 (14.5%) with one to three AS focal lesions, and 38 (16.7%) with more than three AS focal lesions on pre-treatment PET/CT. Patients with more than three AS focal lesions showed significantly shorter progression-free survival (PFS) and overall survival (OS) than did those with fewer lesions (both, p < 0.001). In multivariate analysis, the presence of more than three AS focal lesions remained prognostic for both PFS and OS (both, p < 0.001). Furthermore, the presence of more than three AS focal lesions discriminated patients with both significantly shorter PFS and significantly shorter OS even among patients with established high-risk parameters, including high-risk cytogenetic abnormalities, advanced disease stage, and established high-risk PET/CT findings. CONCLUSION. The presence of more than three focal lesions in the AS on pretreatment PET/CT was an independent predictor of poor survival in patients with newly diagnosed MM. Remarkably, this finding discriminated patients with shorter survival from among those with established high-risk factors. Evaluation of findings in the AS may complement and improve the prognostic performance of known stratification systems as well as PET/CT.

Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma.

According to fluorescent in situ hybridization, t(11;14) is the most common cytogenetic abnormality in amyloid light-chain (AL) amyloidosis, but its prevalence in patients with AL amyloidosis and concurrent multiple myeloma (MM) remains unknown. We aimed to examine the prevalence of t(11;14) and the differences in clinical characteristics of patients with t(11;14) who had AL amyloidosis with or without concurrent MM. We retrospectively analyzed 40 patients with AL amyloidosis between January 2008 and January 2018 at our institution. The prevalence of t(11;14) was significantly higher in patients with AL amyloidosis alone compared with those with concurrent MM (56.5% vs. 17.6%; P = 0.022). This study suggests that AL amyloidosis patients with concurrent MM have a lower prevalence of t(11;14) than those without MM and that the presence of t(11;14) may be associated with poor prognosis, irrespective of the presence or absence of MM.

Higher frequency of false-positive serum galactomannan tests among older subjects and the association with elevated serum immunoglobulin G levels.

BACKGROUND: The incidence of false-positive serum galactomannan (GM) enzyme-linked immunosorbent assay test results has been scarcely examined among older subjects. Additionally, previous studies have highlighted the influence of serum immunoglobulin G (IgG) levels on GM test results. We hypothesised that age-related IgG level elevation might also be associated with false-positive GM test results in older subjects. OBJECTIVES: This study aimed to examine the association between false-positive GM test results and age or serum IgG levels. PATIENTS/METHODS: We investigated the association between false-positive serum GM test results and age in 1071 healthy adult subjects. Then, we validated this association and further explored the correlation with serum IgG levels by retrospectively identifying 700 patients with newly diagnosed haematologic disorders without probable or proven invasive aspergillosis. RESULTS: Healthy subjects with false-positive GM test results were significantly older than those without false-positive results (P < 0.001). Among patients with haematologic disorders, IgG myeloma patients showed significantly higher false-positive rates (57/125 [45.6%]) than patients with other haematologic disorders (non-Hodgkin lymphoma: 48/315 [15.2%], myelodysplastic syndrome/aplastic anaemia: 19/141 [13.5%]; both P < 0.001) or other types of myeloma (IgA myeloma: 13/60 [21.7%], light chain myeloma: 9/52 [17.3%]; both P < 0.01). Furthermore, among non-multiple myeloma patients, advanced age and higher IgG level were also significantly associated with the high frequency of false-positive GM test results. CONCLUSIONS: False-positive serum GM test results were frequent among older subjects and patients with elevated serum IgG levels. These results suggested that age- and/or disease-related IgG level elevation could induce this phenomenon.

Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.

Histone deacetylase inhibitors are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against various T-cell lymphomas. In this study, we examined the in vitro synergistic effects of mogamulizumab and histone deacetylase inhibitors against various T-cell lymphomas. First, we examined the expression of CCR4 mRNA and surface CCR4 in various T-cell lymphoma cell lines and found that it was downregulated upon treatment with vorinostat, a pan-histone deacetylase inhibitor. Next, we used isoform-specific histone deacetylase inhibitors and short-interfering RNA to determine the histone deacetylase isoform involved in the regulation of CCR4, and demonstrated that romidepsin, a class I selective histone deacetylase inhibitor, reduced CCR4 most efficiently. Moreover, among class I histone deacetylases, histone deacetylase 2 knockdown led to a reduction of CCR4 in lymphoma cells, suggesting that CCR4 expression is mainly regulated by histone deacetylase 2. When we examined the CCR4 expression in skin samples from primary cutaneous T-cell lymphoma, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after treatment. Finally, when we conducted an antibody-dependent cell-mediated cytotoxicity assay with mogamulizumab by using various lymphoma cells, we found that the efficacy of mogamulizumab was significantly reduced by pretreatment with vorinostat. Altogether, our results suggest that the primary use of histone deacetylase inhibitors before treatment with mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results have potential implications for optimal therapeutic sequences in various CCR4-positive T-cell lymphomas.

Clinical value of abnormal findings on brain magnetic resonance imaging in patients with intravascular large B-cell lymphoma.

To investigate the prevalence and clinical value of abnormal findings detected via brain magnetic resonance imaging (MRI) in patients with intravascular large B-cell lymphoma (IVLBCL), we identified 33 patients with IVLBCL pathologically diagnosed and evaluated with pretreatment brain MRI. Abnormal findings on brain MRI were categorized into four patterns: (1) hyperintense lesion in the pons on T2-weighted imaging (T2WI), (2) nonspecific white matter lesions, (3) infarct-like lesions, and (4) meningeal thickening and/or enhancement. Abnormal cerebral findings were detected in 29 patients (87.9%). Hyperintense lesion in the pons was the most common finding (n = 19 (57.6%) patients), followed by nonspecific white matter lesions (n = 14 (42.4%) patients), infarct-like lesions (n = 8 (24.2%) patients), and meningeal thickening and/or enhancement (n = 4 (12.1%) patients). Impaired consciousness was seen in most of the patients with infarct-like lesions (87.5%) but less frequently in patients with hyperintense lesion in the pons (47.4%). We reviewed brain MRI findings in 39 patients with diffuse large B cell lymphoma with central nervous system (CNS) involvement and/or high-risk extranodal lesions for CNS involvement as a control group. In contrast to the patients with IVLBCL, no patient had hyperintense lesion in the pons in the control group (P < 0.001). Follow-up brain MRI revealed improvement of abnormal findings in most of the patients who responded to chemotherapy. This study highlighted the diagnostic implication of hyperintense lesion in the pons on T2WI and the clinical usefulness of pretreatment brain MRI in IVLBCL even in patients without impaired consciousness.

Anorexia nervosa-associated pancytopenia mimicking idiopathic aplastic anemia: a case report.

BACKGROUND: Patients with anorexia nervosa (AN) often present with pancytopenia. In most cases described in the literature, AN with pancytopenia demonstrates gelatinous marrow transformation (GMT), which is a typical bone marrow feature of malnutrition. Differentiation of AN-associated pancytopenia from other types of pancytopenia, especially idiopathic aplastic anemia (IAA), has not been studied. We encountered a case of pancytopenia in a patient with AN and relatively poor nutritional status, whose hematological findings mimicked those of IAA, specifically fatty bone marrow and absence of GMT. CASE PRESENTATION: The patient was a 32-year-old woman with poorly controlled AN. At 31 years of age, her body mass index (BMI) had fallen from 17.0 kg/m2 to below 13.8 kg/m2. The patient presented with ongoing fatigue and thus was examined by a hematologist. Hematological findings were consistent with IAA: peripheral blood tests revealed pancytopenia, whereas the bone marrow displayed fatty replacement without GMT. Despite the absence of bone marrow features typically seen in malnutrition, the patient's hematological abnormalities had manifested after a decrease in body weight. Thus, although the bone marrow findings indicated IAA, we considered that the nutritional etiology of pancytopenia could not be thoroughly ruled out. Using nutritional therapy alone, the hematological abnormalities improved as BMI increased to 16.5 kg/m2. The final diagnosis was pancytopenia secondary to malnutrition because pancytopenia and fatty bone marrow improved after implementation of nutritional therapy alone. CONCLUSIONS: The present case is the first documented case of AN with pancytopenia for which bone marrow examination confirmed fatty marrow without any evidence of GMT. IAA and pancytopenia secondary to malnutrition can present the same clinical findings. This case is significant because it suggests a need to differentiate between malnutrition and IAA.

[Durable remission attained with rituximab therapy in a patient with acquired von Willebrand syndrome associated with CD20-positive lymphoproliferative disorder].

A 61-year-old female with no history of bleeding was admitted to our hospital owing to persistent bleeding after the left knee joint injection and activated partial thromboplastin time prolongation. Subsequent coagulation tests revealed a critically declined level of the von Willebrand factor (VWF) antigen (<10%) and activity (<10%) measurement besides a significantly declined factor VIII activity (4%). Despite diagnosing her with acquired von Willebrand syndrome (AvWS) and managing her bleeding with desmopressin acetate hydrate (DDAVP), we could not precisely make a definitive diagnosis the underlying disorder. More than 15 months after the onset of AvWS, CD20-positive atypical lymphocytes appeared in the peripheral blood and bone marrow without systemic lymphadenopathy. We initiated rituximab monotherapy eight times a week for CD20-positive lymphoproliferative disorders. The treatment not only caused the disappearance of the clonal expansion of CD20-positive atypical lymphocytes in both peripheral blood and bone marrow but also exhibited the clinical remission of AvWS. In addition, the maintenance therapy with rituximab every 3 months resulted in the durable remission of over 5 years. AvWS is a rare bleeding disorder, similar to von Willebrand disease, which arises from various underlying diseases. Our experience with this case highlights that rituximab proved to be one of the effective and well-tolerated treatment options for AvWS associated with CD20-positive B-cell lymphoproliferative disorders.

Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma.

Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.

Successful management of splenomegaly with ruxolitinib prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia transformed from post-polycythemia vera myelofibrosis.

A 64-year-old woman was admitted to our hospital to undergo allogeneic stem cell transplantation. She was diagnosed with polycythemia vera with a JAK2 V617F mutation 7 years ago. She was administered ruxolitinib for splenomegaly two years prior to admission but this was discontinued because of progressive pancytopenia. One months after cessation of ruxolitinib, she developed acute myeloid leukemia transformed from post-polycythemia vera myelofibrosis. Although she achieved complete remission after induction therapy, 8-finger-breadth splenomegaly remained below the left costal margin. Ruxolitinib was re-administered following two courses of consolidation therapy. She underwent unrelated peripheral blood stem cell transplantation. Ruxolitinib was administered until the day before transplantation, and the spleen was palpated in 4-finger breadth below costal arc. Neutrophil engraftment was achieved 13 days after transplantation. In allogeneic stem cell transplantation, splenomegaly is one of the risk factors for engraftment failure and/or therapy-related mortality. Hence, a smaller spleen size can theoretically improve the outcome after transplantation. The administration of ruxolitinib prior to transplantation may have contributed to engraftment with a non-invasive reduction in the size of the spleen.