Cranial hypertrophic pachymeningitis with myelodysplastic syndrome.

Hypertrophic pachymeningitis (HP) is a rare inflammatory disease characterized by thickening of the dura mater. HP develops with several inflammatory diseases. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgG4 related disease are reported as 2 major causes. With hematologic diseases, only 3 cases have been reported. We report the case of myelodysplastic syndrome (MDS) developing HP. Our case provides a thought-provoking hypothesis regarding the potential relationship between MDS and HP.

A Case of Myocardial Infarction with Non-obstructive Coronary Arteries Complicated by a Ventricular Septal Rupture: The Challenge of Achieving Hemodynamic Stability Using Impella Devices.

The prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA) is reported to be as worse as myocardial infarction with obstructive coronary arteries. However, its mechanical complications are still poorly understood. A 71-year-old woman developed MINOCA after ascending aortic replacement surgery. During treatment, the patient experienced cardiogenic shock due to a ventricular septal rupture (VSR). The introduction of Impella devices reduced the left-to-right shunt and improved the patient's hemodynamics. Finally, a scheduled surgical repair was performed under stable conditions. In this report, we focused on the pathophysiology of MINOCA-related VSR and discussed the effectiveness of Impella devices as a bridge to surgical repair and circulatory backup during the perioperative period.

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies.

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL.

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Massive hyperphosphatemia in clinical tumor lysis syndrome during prophylactic rasburicase use: risk factors and treatment options.

We report the case of a 76-year-old female with diffuse large B cell lymphoma who developed tumor lysis syndrome (TLS) and subsequent acute kidney injury (AKI) due to massive hyperphosphatemia during the prophylactic use of rasburicase. Our case showed no hyperphosphatemia before chemotherapy but had elevated uric acid and creatinine levels and unilateral hydronephrosis due to paraaortic lymphadenopathy. TLS risk was classified as high risk because of bulky mass, LDH elevation, and renal disturbance. With rasburicase use, uric acid was completely controlled but massive hyperphosphatemia and, subsequently, AKI developed. Immediate kidney replacement therapy led to improvement of hyperphosphatemia and AKI. In the rasburicase era, hyperphosphatemia has been a key target for preventing and treating TLS. Renal replacement therapy is the only effective option for lowering hyperphosphatemia and treating AKI.

Protein-losing Enteropathy Complicated with Primary Intestinal Follicular Lymphoma.

Protein-losing enteropathy (PLE) is a rare syndrome characterized by hypoproteinemia due to gastrointestinal (GI) protein loss. Primary intestinal follicular lymphoma (PIFL), a specific variant of follicular lymphoma with essential only GI involvement, has not been reported as an etiology of PLE. We herein report a case of PLE complicated with PIFL that was successfully treated with rituximab, resulting in rapid improvement of PLE and a complete response of PIFL. Macroscopic findings of ulcerative lesions with diffuse involvement, which were precisely described by capsule and double-balloon enteroscopy at the diagnosis, also improved following the treatment. This case provides a clue suggesting factors that promote PLE in PIFL.

Involvement of activation induced cytidine deaminase in malignant B-cells expressing two distinct M-components as an etiology of biclonal gammopathy.

Biclonal gammopathy (BG) is a rare phenomenon in which 2 M proteins are detected in the same patient, with 2 major hypotheses regarding its etiology. One potential explanation is that completely different malignant B-cell clones produce different M proteins, while the other is that there is a malignant clone that produces both M proteins simultaneously. In this study, we examined 2 cases of B-cell malignancy with BG and found that some cells were double positive for both M proteins by immunofluorescence and flow cytometry. However, most of the remaining cells were single positive cells that produced only one of the M proteins. We hypothesized that double positive cells were in the process of transitioning from 1 single positive cell to another single positive cell, and that class switch recombination (CSR) would be involved as a mechanism. We then examined the expression of activation induced cytidine deaminase (AICDA), which is responsible for CSR, and found that lymphoma/myeloma cells in 2 BG patients were positive for AICDA by immunostaining. Our study is the first report suggesting that AICDA may be involved in the pathogenesis of BG.

[Successful preoperative replacement of prothrombin with prothrombin complex concentrate for Prothrombin Himi].

Dysprothrombinemia is the rarest inherited bleeding disorder that is characterized by a decrease in the prothrombin activity, but normal antigen levels. In this study, we report the case of a compound heterozygote of two mutations in prothrombin; Met337Thr and Arg388His, which has previously been identified as "Prothrombin Himi." A systemic blood coagulation evaluation revealed a prolonged prothrombin time (39%) and activated partial thromboplastin (64.4 sec), with an isolated severe decrease in the prothrombin activity (8.6%). Preoperative replacement of prothrombin with prothrombin complex concentrate, PPSB-HT "Nichiyaku," successfully prevented abnormal postoperative bleeding after laparoscopic hysterectomy for cervical cancer. This is the second reported case of Prothrombin Himi.

Early complete response of primary bone marrow B-cell lymphoma treated with rituximab-based CHOP therapy, assessed by flow cytometry and immunogloblin heavy chain rearrangement.

Evaluation of early response by flow cytometry and immunogloblin heavy chain assessments against primary bone marrow B-cell lymphoma could be valuable for predicting treatment outcome.

Tumor-to-tumor metastasis of diffuse large B cell lymphoma to gastric adenocarcinoma via CXCL12 (SDF-1)/CXCR4 axis: a case report.

BACKGROUND: Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma. CASE PRESENTATION: A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission. CONCLUSIONS: This patient's case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma.

Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study.

OBJECTIVES: Intensive nutritional support during allogeneic hematopoietic stem cell transplantation (allo-HSCT) yields improved clinical outcomes. However, the clinical implications of early enteral nutrition (EN) in allo-HSCT remain unclear. This retrospective study was conducted to determine the significance of early EN in individuals who underwent allo-HSCT, and the association between early nutritional intervention and clinical outcomes, including the status of the intestinal microbiome. METHODS: Thirty-one participants received EN before conditioning. The intestinal microbiota was examined by meta 16S rRNA gene sequencing of fecal samples. RESULTS: The median body mass variation was only -0.35 kg on day 60. The probability of 2-y overall survival was 61.1%. The cumulative incidence of treatment-related mortality was 17.4%, and those of acute graft-versus-host disease were 32.3% (grades II-IV) and 3.2% (grades III-IV). Chronic graft-versus-host disease was observed in four participants. Dysbiosis of the intestines and acute graft-versus-host disease occurred simultaneously, and Enterococcus species were abundant. CONCLUSIONS: Our results suggest that early nutritional support can improve the outcomes for individuals who have undergone allo-HSCT and can maintain homeostasis of their intestinal microbiome. Future prospective clinical trials are required to elucidate the role of EN in allo-HSCT and the association between the intestinal microbiome and EN.

[Diffuse large B cell lymphoma with HIV infection presented with disseminated thromboembolism during antiretroviral therapy].

Patients with HIV are at higher risk of developing thrombosis than the general population. We present a rare case of a 57-year-old Japanese man with HIV infection and a malignant lymphoma. He had fever with unknown origin and cervical lymph node swelling 2 months before his hospital visit. Because he was positive for the HIV antibody, he was referred to our HIV special outpatient section. HIV RNA level was found to be 846,680 copies/ml. Therefore, antiretroviral therapy of DTG/ABC/3TC was initiated. However, the high fever continued for 7 days after treatment initiation; moreover, renal dysfunction was progressive. After admission, antibiotic therapy was initiated, due to which the fever subsided. However, renal dysfunction continued to progress. Fourteen days later, he died due to acute renal failure with hyperkalemia. An autopsy revealed a large mass in the spleen, and histological findings revealed a diffuse large B cell lymphoma (DLBCL). Furthermore, thrombi were detected in the right and left ventricles, right atrium, iliac artery, and renal artery. Pathological findings revealed that the thrombus induced the renal failure. These thrombi contained fibrin with inflammatory cell infiltration but not tumor cells. Patients with HIV and malignant lymphoma are at a higher risk of thrombosis. It is important to consider thrombosis during the treatment of patients with HIV.

Single administration of resveratrol improves social behavior in adult mouse models of autism spectrum disorder.

Resveratrol (RSV) is a natural polyphenol present in grapes, the skin of peanuts, and several other plants with many health benefits. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that may be linked to neural and synaptic development impairments. The present study aimed to analyze the preventive effects of RSV on the development of ASD-like behavior, using oxytocin receptor gene knockout (Oxtr-KO) and valproic acid-induced ASD (VPA-ASD) model mice. Genetic deficiencies in Oxtr are suggested to be involved in ASD etiology. Twenty-four hours after a single RSV injection to the Oxtr-KO mice, the social impairments caused by OXTR deficiency were ameliorated. RSV also improved social impairments in the VPA-ASD mice. Administration of RSV up-regulated silent information regulator 1 (Sirt1) gene and early growth response factor 3 (Egr3) gene expressions in the amygdala of the Oxtr-KO mice. Our data suggest that RSV may have therapeutic effects on ASD with multiple targets.

Successful brentuximab vedotin monotherapy against late relapse of classical Hodgkin lymphoma 6 years after first remission.

Brentuximab vedotin monotherapy for late-relapse CHL is a promising therapeutic with sustained CR benefit and avoiding potential toxicities caused by aPBSCT/HDT.

FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells.

OBJECTIVES: Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects. METHODS: We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib. RESULTS: We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib. CONCLUSIONS: Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells.

Recently, a new erythroid regulator, erythroferrone (ERFE), which downregulates hepatic hepcidin production, has been identified. However, the relationship between ERFE and abnormal iron metabolism in MDS is unclear. In this study, we examined the level of ERFE mRNA during ex vivo erythroid differentiation using cord blood CD34+ cells and we further analyzed whether ERFE could be produced by MDS cells using a public database (GSE58831). ERFE mRNA was increased during normal erythroid differentiation. An analysis of GSE58831 indicated that ERFE expression in bone marrow (BM) MDS cells was higher than that in healthy volunteer (HV)-derived BM cells. ERFE expression significantly and positively correlated with the expression of erythropoietin (EPO) receptors (EPO-R), ALAS2 (5'-Aminolevulinate Synthase 2), STEAP3 (STEAP family member 3) and the presence of ring sideroblasts or the SF3B1 mutation. These results suggest that EPO-R+ MDS cells with ring sideroblasts or an SF3B1 mutation produce high levels of ERFE that may be associated with a reduction in hepcidin.

[Treatment of POEMS syndrome with lenalidomide and dexamethasone].

We report three cases of POEMS syndrome treated with lenalidomide and dexamethasone who presented with peripheral neuropathy. All of them had markedly elevated serum vascular endothelial growth factor (VEGF) levels treated with lenalidomide and dexamethasone for severe peripheral neuropathy, which normalized serum VEGF levels and improved peripheral neuropathy. The standard treatment of POEMS syndrome has not been established, but has been effectively treated with high-dose chemotherapy with autologous stem cell transplantation. Newer agents currently used for plasma cell dyscrasias include bortezomib and immunomodulatory drugs, such as thalidomide and lenalidomide. A randomized controlled trial on thalidomide plus dexamethasone for POEMS syndrome showed reduced serum VEGF levels after therapy; however, the incidence of peripheral neuropathy, a well-known side effect of both thalidomide and bortezomib, increased. Lenalidomide is associated with lower incidence of peripheral neuropathy compared to thalidomide and bortezomib, making it a reasonable treatment option for POEMS syndrome.