Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

[PAX5-positive plasma cell leukemia presenting as lymphocytosis].

An 82-year-old Japanese male patient was initially diagnosed with lymphocytosis. His complete blood count revealed a white blood cell count of 30.9×109/l with 81% abnormal lymphocytes. The abnormal lymphocytes included monoclonal clones of CD38+ and CD138+cytoplasmic κ+ and IgG-κ M-protein, which led to the final diagnosis of plasma cell leukemia (PCL). Bortezomib and dexamethasone therapy was initiated, but the patient succumbed to the disease on the 8th day of hospitalization. A cytogenetic examination revealed a t (9;14)(p13;q32) translocation and the Western blotting confirmed high PAX5 expression. Similar to our present case, PCL cases with "lymphocytosis" have been widely reported, which some speculating the involvement of PAX5 overexpression in the pathogenesis. Such cases, including ours, may be classified as a unique group of disorders (PCL presenting as "lymphocytosis"), which requires accurate differential diagnosis and subsequent urgent multidisciplinary intensive treatment.

A case of Bacillus subtilis var. natto bacteremia caused by ingestion of natto during COVID-19 treatment in a maintenance hemodialysis patient with multiple myeloma.

A 70-year-old woman, who started on hemodialysis 7 months before for end-stage renal disease due to diabetic nephropathy and was diagnosed with symptomatic multiple myeloma 1 month before, was admitted to our hospital with critical coronavirus disease 2019 and treated with long-term immunosuppressive therapy such as steroids and tocilizumab. During treatment, Bacillus subtilis was detected in the blood cultures. We could not exclude the association of natto (fermented soybeans) with B. subtilis var. natto, which the patient had been eating every day from 8 days after admission. She was prohibited from eating natto and treated with vancomycin. Later, B. subtilis detected in the blood culture was identified as B. subtilis var. natto, which was identical with those contained in the natto that the patient consumed daily using a next-generation sequencer. Gut dysbiosis due to old age, malignant tumor, diabetes mellitus, end-stage renal disease, and intestinal inflammation caused by severe acute respiratory syndrome coronavirus 2 increased intestinal permeability and the risk of bacterial translocation, causing B. subtilis var. natto bacteremia. Therefore, careful consideration might be given to the intake of fermented foods containing live bacteria in patients with severe immunocompromised conditions.

Rare evolution of CSF3R-mutated chronic neutrophilic leukemia to t(4;12)(q12;p13) acute myeloid leukemia with SETBP1 mutation.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disease accompanied by mutations in CSF3R. Here, we present a patient with CNL who developed to acute myeloid leukemia (AML) at the same time that a t(4;12)(q12;p13) translocation appeared. The uniqueness of this cytogenetic abnormality led us to delineate the molecular aberrations relevant for clonal evolution. While the CSF3R mutation was present throughout the course of the disease, the SETBP1 mutation was newly acquired at the AML transformation. The present case suggests that careful monitoring of t(4;12)(q12;p13) and SETBP1 is crucial to predict AML evolution in CNL patients.

Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Incidentally Detected by Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography at a Health Checkup.

We herein report a case of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) that was incidentally detected by fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/computed tomography (CT) at a health checkup. At that time, the findings of a physical examination and blood tests were all normal, except for the diffuse bone marrow uptake (maximum standardized uptake value: 6.3). One month later, when the blood counts remained in the normal ranges, a bone marrow examination confirmed the diagnosis of Ph-ALL. Although a diffuse bone marrow uptake of 18F-FDG is observed in some benign conditions, physicians should also consider the possibility of hematological malignancies, including acute leukemia, even when that is the only abnormal finding.

Factors associated with SARS-CoV-2 antibody titers and prognosis of breakthrough infection in hemodialysis patients.

BACKGROUND: The mortality rate of Coronavirus disease 2019 (COVID-19) is extremely high in hemodialysis patients (HDP). These patients also develop lower antibody titers after vaccination. Therefore, factors associated with antibody titers and vaccine efficacy in HDP with breakthrough infection need to be investigated. METHODS: We measured anti-S1 antibody titers in HDP (n = 104) and controls (n = 35), evaluating the influence of background on HDP by multivariable regression analysis. We classified 26 HDP patients admitted with COVID-19 into the unvaccinated (n = 15) and breakthrough infection group (n = 11), performing between-group comparisons of laboratory findings and prognosis. Vaccinated COVID-19 patients were classified into HDP and non-HDP controls, and compared the relationship between antibody titer and severity, and the prognosis of breakthrough infection. RESULTS: The antibody titer was significantly lower in the HDP group than in the control group. Among HDP, age and smoking history were significantly independent factors associated with antibody titer. The breakthrough infection group had significantly better laboratory findings (KL-6 and LDH), severity, and hospitalization period than the unvaccinated group even if antibody titers were lower than the known threshold for neutralization (p < 0.05). There was no significant difference in prognosis between the HDP and non-HDP with breakthrough infection. Severity of COVID-19 tended to be higher with lower antibody titer in non-HDP, but not in HDP. CONCLUSION: Vaccines improved the severity of COVID-19 and hospitalization period of breakthrough infection in HDP, although HDP, especially in elderly smokers had lower antibody titers than control. There was no significant association between antibody titer and severity in HDP.

A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder.

We report a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage. Blood analysis revealed a decreased fibrinogen level with markedly elevated fibrinogen/fibrin degradation products and D-dimer levels. Despite hemostatic surgery and administration of several medications, such as nafamostat mesylate, tranexamic acid, and unfractionated heparin, the coagulation abnormalities were not corrected, and the patient experienced repeated hemorrhagic events. We found that administration of recombinant human thrombomodulin (rhTM) remarkably improved the patient's pathophysiology. Screening and sequencing of the TM gene (THBD) revealed a previously unreported homozygous variation: c.793T>A (p.Cys265Ser). Notably, the Cys265 residue forms 1 of 3 disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of TM. Transient expression experiments using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably because of EGF-like domain 1 misfolding. The reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular-coagulation-like symptoms observed in the patient. In summary, we identified a novel TM variant, c.793T>A (p.Cys265Ser). Patients homozygous for this variant may present with severe bleeding events; rhTM should be considered a possible treatment option for these patients.