[Fatal invasive pneumococcal disease developed 14 years after allogeneic hematopoietic stem cell transplantation in a patient with myelodysplastic syndrome].

Invasive pneumococcal diseases (IPDs) after allogeneic hematopoietic stem cell transplantation have high fatality rates and often develop late after transplantation. The patient was a 58-year-old female. Fourteen years ago, she underwent bone marrow transplantation from a HLA-DR 1-antigen mismatched unrelated donor for myelodysplastic syndrome. She developed pneumonia, chronic graft-versus-host disease, and hypogammaglobulinemia. She received 23-valent pneumococcal capsular polysaccharide vaccine 11 and 6 years earlier. She was presented to our emergency room with fever. Her blood culture was positive for pneumococcus, and she was diagnosed with an IPD. The patient received antibiotic treatment but died on the third day of hospitalization. Because of its seriousness, pneumococcal infection should receive attention even 10 or more years after transplantation. Preventive approaches such as vaccination and early intervention at the time of diagnosis are important.

[Successful outcome of allogeneic hematopoietic stem cell transplantation for systemic mastocytosis complicated with acute myeloid leukemia].

A 60-year-old woman developed a fifth thoracic spine fracture with progressive paraplegia and underwent posterior spine fusion in June 2018. Based on the histopathological analysis of the surgical specimen, she was diagnosed with KIT D816V-positive systemic mastocytosis (SM). In June 2019, peripheral blood examination revealed remarkable eosinophilia. She was given prednisolone, which resulted in the resolution of eosinophilia. In May 2020, she developed acute myeloid leukemia (AML). Induction therapy was initiated and complete remission achieved. Subsequently, she received one course of consolidation therapy and allogeneic hematopoietic stem cell transplantation (allo-SCT). Although the residual mast cell tumor aggravated during chemotherapy for AML, the tumor regressed after allo-SCT, suggesting a graft-versus-mastocytosis effect. Nine months after the transplantation, the patient is alive and healthy without recurrence of AML and SM.

[A Patient with Early-Stage Multiple System Atrophy Showing Augmented Nystagmus in Light].

The ability to fix the eyes on a target, visual fixation, is important for the maintenance of equilibrium. The visual suppression (VS) test is one method of measuring the function of visual fixation. The test records caloric nystagmus by electrooculography, and the maximum slow phase velocity of caloric nystagmus in darkness is compared with the slow phase velocity in light with eyes fixed. Lesions of the cerebellum, brain stem, and cerebrum cause abnormalities of VS. We report a patient whose VS became a clue in the diagnosis of a disorder of the central nervous system. A 54-year-old man complained of dizziness, which gradually increased in frequency over 5 months. He visited several clinics, where vestibular neutritis and cervical spondylosis were suspected and treated without improvement. Although a pure-tone auditory test revealed bilateral normal hearing, a caloric test showed a weak response and VS was lost with augmentation of caloric nystagmus in light on both sides. Both eye tracking and optokinetic nystagmus tests were abnormal. Although magnetic resonance imaging showed no abnormalities, single photon emission computed tomography revealed decreased blood flow in the parietal area. VS of caloric nystagmus towards the side of a lesion is reduced or abolished after unilateral flocculus damage, and is abolished bilaterally after bilateral flocculus damage. In the case of a parietal lobe or pontine lesion, VS is strongly abolished, and even augmentation of caloric nystagmus may be observed. In the present case, the patient was diagnosed with multiple-system atrophy after onset of dizziness.

Serum levels of vault RNA significantly varied in patients with haematological malignancies.

Among extracellular non­coding RNAs, serum levels of microRNAs have been extensively investigated in cancers. In contrast, the serum levels of vault RNAs (vtRNAs) in relation to various disease conditions remain poorly understood. The present study evaluated the clinical significance of serum vtRNA1­1 levels in patients with blood diseases. The stability and sub­localisation of serum vtRNA1­1 was assessed and a reverse transcription­quantitative PCR method using spiked RNA to quantify serum vtRNA1­1 was developed. Serum vtRNA1­1 levels were assessed in 102 individuals with blood diseases. Serum vtRNA1­1 was demonstrated to be stable for three weeks at 4˚C and was not confined to the exosome fractions. Spiking RNA was used to correct for the inconsistency in RNA extraction. The serum vtRNA1­1 levels ranged between 7.28 and 8.76 log10 cps/ml (median 8.05) in control individuals (n=46). Serum vtRNA1­1 levels correlated with leukocyte counts and increased to a maximum of 10.01 log10 cps/ml in patients with bulky leukaemia and lymphoma and decreased to 6.52 log10 cps/ml during intensive chemotherapy. The serum vtRNA1­1 levels varied significantly in patients with haematological malignancies. Serum vtRNA1­1 may originate from haematological cells and are a potential biomarker of normal and malignant haematological activities.

Differential Reactivation of Cytomegalovirus and Epstein-Barr Virus in Patients with B Cell Lymphoma.

Although cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are considered latent viruses, their reactivation occurs in immunosuppressed conditions. We previously reported that CMV and EBV are reactivated in patients receiving immunosuppressive therapy and/or chemotherapy. This retrospective, single-center study aimed to determine the frequency of viral reactivation and clinical characteristics of patients with B cell lymphoma (B-ML) receiving chemotherapy. Twenty-four patients (mean age 73 years, range 40-87 years; male-to-female ratio, 15:9) with diffuse large B cell lymphoma (n = 15), follicular lymphoma (n = 8), or mantle cell lymphoma (n = 1) were enrolled. Serum CMV and EBV DNA levels were analyzed using quantitative real-time polymerase chain reaction in patients with B-ML receiving chemotherapy. We determined the cumulative reactivation of each virus and analyzed the relationship between viral reactivation and clinical characteristics. Three patients experienced relapse or refractory (R/R) disease and the others had de novo lymphomas. The frequencies of CMV and EBV reactivations were 54.2% and 37.5%, respectively. CMV reactivation occurred significantly earlier during chemotherapy courses in R/R patients than in de novo patients (p = 0.0038), while EBV reactivation was frequently found before treatment. Baseline serum levels of soluble interleukin-2 receptor were higher (4318.0 vs. 981.1 U/mL, p = 0.010) and hemoglobin levels were lower (11.1 vs. 13.0 g/dL, p = 0.0038) in patients with EBV reactivation than in those without reactivation. These findings were not observed in patients with CMV reactivation. CMV reactivation was associated with iatrogenic immunosuppression, whereas EBV reactivation was related to immunosuppression by lymphoma, indicating that the mechanisms of these viral reactivations differed.

Fibrin monomer complex as a potential thrombosis marker related to venous thromboembolism risk in pregnant women.

BACKGROUND: Pregnancy is a risk factor for venous thromboembolism (VTE) due to increased coagulation factor activity and decreased protein S activity. However, thrombosis markers for predicting VTE in pregnancy remain controversial. This study aimed to investigate the relationship between VTE risk and thrombosis markers in pregnant women and to identify markers related to VTE risk. METHODS: Archived plasma samples from 107 pregnant women were used in this study, and the concentrations of D-dimer, fibrin monomer complex (FMC), plasmin-plasmin inhibitor complex, prothrombin time, activated partial thromboplastin time, and fibrinogen were measured. VTE risk was scored according to the Royal College of Obstetricians and Gynaecologists green-top guidelines and the patients were divided into low- or high-risk groups. RESULTS: The median (range) of risk score for deep vein thrombosis was 2 (0-8), and we defined the high-risk group included those with a score of ≧3. D-dimer and FMC concentrations were significantly higher in the high-risk group than in the low-risk group (D-dimer 4.5 vs 2.6 µg/mL, p = 0.008; FMC 14.6 vs 3.4 µg/mL, p < 0.001). Although D-dimer concentration significantly increased with gestational age (Spearman's correlation coefficient [rs] = 0.317, p < 0.001), FMC concentration did not (rs = -0.081, p = 0.409). The area under the receiver operating characteristic curve values of D-dimer, FMC, and both D-dimer and FMC for the high-risk group were 0.656, 0.713, and 0.738, respectively. CONCLUSIONS: FMC may be a thrombosis marker related to VTE risk in pregnancy and is potentially preferable over D-dimer concentrations.

Construction of an Automatic Quantification Method for Bone Marrow Cellularity Using Image Analysis Software.

Although rapid, the evaluation of bone marrow (BM) cellularity is semi-quantitative and largely dependent upon visual estimates. We aimed to construct an automatic quantification method using image analysis software. We used hematoxylin and eosin (HE)-stained specimens of BM biopsies and clots from patients who underwent BM examination at Tottori University Hospital from 2020 to 2022. We compared image analysis (Methods A, B, and C) with visual estimates in pathology reports of 91 HE specimens in 54 cases (29 males, 25 females), including 38 biopsy and 53 clot specimens. Cellularity was visually scored as hypocellular (n = 17), normocellular (n = 44), or hypercellular (n = 30). Compared with the visual estimates, intraclass correlation coefficients for Methods A, B, and C were 0.80, 0.85, and 0.88, respectively. The most appropriate values were obtained with Method C which detected both non-fatty and cell nuclear areas.

Development of a Prognostic Scoring System using MYC Expression and Soluble Interleukin Receptor -2 level for Diffuse Large B-cell Lymphoma.

Background: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), is the most frequent type of lymphoid neoplasm. Methods: We investigated the relationships between clinical factors of DLBCL-NOS and MYC immunohistochemistry (IHC) staining. Results: A total of 110 patients diagnosed with DLBCL-NOS from 2012 to 2020 at Tottori University Hospital and treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy were included. IHC staining of MYC in formalin-fixed, paraffin-embedded tumor specimens was performed, and ROC-curve analysis revealed the cut-off value of the MYC positive rate as 55%. The 2-year overall survival (OS) rates of the MYC-negative and -positive groups were 84.7% vs 57.7% (P = 0.0091), and the progression-free survival rates were 77.8% vs 54.7% (P = 0.016), respectively. Multivariate analysis for OS showed prognostic significance of MYC positivity [hazards ratio (HR): 2.496; P = 0.032], and serum levels of soluble interleukin-2 receptor (sIL-2R) > 2000 U/mL (HR: 3.950; P = 0.0019), as well as age > 75 (HR: 2.356; P = 0.068). The original scoring system was developed based on these findings. By assigning one point to each item, age (> 75), MYC positivity, and sIL-2R level (> 2000), all patients were classified into three risk categories: group 1 (0 points), group 2 (1 point), and group 3 (2-3 points). The 2-year survival rates were 100%, 83.0%, and 47.1% for the groups 1, 2, and 3, respectively (P < 0.0001). Conclusion: We suggest that a prognostic scoring system using MYC expression and soluble interleukin receptor -2 level is useful for the prediction of prognosis, contributing to further stratification in DLBCL-NOS.

Clinical Characteristics and Predictors Related to the Progression of Multinodular Goiter Causing Tracheal Compression and Deviation: A Report of Two Cases and Review of the Literature.

We describe the clinical course of two patients who developed tracheal compression and deviation by multinodular goiter (MNG). Case 1: A 66-year-old woman presented with thyroid swelling. Five years after the initial admission, she was diagnosed with hyperthyroidism by Graves' disease and increased bilateral thyroid lobes compressing the trachea. Thyroglobulin was elevated from 210 to 472 ng/mL. Case 2: A 52-year-old woman presented with thyroid swelling. Five years after the initial admission, the increased right lobe deviated the trachea and compressed the right recurrent laryngeal nerve. Thyroglobulin was elevated from 122 to 392 ng/mL. Two cases and literature review indicated that MNG with >50 mm, solid components, and extension to the mediastinum or paralarynx were risk factors of tracheal compression and deviation. Monitoring thyroglobulin elevation can help predict the clinical course.

Successful HLA-haploidentical stem cell transplantation with post-transplant cyclophosphamide in an older patient with chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a subtype of EBV-associated T/NK cell lymphoproliferative disease and is only curable by allogeneic hematopoietic stem cell transplantation. However, finding a human leukocyte antigen (HLA)-matched donor at a suitable time can sometimes be difficult. We report the case of a 60-year-old woman who received prednisolone (PSL) after being diagnosed with autoimmune hepatitis 3 years earlier. She suddenly developed high fever and impaired liver function. Based on a high EBV DNA load in the peripheral blood, CAEBV was diagnosed. The patient was started on cooling therapy with PSL, cyclosporine, and etoposide, which reduced symptoms. Subsequently, she received HLA-haploidentical stem cell transplantation (haplo-SCT) with reduced-intensity conditioning (fludarabine 25 mg/m2 for 5 days, melphalan 50 mg/m2 for 2 days, and total body irradiation at 2 Gy) and post-transplant cyclophosphamide (PTCy) because she lacked an HLA-matched donor. Liver function was restored, and EBV DNA load in peripheral white blood cells became undetectable. The patient is alive without relapse or severe complications over 1 year after transplantation. To our knowledge, this is the first report of successful haplo-SCT with PTCy for CAEBV. This approach may be an alternative therapeutic option for CAEBV patients lacking an HLA-matched donor.

Regression Analysis to Estimate the Factor VIII Activity of Patients with Hemophilia A Without Inhibitor who Received Emicizumab Therapy.

BACKGROUND: Emicizumab, a bispecific monoclonal antibody for hemophilia A (HA), has strong pharmacodynamic effects in several coagulation assays resulting in dosing difficulties with Factor VIII (FVIII) concentrates during bleeding emergencies. MATERIALS AND METHODS: Single and multiple regression models were studied to estimate FVIII activity using 27 archived plasma samples from three patients with HA without inhibitor under emicizumab treatment. Explanatory variables were FVIII chromogenic assay (CSA), Ad|min1|, Ad|min2|, the number of seconds of APTT, and the FVIII one-stage assay (OSA), which were measured without idiotype antibodies. The response variable was FVIII OSA measured with idiotype antibodies. RESULTS: In the simple linear model, the FVIII CSA regression coefficient was 1.04 and the intercept was -14.55 (r2 = 0.95; p < 0.001). In the multiple regression model, FVIII OSA and FVIII CSA were selected based on the Akaike Information Criterion, with regression coefficients of 1.74 and 1.15, respectively, and an intercept of -92.03 (r2 = 0.96, p < 0.001). CONCLUSIONS: The regression models can estimate the FVIII:C levels in patients with HA receiving emicizumab and would be useful in a bleeding emergency and/or surgery.

Frequent co-reactivation of Epstein-Barr virus in patients with cytomegalovirus viremia under immunosuppressive therapy and/or chemotherapy.

OBJECTIVE: Co-reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) occurs in iatrogenically immunosuppressed patients, but the clinical relevance of this is unknown. We aimed to determine the frequency of EBV reactivation in patients with CMV viremia and to explore its clinical significance. METHODS: Serum or plasma CMV and EBV DNA was detected by quantitative real-time PCR in 82 patients who received immunosuppressive therapy and/or chemotherapy and underwent CMV antigenemia tests. RESULTS: CMV DNA was positive in 55 patients, with EBV reactivation being found in 29 of these (52.7%). EBV co-reactivation was significantly associated with aging (>64 years vs. ≤64 years, odds ratio 4.07, 95% confidence interval 1.06-15.6). When older patients were divided into two groups according to age, EBV co-reactivation occurred more frequently in early-old patients (aged 65-74 years) than in late-old patients (aged ≥75 years) (100.0% vs. 53.3%, respectively). Steroid pulse treatment was administered significantly more often in the early-old group than in those aged ≤64 years and ≥75 years (72.7% vs 27.6% vs 14.3%, respectively). CONCLUSIONS: Co-reactivation of EBV in patients with CMV viremia highlighted early-old patients and may reflect treatment intensity as well as immunosenescence.

Turning Point in the Treatment of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an incurable type of B-cell lymphoma. It is typically composed of small-to-medium-sized cleaved lymphoid cells with cyclin D1 protein expression due to the chromosomal translocation t(11;14)(q13;q32). Even with the development of rituximab, an anti-CD20 antibody drug, the long-term outcome of patients with MCL has not improved. Recently, new agents have been used in clinical settings, and the outcome of patients with MCL is expected to improve. The treatment of MCL may be at a turning point from intensive chemotherapy to chemotherapy-free treatment. In this study, a recent progress in the diagnosis and treatment of MCL is reviewed.

False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation.

OBJECTIVES: Although Aspergillus galactomannan (GM) antigen detection is widely applied in the diagnosis of invasive aspergillosis (IA), false-positive reactions with fungus-derived antibiotics, other fungal genera or the passage of dietary GM through injured mucosa are a matter of concern. The aim of this study was to investigate the cumulative incidence and risk factors for false-positive GM antigenaemia. PATIENTS AND METHODS: The records of 157 adult allogeneic haematopoietic stem cell transplantation (HSCT) recipients were retrospectively analysed. Episodes of positive GM antigenaemia, defined as two consecutive GM results with an optical density index above 0.6, were classified into true, false and inconclusive GM antigenaemia by reviewing the clinical course. RESULTS: Twenty-five patients developed proven or probable IA with a 1 year cumulative incidence of 12.9%, whereas 50 experienced positive GM antigenaemia with an incidence of 32.2%. Among the total 58 positive episodes of the 50 patients, 29 were considered false-positive. The positive predictive value (PPV) was lower during the first 100 days than beyond 100 days after HSCT (37.5% versus 58.8%). Gastrointestinal chronic graft-versus-host disease (GVHD) was identified as the only independent significant factor for the increased incidence of false-positive GM antigenaemia (PPV 0% versus 66.7%, P = 0.02). CONCLUSIONS: GM antigen results must be considered cautiously in conjunction with other diagnostic procedures including computed tomography scans, especially during the first 100 days after HSCT and in patients with gastrointestinal chronic GVHD.

Case report: persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes.

Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation.

A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy.

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.

Herpes simplex encephalitis and subsequent cytomegalovirus encephalitis after chemoradiotherapy for central nervous system lymphoma: a case report and literature review.

Neurological complications during the treatment of hematological malignancies have a wide range of causes. Treatment-related leukoencephalopathy has been recognized as a major complication of combined chemotherapy and radiotherapy for central nervous system (CNS) lymphoma, and can complicate the diagnosis of CNS infection. Herein, we present a patient with diffuse large B-cell lymphoma who developed herpes simplex encephalitis (HSE) and subsequent cytomegalovirus encephalitis after chemoradiotherapy for CNS relapse. Although cerebrospinal fluid examination (CSF) showed no significant pleocytosis, brain magnetic resonance imaging and polymerase chain reaction analysis of the CSF were useful in the diagnosis. With a review of the literature on the association between HSE and radiotherapy for CNS malignancies, our case suggests that an awareness of viral encephalitis is important in the differential diagnosis of acute neurologic disturbance during chemoradiotherapy for CNS lymphoma.

ESHAP therapy effective in a patient with Langerhans cell sarcoma.

We describe the rare case of a 53-year-old woman with systemic involvement of Langerhans cell sarcoma (LCS) who had undergone living-related liver transplantation. We chose the CHOP regimen as first-line chemotherapy, and clinical improvement of LCS was obtained. Intensive care was necessary due to the systemic involvement of LCS and severe infectious diseases. After the third cycle of CHOP therapy, however, disease progression was observed, and we administrated a modified ESHAP regimen (etoposide, carboplatin, cytarabine, methylprednisolone) as second-line therapy. A marked response was obtained after four cycles of this combination chemotherapy. Modified ESHAP may be a very effective combination chemotherapy regimen for LCS.

Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation.

Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.