Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

[Drug Administration for Childhood Neurological Disorders].

In this review, we summarized drug administration strategies for childhood diseases, such as childhood epilepsy and attention-deficit hyperactivity disorder (ADHD). Therapeutic drug monitoring is recommended for most antiepileptic drugs; however, dosage of these in the clinical setting is usually based solely on body weight or age. Other factors to be considered are dosage form and taste; these are particularly important in infants and toddlers as they affect the adherence to a given medicine and may impose a limitation on drug administration. In addition, we should be cautious about such side-effects as the effect on appetite. Special attention should be paid if there is a history of long-time treatment during childhood, because appetite loss or stimulation might have had a substantial negative impact on growth during childhood. We also briefly summarized newly introduced drug therapies for spinal muscular atrophy. These include gene therapy and exon-skipping drugs, which increase the amount of functioning SMN2 protein in skeletal muscles. In particular, the focus of this treatment is on the age of the patient and copy number of the SMN2 gene, both of which are key parameters.

In utero Exposure to Valproic Acid throughout Pregnancy Causes Phenotypes of Autism in Offspring Mice.

Valproic acid (VPA) is an antiepileptic drug that inhibits the epileptic activity of neurons mainly by inhibiting sodium channels and GABA transaminase. VPA is also known to inhibit histone deacetylases, which epigenetically modify the cell proliferation/differentiation characteristics of stem/progenitor cells within developing tissues. Recent clinical studies in humans have indicated that VPA exposure in utero increases the risk of autistic features and intellectual disabilities in offspring; we have previously reported that low-dose VPA exposure in utero throughout pregnancy increases the production of projection neurons from neuronal stem/progenitor cells that are distributed in the superficial neocortical layers of the fetal brain. In the present study, we found that in utero VPA-exposed mice exhibited abnormal social interaction, changes in cognitive function, hypersensitivity to pain/heat, and impaired locomotor activity, all of which are characteristic symptoms of autism spectrum disorder in humans. Taken together, our findings indicate that VPA exposure in utero throughout pregnancy alters higher brain function and predisposes individuals to phenotypes that resemble autism and intellectual disability. Furthermore, these symptoms are likely to be due to neocortical dysgenesis that was caused by an increased number of projection neurons in specific layers of the neocortex.

[Acute lymphoblastic leukemia with "masked" Philadelphia chromosome].

A 76-year-old woman with leukocytosis and thrombocytopenia was admitted to our hospital. A bone marrow examination showed a composition of 82.0% blasts, i.e., positive for TdT, CD10, CD19, CD34, and HLA-DR and negative for cyCD3, CD13, CD33, MPO, and cyµ. The reverse transcription-polymerase chain reaction analysis revealed a minor BCR-ABL1 fusion gene, leading to a diagnosis of acute lymphocytic leukemia (ALL) with a BCR-ABL1 fusion gene. G-band assay was negative for Philadelphia (Ph) chromosome and also revealed add (21) (q22. 1) and del (20) (q11. 2q13.3). Fluorescence in situ hybridization (FISH) assaying revealed a positive BCR-ABL1 fusion signal. Thus, this patient was diagnosed as Ph chromosome-negative and BCR-ABL1-positive fusion gene ALL, which suggested the presence of ALL with the "masked" Ph chromosome found in approximately 1% of chronic myeloid leukemia. Therefore, the FISH analysis may complement cytogenetic analysis when cytogenetic and molecular genetic findings are contradictory in ALL.

Performance evaluation of a novel reticulocyte identification method that uses metachromatic nucleic acid staining based on a crossover analysis of emission DNA/RNA light (RNP Determination™) in hematology analyzer Celltac G.

INTRODUCTION: Assessing the percentage of reticulocytes (%Retic) is useful for diagnosing and treating blood diseases that present with anaemia. The Celltac G+™ hematology analyzer (HA) uses a novel reticulocyte identification method that involves metachromatic nucleic acid staining with acridine orange and crossover analysis of emission light of DNA/RNA (determination of red cells, nucleic acid-containing cells, and platelets, RNP Determination™). The red and green fluorescence generated by stained single-stranded RNA and double-stranded DNA express immaturity and morphological abnormality of erythrocytes by detecting erythrocyte RNA and DNA content. METHODS: The basic performance of the test automated analyzer (TAA) Celltac G+ was evaluated and compared with the flow cytometry reference method and the comparative automated analyzer (CAA) XN-1000/2000™. In addition, its precision, limit of quantity (LoQ), linearity, analytical measurement interval (AMI), accuracy, and comparability and the effects of interfering substances were evaluated. RESULTS: Evaluation of %Retic by the TAA demonstrated good precision and linearity. The AMI was confirmed from 0.02 to 8.23, and the LoQ in %Retic as the coefficient of variation within an 11% limit (SD, within a 0.01 limit) was 0.14. TAA correlated well with the reference method and routine HA (CAA). Some deviations were found between TAA and CAA in DNA measurements of erythrocytes from abnormal samples. CONCLUSION: Celltac G+ uses a novel measurement principle and can assess erythrocyte immaturity independent of DNA contents. It represents a new HA that provides novel, useful information on immaturity and morphological abnormality of erythrocytes.

The reappearance of de Winter's pattern caused by acute stent thrombosis: A case report.

A 78-year-old man suffering from epigastric discomfort presented with an initial electrocardiogram showing complete right bundle branch block (RBBB) and ST-segment depression continuing to positive symmetrical T waves in leads V2 to V4, suggestive of de Winter's pattern. Emergent coronary angiography demonstrated 2-vessel disease with 90% stenosis in the proximal segment of the left anterior descending artery (LAD) with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, and 75% in the mid portion and 90% in the distal portion of the right coronary artery, without collateral flow to LAD. A drug-eluting stent was deployed at the proximal LAD, and the flow of the diagonal branch deteriorated to TIMI grade 1 flow on the final angiogram. De Winter's pattern temporarily disappeared, and the procedure was finished. However, when the patient was admitted to the coronary care unit, de Winter's pattern emerged again with less severe epigastric discomfort. Subsequently, chest X-ray showed pulmonary edema in both lungs. Repeat angiography revealed acute stent thrombosis of LAD with TIMI grade 1 flow. De Winter's pattern with the combination of RBBB can be observed not only on admission but also at the time of occurrence of stent thrombosis. .

[De novo blast phase of chronic myeloid leukemia with 3q26 abnormality diagnosed by cytogenetic analysis of extramedullary lesion].

A 62-year-old woman was presented at our hospital with visual disturbance. An ocular examination revealed bilateral Roth spots. Laboratory data revealed leukocytosis (236,200 µl) with an excess blast (11%). Physical examination and computed tomography (CT) showed systemic lymphadenopathy. A bone marrow examination revealed a composition of 9.2% blast. Chromosomal analysis on bone marrow cells revealed 46,XX,t (3;12)(q26.2;p13),t (9;22)(q34.1;q11.2) in 80% of metaphases (16/20). Inguinal lymph node biopsy revealed diffuse proliferation of myeloperoxidase (MPO)-positive abnormal cells. Fluorescence in situ hybridization analysis was used to detect the BCR-ABL1 fusion gene and split the signals of MECOM and ETV6. She was diagnosed with de-novo chronic myeloid leukemia (CML) extramedullary blast crisis. She received tyrosine kinase inhibitor (TKI) combination chemotherapy and allogeneic hematopoietic stem cell transplantation and achieved a major molecular response. In this study, we reported a case of CML in blast-phase initially presenting as extramedullary, in which cytogenetic and molecular analyses were useful in the staging method.

Alinity hq platelet results are equivalent with the international reference method in thrombocytopenic samples.

INTRODUCTION: Accurate and precise platelet (PLT) count is critical for the appropriate management of patients with thrombocytopenia. This study evaluated the performance of PLT counting with the Abbott Alinity hq hematology analyzer, which utilizes multi-dimensional optical technology. METHODS: Imprecision, linearity, and accuracy were assessed per CLSI guidelines. Alinity hq PLT results were compared to the international flow cytometry reference method (IRM) in the concentration range of 6.3 to 103.0 × 109 /L. Additional comparisons were made with Sysmex XN-3000 PLT counts: impedance (PLT-I), optical (PLT-O), and optical fluorescent (PLT-F) methods. RESULTS: The average within-run %CV was 4.7% on patient samples with PLT concentrations ranging from 13.1 to 41.7 × 109 /L, and the within-laboratory %CV was 3.6% at the level of 68.2 × 109 /L. Linearity evaluation indicated a maximum deviation of 3.1% from the linear fit in the range of 0.1 to 316.8 × 109 /L. Comparison between Alinity hq and the IRM PLT counts yielded a correlation coefficient of 0.99 and predicted bias of 0.0 and -0.5 × 109 /L at 10.0 and 20.0 × 109 /L transfusion thresholds, respectively. Alinity hq PLT counts also correlated well with Sysmex PLT counts, with strongest correlation obtained with PLT-F and PLT-O (r = .99) methods. CONCLUSION: This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.

Reference intervals of white blood cell parameters for healthy adults in japan.

INTRODUCTION: While white blood cell (WBC) parameters have been suggested to depend on ethnicity and gender, reference intervals in healthy Asian populations are limited. The present study established reference intervals of WBC parameters for healthy adults in Japan. METHODS: A total of 750 healthy adults (447 women and 303 men; 18-67 years old, median 40 years old) at 7 Japanese centers who participated in regular medical checkups entered this study. The WBC parameters were measured using automated hematocytometers and blood film reviews by a manual microscopic examination. RESULTS: The reference intervals of the WBC parameters according to gender in healthy adults were determined. Age-specific decreases in WBC counts of both gender groups and in neutrophil counts of women were noted. Favorable correlations between the hematocytometer and microscopic methods were found in neutrophils, lymphocytes, and eosinophils but not in monocytes or basophils. CONCLUSION: This study suggests the need to consider gender and age in the clinical use of reference intervals of WBC parameters.

Establishment of a High-risk MDS/AML Cell Line YCU-AML1 and its Xenograft Model Harboring t(3;3) and Monosomy 7.

Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with both inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 defines an extremely aggressive myeloid cancer whose molecular pathogenesis and optimal therapeutic strategy still remain unclear. We established a new MDS/AML cell line, YCU-AML1, and its patient-derived xenograft (PDX) model from a high-risk MDS patient who later transformed into AML harboring both t(3;3)(q21;q26.2) and monosomy 7. YCU-AML1 cells propagated in co-culture system with stromal cells in granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent manner. CD34+ bone marrow cells derived from our PDX model showed high EVI1 and low GATA2 expression. Moreover, mutational profile of our MDS/AML model was consistent with recently published mutational spectrum of myeloid malignancies with inv(3)/t(3;3). These data suggest that YCU-AML1 cells and its MDS/AML model strongly mimics a high-risk human myeloid cancer with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 in terms of both clinical phenotype and molecular basis. We believe our model can be used as a feasible tool to further explore molecular pathogenesis and novel treatment strategy of high-risk MDS/AML with t(3;3)(q21;q26.2) and monosomy 7.

Large-Area Fluorescence and Electron Microscopic Correlative Imaging With Multibeam Scanning Electron Microscopy.

Recent improvements in correlative light and electron microscopy (CLEM) technology have led to dramatic improvements in the ability to observe tissues and cells. Fluorescence labeling has been used to visualize the localization of molecules of interest through immunostaining or genetic modification strategies for the identification of the molecular signatures of biological specimens. Newer technologies such as tissue clearing have expanded the field of observation available for fluorescence labeling; however, the area of correlative observation available for electron microscopy (EM) remains restricted. In this study, we developed a large-area CLEM imaging procedure to show specific molecular localization in large-scale EM sections of mouse and marmoset brain. Target molecules were labeled with antibodies and sequentially visualized in cryostat sections using fluorescence and gold particles. Fluorescence images were obtained by light microscopy immediately after antibody staining. Immunostained sections were postfixed for EM, and silver-enhanced sections were dehydrated in a graded ethanol series and embedded in resin. Ultrathin sections for EM were prepared from fully polymerized resin blocks, collected on silicon wafers, and observed by multibeam scanning electron microscopy (SEM). Multibeam SEM has made rapid, large-area observation at high resolution possible, paving the way for the analysis of detailed structures using the CLEM approach. Here, we describe detailed methods for large-area CLEM in various tissues of both rodents and primates.

[Evans syndrome complicated with multicentric Castleman disease successfully treated with tocilizumab].

A 26-year-old man presented with fever, multiple lymphadenopathies, polyclonal hypergammaglobulinemia, and an elevated serum interleukin-6 (IL-6) level. Multicentric Castleman disease (MCD) was diagnosed by lymph node biopsy. Treatment with prednisolone (PSL) was initiated; however, its efficacy was limited. During PSL tapering, rapidly progressive anemia and thrombocytopenia developed concurrently with increased reticulocyte level, elevated serum LDH level, decreased haptoglobin level, and positive direct Coombs test. Based on these findings, Evans syndrome, which is a concurrent development of autoimmune hemolytic anemia and immune thrombocytopenia, was confirmed. The PSL dose was increased but was ineffective. Therefore, treatment with tocilizumab was initiated, and the clinical findings of both MCD and Evans syndrome improved. The clinical course of this case suggests that tocilizumab could be a treatment option for Evans syndrome complicated with MCD. Three other cases of Evans syndrome complicated with MCD have also been reported; however, this is the first case that shows the efficacy of tocilizumab as treatment for both MCD and Evans syndrome.

Very Late Relapse of Acute Promyelocytic Leukemia 17 Years after Continuous Remission.

The prognosis of acute promyelocytic leukemia (APL) has been improved by the combination of all-trans retinoic acid (ATRA) with chemotherapy. Nonetheless, relapse occurs in a certain proportion of patients, mostly within three to four years after treatment. We herein report a patient treated with ATRA and chemotherapy achieving remission who relapsed approximately 17 years after the treatment. A literature review identified 5 additional reported cases of APL relapse after more than 10 years. None of them presented with generally established risk factors for relapse, such as a high leukocyte count. The potential for late relapse of APL occurring more than 10 years after treatment should be recognized.

Association of Admission Glucose Level and Improvement in Pulmonary Artery Pressure in Patients with Submassive-type Acute Pulmonary Embolism.

Objective The admission glucose level is a predictor of mortality even in patients with acute pulmonary embolism (APE). However, whether or not the admission glucose level is associated with the severity of APE itself or the underlying disease of APE is unclear. Methods This study was a retrospective observational study. A pulmonary artery (PA) catheter was used to accurately evaluate the severity of APE. The percentage changes in the mean PA pressure (PAPm) upon placement and removal of the inferior vena cava filter (IVCF) were evaluated. We hypothesized that the admission glucose level was associated with the improvement in the PA pressure in patients with APE. Patients A total of consecutive 22 patients with submassive APE who underwent temporary or retrievable IVCF insertion on admission and repetitive PA catheter measurements upon placement and removal of IVCFs were enrolled. Results There was a significant positive correlation between the admission glucose levels and the percentage changes in the PAPm (r=0.543, p=0.009). A univariate linear regression analysis showed that the admission glucose level was the predictor of the percentage change in PAPm (ß coefficient=0.169 per 1 mg/dL; 95% confidence interval, 0.047-0.291; p=0.009). A multivariate linear regression analysis with the forced inclusion model showed that the admission glucose level was the predictor of the percentage change in PAPm independent of diabetes mellitus, PAPm on admission, troponin positivity, and brain natriuretic peptide level (all p<0.05). Conclusion The admission glucose level was associated with the improvement in the PAPm in patients with submassive-type APE.

Progress in Myelodysplastic Syndromes: Clinicopathologic Correlations and Immune Checkpoints.

BACKGROUND: Myelodysplastic syndromes (MDS) are a group of clonal neoplasms characterized by ineffective hematopoiesis. Hypomethylating agent (HMA) therapy is one of the mainstays of MDS therapy. Failure of HMA therapy is related to poor outcome; hence, new therapeutic approaches are warranted in these patients. In MDS, the immune system has a pivotal role in modulation of hematopoiesis and clonal expansion. In neoplastic conditions, immune checkpoint (PD-1 and CTLA4 molecules) hide tumor cells from immune surveillance. Identification of the pattern of expression of these molecules in MDS provides an interesting alternative within clinical trials. MATERIALS AND METHODS: We describe the clinicopathologic correlations by morphology, immunohistochemistry (PD-L1) and flow cytometry immunophenotypic analysis in an MDS patient treated with immune checkpoint PD-1 inhibitor. RESULTS: Bone marrow (BM) morphology, differential counts and aberrant flow markers were assessed before and after anti PD-1 inhibitor therapy. At baseline, BM showed severe trilineage dysplasia with decreased granulopoiesis; after therapy, BM showed normal trilineage hematopoiesis. A decrease in PD-L1 expression, by manual and automatic analysis, was also noted from 15% to 5% after 26 months of treatment. The findings correlated with the recovery of peripheral blood counts and transfusion independency. CONCLUSION: BM morphology and PD-L1 expression by immunohistochemistry can be used to assess treatment response in immune checkpoints therapy.

Single-institutional retrospective analysis of Japanese patients with chronic lymphocytic leukemia.

Unlike in Western countries, chronic lymphocytic leukemia (CLL) is a rare lymphoid malignancy in Japan, and its clinical features remain to be elucidated in the Japanese population. Therefore, we retrospectively analyzed 29 Japanese CLL patients newly diagnosed at our institute. Seventeen (59%) were male, and their median age was 62 years. With a median follow-up period from diagnosis of 69 months (range, 3-170 months), 9 patients received some form of treatment for CLL. Three patients died of disease progression with or without infection (n=2) or skin cancer (n=1). Five-year overall and treatment-free survival rates were 83% (95%CI, 46-96%) and 67% (95%CI, 45-81%), respectively. Two patients received allogeneic hematopoietic stem cell transplantation for refractory disease, and both were alive without disease relapse at 53 and 110 months, respectively, after transplantation. These results suggest the clinical courses of Japanese patients with CLL to be comparable to those in Western countries. However, future studies of larger numbers of patients are needed to further elucidate the features and long-term clinical courses of CLL in the Japanese population.

Adverse effects of prenatal and early postnatal exposure to antiepileptic drugs: Validation from clinical and basic researches.

Epilepsy requires the long-term administration of antiepileptic drugs (AEDs), and thus, we must consider the effects of prenatal AED exposure on fetus when treating female patients of child bearing age. Large prospective clinical researches in humans have demonstrated the following: (1) prenatal exposure to valproic acid (VPA), carbamazepine, and phenobarbital increases the risk of congenital malformations in a dose-dependent manner and (2) prenatal exposure to VPA increases the risk of higher brain function impairments including intellectual disabilities and autistic spectrum disorders in the offspring. Furthermore, basic researches in animals have shown that prenatal exposure to specific AEDs causes microscopic structural abnormalities in the fetal brain. Specifically, prenatal exposure to VPA has been reported to inhibit the differentiation of neural progenitor cells during the early to middle phases of neuronogenesis, leading to increased number of projection neurons in the superficial layers of postnatal neocortices in mice. It is indispensable to prescribe AEDs that are associated with lower risk of congenital malformations and impairment of higher brain functions as well as to administer them at requisite minimum doses.

In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.

Valproic acid (VPA), a widely used antiepileptic drug, is an inhibitor of histone deacetylases, which epigenetically modify cell proliferation/differentiation in developing tissues. A series of recent clinical studies in humans reported that VPA exposure in utero impaired histogenesis and the development of the central nervous system, leading to increased risks of congenital malformation and the impairment of higher brain functions in children. In the present study conducted in mice, we report that VPA exposure in utero (1) increases the amount of acetylated histone proteins, (2) alters the expression of G1-phase regulatory proteins, (3) inhibits the cell cycle exit of neural progenitor cells during the early stage of neocortical histogenesis, and (4) increases the production of projection neurons distributed in the superficial neocortical layers in embryonic brains. Together, our findings show that VPA exposure in utero alters proliferation/differentiation characteristics of neural progenitor cells and hence leads to the neocortical dysgenesis. SIGNIFICANCE STATEMENT: This study provides new insight into the mechanisms of how an altered in utero environment, such as drug exposure, affects the generation of neurons prenatally. The antiepileptic drug valproic acid (VPA) is a good target molecule as in utero exposure to VPA has been repeatedly reported to increase the risk of nervous system malformations and to impair higher brain functions in children. We show that VPA decreases the probability of differentiation of the neural progenitor cells (NPCs) in mice, resulting in an abnormally increased number of projection neurons in the superficial layers of the neocortex. Further, we suggest that histone deacetylase inhibition by VPA may be involved in the dysregulation of proliferation/differentiation characteristics of NPCs.

Beneficial effect of early infusion of landiolol, a very short-acting beta-1 adrenergic receptor blocker, on reperfusion status in acute myocardial infarction.

BACKGROUND: An early IV beta blocker during primary percutaneous coronary intervention (PCI) has been shown to reduce infarct size in ST-segment elevation acute myocardial infarction (STEMI), although the underlying mechanism is unknown. The aim of this study was to investigate the efficacy of early infusion of landiolol, the short-acting beta-1 adrenergic receptor blocker, on the reperfusion status in a STEMI. METHODS: We conducted a prospective, single-group trial of landiolol during the primary PCI for a STEMI. Landiolol was started intravenously just before reperfusion. The reperfusion status and outcomes in 55 treated patients were compared with those in 60 historical controls treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, and myocardial brush grade (MBG) after reperfusion. RESULTS: Patients in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p=0.023) and MBG 2/3 (64% vs. 45%, p=0.045), whereas coronary flow was comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (odds ratio 2.99, 95% confidence interval 1.25-7.16, p=0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p=0.014), hypotension (15% vs. 32%, p=0.046), and progression to Killip class grade III or IV (0% vs. 10%, p=0.028) were lower in the landiolol group. CONCLUSION: Early infusion of landiolol during the primary PCI was associated with optimal reperfusion and a lower incidence of adverse events in comparison with the control group.