18F-sodium fluoride positron emission tomography following coronary computed tomography angiography in predicting long-term coronary events: a 5-year follow-up study.

PURPOSE: The predictive value of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) in combination with coronary computed tomography (CT) angiography (CCTA) for future coronary events has attracted interest. We evaluated the potential of 18F-NaF PET/CT following CCTA to predict major coronary events (MACE) during a 5-year follow-up period. METHODS: Forty patients with coronary atherosclerotic lesions detected on CCTA underwent 18F-NaF PET/CT examination. Each lesion was evaluated for luminal stenosis and high-risk plaque (HRP) with < 30 Hounsfield units and a > 1.1 remodeling index on CCTA. Focal 18F-NaF uptake in each lesion was quantified using the maximum tissue-to-background ratio (TBRmax), and the maximum TBRmax per patient (M-TBRmax) was determined. We followed MACE (cardiac death, acute coronary syndrome, and/or coronary revascularization > 6 months after 18F-NaF PET/CT) for 5 years. RESULTS: In total, 142 coronary lesions were analyzed. Eleven patients experienced any MACE. Patients with MACE showed a higher M-TBRmax than those without (1.40 ± .19 vs. 1.18 ± .18, P = .0011), and the optimal M-TBRmax cutoff to predict MACE was 1.29. Patients with M-TBRmax of ≥ 1.29 had a higher risk of MACE than those with lower values (P = .012, log-rank test), whereas patients with obstructive stenosis and those with HRP did not. Multivariate Cox proportional analysis adjusted for age, sex, coronary risk factors, and CCTA findings showed that M-TBRmax of ≥ 1.29 remained an independent predictor of 5-year MACE (hazard ratio, 5.4; 95% confidence interval, 1.1-25.4; P = .034). CONCLUSION: 18F-NaF PET/CT following CCTA provides useful strategies to predict 5-year MACE.

Progression to B acute lymphoblastic leukemia in 8p11 myeloproliferative syndrome with t(6;8)(q27;p12).

8p11 myeloproliferative syndrome is a rare hematological malignancy caused by the translocation of FGFR1. Patients present with a myeloproliferative neoplasm that frequently transforms into acute myeloid leukemia or T-lymphoblastic lymphoma/leukemia. Here, we report a molecular study of a patient with 8p11 myeloproliferative syndrome who developed acute B-lymphoblastic leukemia and then transformed to mixed-phenotype acute leukemia. A 67-year-old woman was diagnosed with a myeloproliferative neoplasm with t(6;8)(q27;p12) and was monitored for polycythemia vera. Four years later, she developed acute B-lymphoblastic leukemia with an additional chromosomal abnormality of - 7. Despite two induction regimens, she failed to achieve complete remission, and leukemia transformed into mixed-phenotype leukemia. Targeted sequencing of serial bone marrow samples identified the RUNX1 L144R mutation upon transformation to B-cell leukemia. After those two induction regimens, some RUNX1 mutation-positive leukemic cells obtained the JAK2 V617F mutation, which was associated with the emergence of myeloid markers, including myeloperoxidase.

A longitudinal pilot study to assess temporal changes in coronary arterial 18F-sodium fluoride uptake.

PURPOSE: How coronary arterial 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography changes over the long term and what clinical factors impact the changes remain unclear. We sought to investigate the topics in this study. METHODS: We retrospectively studied 15 patients with ≥1 coronary atherosclerotic lesion/s detected on cardiac computed tomography who underwent baseline and follow-up (interval of >3 years) 18F-NaF positron emission tomography/computed tomography scans. Focal 18F-NaF uptake in each lesion was quantified using maximum tissue-to-background ratio (TBRmax). The temporal change in TBRmax was assessed using a ratio of follow-up to baseline TBRmax (R-TBRmax). RESULTS: A total of 51 lesions were analyzed. Mean R-TBRmax was 0.96 ± 0.21. CT-based lesion features (location, obstructive stenosis, plaque types, features of high-risk plaque) did not correlate with an increase in R-TBRmax. In multivariate analysis, baseline TBRmax significantly correlated with higher follow-up TBRmax (ß = 0.57, P < 0.0001), and the presence of diabetes mellitus significantly correlated with both higher follow-up TBRmax (ß = 0.34, P = 0.001) and elevated R-TBRmax (ß = 0.40, P = 0.003). CONCLUSION: Higher coronary arterial 18F-NaF uptake is likely to remain continuously high. Diabetes mellitus affects the long-term increase in coronary arterial 18F-NaF uptake.

Emergence of t(3;21)(q26.2;q22) during eltrombopag treatment in a patient with relapsed aplastic anemia who received chemotherapy for angioimmunoblastic T-cell lymphoma.

A 65-year-old man with nonsevere aplastic anemia received rabbit anti-thymocyte globulin and cyclosporine and partially responded. Six months after the initiation of treatment, he was diagnosed with stage IV angioimmunoblastic T-cell lymphoma and received chemotherapy. PET/CT scan analysis indicated a complete response. However, he showed sustained myelosuppression and was diagnosed with relapse of aplastic anemia. He did not respond to cyclosporine, eltrombopag or methenolone. Fifteen months after eltrombopag administration, he developed MDS with t(3;21)(q26.2;q22). Patients should be monitored carefully for the emergence of not only -7/del(7q) but also 3q26 abnormalities, including t(3;21)(q26.2;q22), during and after eltrombopag treatment.

Essential thrombocythaemia with aggressive megakaryocytosis after myelofibrotic transformation.

BACKGROUND: Among myeloproliferative neoplasms, it is often difficult to distinguish essential thrombocythaemia (ET) from prefibrotic-stage primary myelofibrosis (PMF) with thrombocytosis given their overlapping clinicopathological phenotypes. CASE PRESENTATION: We encountered a 45-year-old male who was initially diagnosed with ET and eventually became transformed to secondary myelofibrosis 20 years later. Two distinct types of aberrant megakaryocytes were observed at diagnosis: one type characteristic of ET and the other type characteristic of PMF. With a proliferation in the bone marrow, aberrant megakaryocytes were infiltrated into the extramedullary organs and were even present in the thrombus were observed at autopsy. As a result of next-generation sequencing, the significant increase of variant allele frequency (VAF) of JAK2 V617F and U2AF1 S34Y mutations was observed in the bone marrow cells at the final stage. CONCLUSIONS: This patient could be recognized as an atypical case of aggressive megakaryocytosis transformed from ET.

Acute Subdural Hematoma in High School Rugby Players in Japan: The Importance of Playing Experience for Injury Prevention.

OBJECTIVES: Acute subdural hematoma (ASDH) is known to be devasting sport-related head injury but it is relatively rare in rugby compared with other contact sports. Certain cases of ASDH have happened in high school rugby players in Japan. To prevent them from the injury we report a background of the players. METHODS: Data of high school rugby players who suffered ASDH were extracted from injury reports in the Japan Rugby Football Union between April 2004 and March 2020. The number of injured players, diagnosis on the report, school year, phase of play where the injury occurred, and playing career were analyzed. RESULTS: There were 30 cases of ASDH including 16 cases in the first year, 9 in the second year, and 5 in the third year of playing. Phase of play was mainly being tackled in 11 (37%), and tackling in 13 (43%). Novice players, defined as a player having less playing experience of rugby during junior high school, accounted for 77% of phase of tackling, 82% of being tackled. First year novice players accounted for 100% of phase of being tackled. Outcome within 6 months after injury was recovery in 14, morbidity in 6, mortality in 2, and unknown in 8. CONCLUSIONS: Playing experience in high school rugby players should be considered as an important factor for prevention of ASDH-in particular, phase of being tackled is riskier than that of tackling for first year novice players.

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.

Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.

Clinical implications of 18F-sodium fluoride uptake in subclinical aortic valve calcification: Its relation to coronary atherosclerosis and its predictive value.

BACKGROUND: Uptake of 18F-sodium fluoride (18F-NaF) on positron emission tomography (PET) reflects active calcification. Application of this technique in the early phase of aortic valve calcification (AVC) is of clinical interest. We investigated clinical implications of 18F-NaF uptake in subclinical AVC evaluated simultaneously with coronary atherosclerosis, and the utility of 18F-NaF uptake in predicting AVC progression. METHODS: We studied 25 patients with subclinical AVC and coronary plaques detected on computed tomography (CT) who underwent 18F-NaF PET/CT. AVC score, volume, mean density, and the presence of high-risk coronary plaque were evaluated on CT in each patient. Focal 18F-NaF uptake in AVC and in coronary plaques was quantified with the maximum tissue-to-background ratio (TBRmax). RESULTS: There were positive correlations between AVC TBRmax (A-TBRmax) and AVC parameters on CT. The 14 patients with high-risk coronary plaque had significantly higher A-TBRmax than those without such plaque (1.60 ± 0.18 vs 1.42 ± 0.13, respectively; P = 0.012). A-TBRmax positively correlated with maximum TBRmax of coronary plaque per patient (r = 0.55, P = 0.0043). In the 11 patients who underwent follow-up CT scan, A-TBRmax positively correlated with subsequent increase in AVC score (r = 0.74, P = 0.0091). CONCLUSION: Our 18F-NaF PET- and CT-based data indicate relationships between calcification activity in subclinical AVC and characteristics of coronary atherosclerosis. 18F-NaF PET may provide new information regarding molecular conditions and future progression of subclinical AVC.

Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.

The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells.

Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/ß-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.

[Effective treatment of POEMS syndrome accompanied by plasmacytoma with lenalidomide, dexamethasone, and local irradiation].

A 70-year-old woman experienced pain in both gastrocnemius muscles, numbness in the toes, and muscle weakness in both the legs that lasted for two months. After getting admitted to our hospital, the muscle weakness extended to both her arms, and nerve conduction studies revealed decreased nerve conduction velocity, which was more prominent in the elbow and the axilla than in the wrist. A magnetic resonance imaging revealed a tumor in the right femoral neck, which was histologically diagnosed as plasmacytoma. Laboratory findings revealed IgA lambda type M protein and an elevated VEGF level of 2,320 pg/ml; edema was present in both the legs. After a diagnosis of POEMS syndrome, lenalidomide and dexamethasone treatment were initiated simultaneously, along with irradiation. The treatment improved polyneuropathy, along with a decrease in the VEGF level. Increased vascular permeability due to elevated VEGF led to the development of neuropathy of POEMS syndrome, and treatment against proliferating monoclonal plasma cells is effective. In the present case, we believe that a prompt control of the plasmacytoma with novel therapeutic agents for myeloma with irradiation resulted in the improvement of the neurological symptoms.

Relationship between coronary arterial 18F-sodium fluoride uptake and epicardial adipose tissue analyzed using computed tomography.

PURPOSE: 18F-Sodium fluoride (18F-NaF) positron emission tomography (PET) has the potential to detect high-risk coronary plaques. Epicardial adipose tissue (EAT) reportedly correlates with coronary atherosclerosis progression. We evaluated the relationship between coronary arterial 18F-NaF uptake and EAT findings using computed tomography (CT). METHODS: We studied 40 patients with ≥ 1 coronary plaque detected on cardiac CT who underwent 18F-NaF PET/CT. EAT volume was measured using CT and indexed to body surface area in each patient. Each plaque was evaluated for CT-based luminal stenosis and high-risk features. The mean EAT density surrounding each plaque was calculated as perilesional EAT density (PLED) using non-contrast CT images. Focal 18F-NaF uptake in each plaque was quantified using the maximum tissue-to-background ratio (TBRmax). RESULTS: EAT volume index was similar between patients with TBRmax ≥ 1.28 (previously reported optimal cutoff to predict coronary events) and those with lower TBRmax, but patients with TBRmax ≥ 1.28 showed higher maximum PLED per patient (- 86 ± 12 Hounsfield units (HU) versus - 98 ± 11 HU, P = 0.0044). In the lesion-based analysis (n = 92), PLED was positively correlated with TBRmax, and the optimal PLED cutoff to identify TBRmax ≥ 1.28 was - 97 HU. On multivariate analysis adjusted for lesion location, obstructive stenosis, and high-risk plaque on CT, PLED ≥ - 97 HU remained a significant predictor of TBRmax ≥ 1.28. CONCLUSIONS: Increased PLED was associated with significant coronary arterial 18F-NaF uptake. Step-by-step analyses of EAT density on CT and coronary arterial 18F-NaF uptake on PET may offer novel strategies for risk prediction in coronary artery disease.

[Acquired hemophilia A requiring plasma exchange and mechanical ventilation].

A 56-year-old man who sustained a right waist injury 1 month ago, reported to our department complaining of pain in the right waist and femur for 1 day. In a computed tomography examination, hematoma of the right iliopsoas muscle was revealed, and arterial embolization was immediately performed but was not effective. Laboratory findings showed hemoglobin levels as 5.4 g/dl, platelet of 20.2×104/µl, prothrombine time of 13.1 s, partial thromboplastin time (APTT) of 81.1 s, and a convex upward curve of the APTT cross-mixing test. The activity of the coagulation factor VIII was <1.0%, but its amount was 120%, and the level of factor VIII inhibitor was 130 Bethesda Unit/ml. Disseminated intravascular coagulation was not noted. Under the diagnosis of acquired hemophilia A, treatment with prednisolone and recombinant activated factor VII was initiated. However, APTT remained prolonged, and intubation and mechanical ventilation were required because of right hemothorax. After steroid pulse therapy and plasma exchange, APTT returned to its normal range, and the inhibitor disappeared. Thus, we finally succeeded in extubation. This case indicated that intensive care may be necessary in the early phase treatment for acquired hemophilia A.

Predictive Value of 18F-Sodium Fluoride Positron Emission Tomography in Detecting High-Risk Coronary Artery Disease in Combination With Computed Tomography.

Background Application of 18F-sodium fluoride (18F-NaF) positron emission tomography ( PET ) to coronary artery disease has attracted interest. We investigated the utility of 18F-NaF uptake for predicting coronary events and evaluated the combined use of coronary computed tomography (CT) angiography ( CCTA ) and 18F-NaF PET /CT in coronary artery disease risk assessment. Methods and Results This study included patients with ≥1 coronary atherosclerotic lesion detected on CCTA who underwent 18F-NaF PET / CT . High-risk plaque on CCTA was defined as plaque with low density (<30 Hounsfield units) and high remodeling index (>1.1). Focal 18F-NaF uptake in each lesion was quantified using the maximum tissue:background ratio ( TBR max), and maximum TBR max per patient (M- TBR max) was determined. Thirty-two patients having a total of 112 analyzed lesions were followed for 2 years after 18F-NaF PET / CT scan, and 11 experienced coronary events (acute coronary syndrome and/or late coronary revascularization [after 3 months]). Patients with coronary events had higher M- TBR max than those without (1.39±0.18 versus 1.19±0.17, respectively; P=0.0034). The optimal M- TBR max cutoff to predict coronary events was 1.28 (area under curve: 0.79). Patients with M- TBR max ≥1.28 had a higher risk of earlier coronary events than those with lower M- TBR max ( P=0.0062 by log-rank test). In patient-based (n=41) and lesion-based (n=143) analyses of CCTA findings that predicted higher coronary 18F-NaF uptake, the presence of high-risk plaque was a significant predictor of both M- TBR max ≥1.28 and TBR max ≥1.28. Conclusions 18F-NaF PET / CT has the potential to detect high-risk coronary artery disease and individual coronary lesions and to predict future coronary events when combined with CCTA . Clinical Trial Registration URL : www.umin.ac.jp . Unique identifier: UMIN 000013735.

RUNX1-EVI1 induces dysplastic hematopoiesis and acute leukemia of the megakaryocytic lineage in mice.

The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1-expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells.

Data on analysis of coronary atherosclerosis on computed tomography and 18F-sodium fluoride positron emission tomography.

This article contains the data showing illustrative examples of plaque classification on coronary computed tomography angiography (CCTA) and measurement of 18F-sodium fluoride (18F-NaF) uptake in coronary atherosclerotic lesions on positron emission tomography (PET). We divided the lesions into one of three plaque types on CCTA (calcified plaque, non-calcified plaque, partially calcified plaque). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio. This article also provides a representative case with a non-calcified coronary plaque detected on CCTA and identified on 18F-NaF PET/non-contrast computed tomography based on a location of a vessel branch as a landmark. These complement the data reported by Kitagawa et al. (2017) [1].

18F-sodium fluoride positron emission tomography for molecular imaging of coronary atherosclerosis based on computed tomography analysis.

BACKGROUND AND AIMS: We aimed at evaluating the relation of 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) to coronary atherosclerosis detected and assessed by computed tomography (CT). METHODS: Thirty-two patients with one or more coronary atherosclerotic lesions detected on cardiac CT underwent 18F-NaF PET/CT. Each coronary atherosclerotic lesion was evaluated on CT angiography for plaque types (calcified plaque [CP], non-calcified plaque [NCP], partially calcified plaque [PCP]), and the presence of CT-based high-risk features (minimum CT density <30 Hounsfield units and vascular remodeling index >1.1). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio (TBRmax). RESULTS: A total of 111 lesions were studied. In a patient-based analysis, logarithmically transformed coronary calcium score correlated positively with maximum TBRmax per patient, and 15 patients with myocardial infarction or unstable angina history showed a higher maximum TBRmax per patient than those without (1.36 ± 0.15 versus 1.15 ± 0.15, p = 0.0006). In a lesion-based analysis, PCP showed a higher TBRmax than CP and NCP (1.17 ± 0.19 versus 1.00 ± 0.24 and 0.92 ± 0.18, respectively, p < 0.0001), and the lesions with high-risk features had a higher TBRmax than those without (1.20 ± 0.21 versus 1.02 ± 0.20, p = 0.0011). CONCLUSIONS: Coronary arterial 18F-NaF uptake is related to total plaque burden, coronary event history, and specific features of coronary atherosclerosis based on CT analysis. 18F-NaF PET/CT, in combination with cardiac CT, may provide a new molecular imaging approach to identify high-risk patients and coronary atherosclerotic lesions.