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.

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.

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.

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.

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.

[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.

[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.

[Systemic organ invasion accompanied by immunophenotypic change observed in extraosseous plasmacytoma].

We report a 57-year-old man who was diagnosed based on morphological findings as having extraosseous plasmacytoma of the left lower eyelid. Tumor cells were positive not only for CD38 and CD138, but also for CD19 and surface immunoglobulin lambda chain. He obtained a complete remission with irradiation and VAD therapy, but the disease relapsed one year later in the testis and popliteal fossa. Because tumor cells appeared to be blastoid, CHOP therapy was administered, and the patient achieved a temporary remission. Cytoplasmic lambda chain-positive and CD19-negative tumors eventually recurred at multiple sites including the central nervous system but not in the bone marrow. Treatment with the BD regimen and lenalidomide failed, and he died four years after the initial diagnosis.

Prednisone versus high-dose dexamethasone for untreated primary immune thrombocytopenia. A retrospective study of the Japan Hematology & Oncology Clinical Study Group.

High-dose dexamethasone (HDD) has been shown to be an effective initial treatment for immune thrombocytopenia (ITP), but it is not clear whether HDD offers any advantages over conventional-dose prednisone (PSL). We retrospectively compared the efficacy and toxicity of HDD and PSL for newly diagnosed ITP. The response was evaluated according to the International Working Group (IWG) criteria. We analyzed data from 31 and 69 patients in the HDD and PSL groups, respectively. There were no significant differences in patient characteristics between the two groups except for the incidence of the eradication of Helicobacter pylori. The response rate was better in the HDD group (42.7 vs. 28.4 %), and this difference was statistically significant when adjusted for other factors including the eradication of H. pylori. In the HDD group, a response was achieved earlier (28 vs. 152 days in median) and steroids were more frequently discontinued at 6 months (64.5 vs. 37.7 %). Among patients who achieved a response, there was no significant difference in the incidence of loss of response. There were no significant differences in the rate of adverse events, transition to chronic ITP, and splenectomy. In conclusion, HDD might enable the early cessation of steroids without a loss of response.

[Inv(16)-type acute myeloid leukemia with repeated skin infiltration without bone marrow relapse before and after allogeneic hematopoietic stem cell transplantation].

We report a 40-year-old woman diagnosed as having acute myeloid leukemia with CBFB-MYH11. Before and after stem cell transplantation in the phase of molecular remission of the marrow, CBFB-MYH11-positive cells were detected by RT-PCR analysis in skin lesions. The former was pathologically diagnosed as leukemic infiltration, while the latter was considered to be graft-versus-host disease. We can speculate that a low level of leukemic stem cells not detectable by RT-PCR analysis remained in the bone marrow, at least prior to transplantation. This case may suggest interesting biological features of inv(16)-type acute myeloid leukemia.

[Detection of BCR-ABL1 chimeric gene-positive neutrophils in a patient with mixed phenotype acute leukemia].

We experienced two patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1 according to the WHO classification 2008. The type of BCR/ABL1 was major in both patients, and the chimeric gene was also detected in neutrophils from peripheral blood by the fluorescence in situ hybridization technique. Patient 1 was a 59-year-old Japanese woman, and patient 2 a 45-year-old Japanese man. They had both developed leukemia suddenly. Their leukemic blasts expressed B cell and myeloid cell antigens, but concomitantly in patient 1 (biphenotypic) and separately in patient 2 (biclonal). Percentages of BCR-ABL1-positive neutrophils were 98% and 89%, respectively. Both patients received an imatinib (600 mg/day)-combined Hyper-CVAD regimen as induction therapy, followed by treatment with dasatinib (140 mg/day). MEC therapy was also applied between these two treatments in patient 2. At present, patient 1 has obtained complete molecular remission quantitatively and qualitatively, and patient 2 only quantitatively. Considering their acute onsets with no prior history of chronic myelocytic leukemia (CML), they were both diagnosed as having acute leukemia with Ph1, but not blastic crisis of CML. In this tyrosine kinase inhibitor era, it has become more difficult to differentiate these two types of Ph1-positive leukemia development.

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.

[CD20-positive peripheral T-cell lymphoma, not otherwise specified].

We report a 69-year-old male with CD3-positive peripheral T-cell lymphoma, not otherwise specified (PTCL-nos). Interestingly, tumor cells slightly expressed CD20 as well. Southern analyses of the tumor cells showed rearrangement for only the T cell receptor gene but not the immunoglobulin genes. This patient achieved partial remission with a treatment regimen of THP-COP excluding prednisolone, but died of pneumonia. Although CD20-positive PTCL is rare, a review of the reported cases suggests that CD20-positive PTCL has a poor prognosis and that bone marrow infiltration of tumor cells results in a poorer prognosis in CD20-positive PTCL than in usual PTCL. By accumulating cases of this rare entity of lymphoma, we need to clarify the biological nature of the tumor cells and usefulness of rituximab combined with standard chemotherapy.

[CAG-GO therapy for patients with relapsed or primary refractory CD33-positive acute myelogenous leukemia].

We previously tested a less toxic CAG regimen consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of patients with relapsed or refractory myeloid malignancies or elderly patients with untreated ones, obtaining a satisfactory complete remission rate of 62%. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, has recently been approved as a single agent in Japan for the treatment of relapsed/refractory CD33-positive acute myelogenous leukemia (9 mg/m(2) on days1 and 15). Complete remission rate was reported as 30% in a phase 2 trial in Japan. In this study, effectiveness and safety of combining dose-attenuated gemtuzumab ozogamicin (3 mg/m(2) on day5) and original CAG regimen were assessed in nine patients with relapsed/refractory CD33-positive acute myelogenous leukemia and a median age of 70 years. Rate of complete remission with or without platelet recovery was 44% (4/9). The median duration of complete remission and overall survival were 5.5 and 16 months, respectively. Reversible myelosuppression and liver toxicity were the main adverse events, but no regimen-related death was recorded. Although only a small number of cases were included in this preliminary study, this CAG-GO regimen was found to be feasible and useful even in high-risk relapsed or refractory patients.

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.

Effects of chronic kidney disease and post-angiographic acute kidney injury on long-term prognosis after coronary artery angiography.

BACKGROUND: Both chronic kidney disease (CKD) and post-angiographic acute kidney injury (AKI) are regarded as risks factors for long-term mortality after coronary angiography. On the other hand, acute haemodynamic disturbances requiring haemodynamic support have a strong impact on both the incidence of AKI and on prognosis after coronary angiography. The aim of this study was to determine the impact of CKD and AKI on long-term prognosis after coronary angiography among hospital survivors and to determine relationships with haemodynamic variables. METHODS: We studied 2439 patients who underwent coronary angiography or percutaneous coronary intervention. Relationships between both CKD and AKI and mortality or cardiovascular diseases were measured using unadjusted and adjusted Cox models for case-mix and laboratory variables. RESULTS: Multivariable Cox regression analysis identified CKD as an independent predictor of long-term mortality [adjusted hazard ratio (AHR) 1.51; 95% confidence interval (95% CI) 1.07-2.13] and composite end points (AHR 1.72; 95% CI 1.40-2.11). Lower estimated glomerular filtration ratio levels below 50 mL/min/1.73 m(2) were significantly associated with mortality after adjustments. A similar association was found even in haemodynamically stable patients. AKI was also a predictor of long-term composite end points (AHR 1.64; 95% CI 1.09-2.46); however, its impact was attenuated in haemodynamically stable patients. CONCLUSIONS: Among hospital survivors, CKD is an independent predictor for both long-term mortality and composite end points, regardless of haemodynamic conditions. AKI is also a predictor of long-term prognosis; however, its impact may be attenuated in haemodynamically stable hospital survivors.

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.

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.