Characteristics of Perfusion Computed Tomography Imaging in Patients with Seizures Mimicking Acute Stroke.

INTRODUCTION: Seizures as acute stroke mimics are a diagnostic challenge. OBJECTIVE: The aim of the study was to characterize the perfusion patterns on perfusion computed tomography (PCT) in patients with seizures masquerading as acute stroke. METHODS: We conducted a study on patients with acute seizures as stroke mimics. The inclusion criteria for this study were patients (1) initially presenting with stroke-like symptoms but finally diagnosed to have seizures and (2) with PCT performed within 72 h of seizures. The PCT of seizure patients (n = 27) was compared with that of revascularized stroke patients (n = 20) as the control group. RESULTS: Among the 27 patients with seizures as stroke mimics, 70.4% (n = 19) showed characteristic PCT findings compared with the revascularized stroke patients, which were as follows: (1) multi-territorial cortical hyperperfusion {(73.7% [14/19] vs. 0% [0/20], p = 0.002), sensitivity of 73.7%, negative predictive value (NPV) of 80%}, (2) involvement of the ipsilateral thalamus {(57.9% [11/19] vs. 0% [0/20], p = 0.007), sensitivity of 57.9%, NPV of 71.4%}, and (3) reduced perfusion time {(84.2% [16/19] vs. 0% [0/20], p = 0.001), sensitivity of 84.2%, NPV of 87%}. These 3 findings had 100% specificity and positive predictive value in predicting patients with acute seizures in comparison with reperfused stroke patients. Older age was strongly associated with abnormal perfusion changes (p = 0.038), with a mean age of 66.8 ± 14.5 years versus 49.2 ± 27.4 years (in seizure patients with normal perfusion scan). CONCLUSIONS: PCT is a reliable tool to differentiate acute seizures from acute stroke in the emergency setting.

Characteristics of seizure-induced signal changes on MRI in patients with first seizures.

PURPOSE: The aim of this study was to investigate the predictive factors and identify the characteristics of the seizure-induced signal changes on MRI (SCM) in patients with first seizures. METHODS: We conducted a retrospective study of patients with first seizures from March 2010 to August 2014. The inclusion criteria for this study were patients with 1) first seizures, and 2) MRI and EEG performed within 24h of the first seizures. The definition of SCM was hyper-intensities in the brain not applying to cerebral arterial territories. Multivariate logistic regression was performed with or without SCM as a dependent variable. RESULTS: Of 431 patients with seizures visiting the ER, 69 patients met the inclusion criteria. Of 69 patients, 11 patients (15.9%) had SCM. Epileptiform discharge on EEG (OR 29.7, 95% CI 1.79-493.37, p=0.018) was an independently significant variable predicting the presence of SCM in patients with first seizures. In addition, the topography of SCM was as follows; i) ipsilateral hippocampus, thalamus and cerebral cortex (5/11), ii) unilateral cortex (4/11), iii) ipsilateral thalamus and cerebral cortex (1/11), iv) bilateral hippocampus (1/11). Moreover, 6 out of 7 patients who underwent both perfusion CT and MRI exhibited unilateral cortical hyperperfusion with ipsilateral thalamic involvement reflecting unrestricted vascular territories. CONCLUSION: There is an association between epileptiform discharges and SCM. Additionally, the involvement of the unilateral cortex and ipsilateral thalamus in SCM and its hyperperfusion state could be helpful in differentiating the consequences of epileptic seizures from other pathologies.

Patterns of relapse or progression after bortezomib-based salvage therapy in patients with relapsed/refractory multiple myeloma.

INTRODUCTION: Bortezomib-based therapy is commonly used in treatment for relapsed or refractory multiple myeloma (MM). Unfortunately, many patients show relapse or progression in heterogeneous patterns. PATIENTS AND METHODS: In this study, we retrospectively evaluated patterns of relapse or progression after bortezomib-based salvage therapy in patients with MM and analyzed prognostic significance according to patterns of relapse or progression. One hundred forty-eight patients were treated with bortezomib-based therapy between November 2004 and April 2012. Of these patients, 104 (70.3%) patients relapsed or progressed after bortezomib-based salvage therapy. We divided the patterns of relapse or progression to the 2 groups: (1) the isoform relapse or progression (group A) in 89 (85.6%) patients as disease findings at initiation of bortezomib-based therapy; and (2) transformed relapse or progression (group B) in 15 (14.4%) patients (plasmacytoma, n = 7; light chain escape, n = 6; and plasma cell leukemia, n = 2) different from initial disease findings. RESULTS: Median overall survival in group A and group B were 32.7 months (95% confidence interval [CI], 21.3-44.1) and 10.7 months (95% CI, 2.0-19.4) (P < .001), respectively. CONCLUSION: MM patients who relapsed or progressed as the transformed pattern for bortezomib-based salvage therapy have an extremely poor prognosis and might require new innovative approaches.

Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens.

Bortezomib is a proteasome inhibitor with potent antimyeloma activity in relapsed/refractory multiple myeloma (MM) patients. We evaluated the types and factors affecting the onset of infectious complications and mortality owing to infection in MM patients treated with bortezomib-based regimens. We reviewed 139 patients with MM treated with regimens containing bortezomib in order to assess the types and factors affecting the development of severe infections. Infections occurred in 56 (40.3 %) of 139 patients and 83 (7.8 %) cases of the 1,069 evaluable cycles. Severe infections developed in 43 (30.9 %) patients and ten patients (7.1 %) died during bortezomib-based treatment. Multivariate analysis determined lymphocytopenia grade 3-4 (OR 3.17, 95 % CI 1.38-7.31, P = 0.007) and number of cycles ≤ 8 (OR 3.91, 95 % CI 1.39-11.02, P = 0.010) as risk factors associated with increased severe infection. This study showed that MM patients who received bortezomib-based regimens are at a higher risk of severe infections within eight cycles of treatment during especially severe lymphocytopenic periods. MM patients treated with bortezomib-based regimens should be closely monitored for the development of infectious complications during lymphocytopenia.

Successful Treatment of Pure Red Cell Aplasia with Rituximab in Patients after ABO-Compatible Allogeneic Hematopoietic Stem Cell Transplantation.

Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (HSCT) has been mostly reported in situations involving major ABO incompatibility between donor and recipient. Conventional treatments such as plasma exchange, erythropoietin, and steroid are often unsatisfactory. Rituximab has been reported to be highly effective for PRCA following major ABO-incompatible allogeneic HSCT. A 49-year-old woman with PRCA following ABO-matched allogeneic HSCT for acute lymphoblastic leukemia, refractory to erythropoietin treatment, received 4 doses of rituximab 375 mg/m(2) weekly. After the 3rd dose of rituximab, she exhibited a striking rise in her reticulocyte count with an increase in her hemoglobin level. To our knowledge, this is the first case of PRCA following major ABO-compatible allogeneic HSCT resolving completely after rituximab treatment.

A comparison of bortezomib, cyclophosphamide, and dexamethasone (Vel-CD) chemotherapy without and with thalidomide (Vel-CTD) for the treatment of relapsed or refractory multiple myeloma.

We compared the clinical responses and toxicities between bortezomib-based salvage chemotherapy combined with cyclophosphamide, thalidomide, and dexamethasone(Vel-CTD) and without thalidomide (Vel-CD) in patients with relapsed or refractory MM. Eighty-six patients received at least two cycles of treatment with Vel-CTD (bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, and 11; cyclophosphamide 150 mg/m2 orally on days 1­4; thalidomide 50­100 mg/day orally every day; and dexamethasone 20 mg/m2 i.v. on days 1, 4, 8, and 11 every 3 weeks), and 67 patients were given at least two cycles of Vel-CD, which is the same regimen as Vel-CTD except without thalidomide. The overall response rates of the Vel-CD and Vel-CTD groups were 88% and 90% (p>0.05), respectively. There was no difference in the progression free survival (p = 0.69) and overall survival rates(p = 0.49) between the two groups. Grade 3 or more adverse hematologic events occurred in the same proportion of patients in both groups. In terms of non-hematologic toxicities, the Vel-CTD group showed a higher proportion of autonomic neuropathy, motor neuropathy, and sensory neuropathy compared to the Vel-CD group (each, p<0.05). Only three patients in the Vel-CTD group showed thrombotic events despite aspirin prophylaxis. The Vel-CD regimen inpatients with relapsed or refractory MM is an effective and more tolerable salvage therapy compared to Vel-CTD in terms of its comparable response rate and less severe of non-hematologic toxicities.

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy.

Dendritic cell (DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy. DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1 (Th1) or Th2 responses. DCs play a role in natural killer (NK) cell activation, and NK cells are also able to activate and induce the maturation of DCs. We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur. DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70. NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses. Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T-cell responses, which suggests that these cells may be useful for cancer immunotherapy.

Fludarabine-containing chemotherapy for patients with previously untreated low-grade non-Hodgkin's lymphoma.

BACKGROUND: The clinical efficacy and safety of fludarabine combination chemotherapy was investigated for the treatment of previously untreated patients with low-grade (NHL). METHODS: Twenty-five patients who were newly diagnosed as low-grade NHL were treated with fludarabine combination chemotherapy. Fludarabine combination regimens consisted of fludarabine, mitoxantrone and dexamethasone or fludarabine, cyclophosphamide and mitoxantrone with or without rituximab and repeated every 4 weeks. RESULTS: The median age was 60 years (range, 35-77 years), with 13 of 25 patients (52%) ≥60 years of age. Seven of 25 patients (28%) with an intermediate risk follicular lymphoma international prognostic index (FLIPI) and 9 of 25 patients (36%) with a high risk FLIPI were enrolled in this study. The delivered median number of chemotherapy was six (range, 2-9 cycles). The overall response rate with fludarabine-based treatment was 88%, including 52% complete remission and 36% partial remission. During the median follow-up of 19 months, the estimated 2-year event-free survival was 63±10% (95% CI, 43-83) and the 2-year overall survival was 78±9% (95% CI, 60-96). Fludarabine combination chemotherapy was frequently associated with grade 3 or 4 neutropenia in 84% patients. However, neutropenic infection was observed in only one (4%) patient. Four patients (16%) showed grade 3 or more non-hematologic toxicities, such as acute coronary syndrome, intracranial hemorrhage, anaphylaxis and gastric cancer. CONCLUSION: Fludarabine-combination treatment was a highly active regimen with well toleration in untreated low-grade NHL.

A Case of Disseminated and Fulminant Plasmacytomas That Developed during Bortezomib Treatment.

Multiple myeloma is an incurable and slow growing plasma cell neoplasm. The introduction of new drugs has increased the number of treatment options. Bortezomib, the first-in-class proteasome inhibitor, has been shown to have a significant antitumor activity in the treatment of relapse/refractory patients with multiple myeloma. Additionally, plasmacytomas have shown significant response to bortezomib. In this case report, we describe a patient who developed disseminated and fulminant extramedullary plasmacytomas during combination chemotherapy treatment with bortezomib within a short period, after having shown clinical improvement.

Successful cross-presentation of allogeneic myeloma cells by autologous alpha-type 1-polarized dendritic cells as an effective tumor antigen in myeloma patients with matched monoclonal immunoglobulins.

For wide application of a dendritic cell (DC) vaccination in myeloma patients, easily available tumor antigens should be developed. We investigated the feasibility of cellular immunotherapy using autologous alpha-type 1-polarized dendritic cells (αDC1s) loaded with apoptotic allogeneic myeloma cells, which could generate myeloma-specific cytotoxic T lymphocytes (CTLs) against autologous myeloma cells in myeloma patients. Monocyte-derived DCs were matured by adding the αDC1-polarizing cocktail (TNFα/IL-1ß/IFN-α/IFN-γ/poly-I:C) and loaded with apoptotic allogeneic CD138(+) myeloma cells from other patients with matched monoclonal immunoglobulins as a tumor antigen. There were no differences in the phenotypic expression between αDC1s loaded with apoptotic autologous and allogeneic myeloma cells. Autologous αDC1s effectively took up apoptotic allogeneic myeloma cells from other patients with matched subtype. Myeloma-specific CTLs against autologous target cells were successfully induced by αDC1s loaded with allogeneic tumor antigen. The cross-presentation of apoptotic allogeneic myeloma cells to αDC1s could generate CTL responses between myeloma patients with individual matched monoclonal immunoglobulins. There was no difference in CTL responses between αDC1s loaded with autologous tumor antigen and allogeneic tumor antigen against targeting patient's myeloma cells. Our data indicate that autologous DCs loaded with allogeneic myeloma cells with matched immunoglobulin can generate potent myeloma-specific CTL responses against autologous myeloma cells and can be a highly feasible and effective method for cellular immunotherapy in myeloma patients.

Prognostic significance of interim ¹8F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma.

PURPOSE: (18)F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerised tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. METHODS: One hundred and sixty-one patients with newly diagnosed DLBCL were enroled; the assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of rituxibmab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). RESULTS: Sixty-seven patients (41.6%) presented with advanced stage disease and 27 (16.8%) had bulky lesions. Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8months, the positivity of interim PET/CT was found to be a prognostic factor for both overall survival (OS) and progression-free survival (PFS), with a hazard ratio of 4.07 (2.62-6.32) and 5.46 (3.49-8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rates were significantly different in the patients with positive (53.3% and 52.5%) and negative (93.8% and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P<0.01). CONCLUSIONS: Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk.

Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis.

We assessed the clinical significance of T or B cell clonality and Epstein-Barr virus (EBV) infection in adult patients with hemophagocytic lymphohistiocytosis (HLH) to identify factors related to prognosis. A total of 30 adult patients with diagnosed HLH were included in the study. In all patients, EBV-DNA in peripheral blood was examined by quantitative real-time polymerase chain reaction and bone marrow cells were examined for clonal rearrangement of T cell receptor gamma(TCRG) and immunoglobulin heavy chain (IGH) genes. TCRG clones were detected in 10 patients (33.3%) and IGH clones were detected in 8 patients (26.7%). We found no correlation between clonality and patient outcome. The patients less than 1,000 copies (mL)21 of EBVDNA showed a significantly higher clinical response (P 5 0.008) and longer overall survival (P 5 0.01) than those with high viral load of EBV-DNA. Our results suggest that TCRG and IGH rearrangement do not have any clinical significance in adult patients with HLH, but that high viral load of EBV-DNA may be a risk factor for poor outcomes. In HLH, high viral load of EBV-DNA should thus suggest a prompt approach with aggressive therapeutic interventions.

Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity.

Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.

Acute and subacute stent thrombosis in a patient with clopidogrel resistance: a case report.

Drug-eluting stents (DES) are considered the treatment of choice for most patients with obstructive coronary artery disease when percutaneous intervention (PCI) is feasible. However, stent thrombosis seems to occur more frequently with DES and occasionally is associated with resistance to anti-platelet drugs. We have experienced a case of recurrent stent thrombosis in a patient with clopidogrel resistance. A 63-year-old female patient suffered from acute myocardial infarction and underwent successful PCI of the left anterior descending coronary artery (LAD) with two DESs. She was found to be hyporesponsive to clopidogrel and was treated with triple anti-platelet therapy (aspirin 100 mg, clopidogrel 75 mg, and cilostazol 200 mg daily). Three days after discharge, she developed chest pain and was again taken to the cardiac catheterization laboratory, where coronary angiography (CAG) showed total occlusion of the mid-LAD where the stent had been placed. After intravenous administration of a glycoprotein IIb/IIIa inhibitor, balloon angioplasty was performed, resulting in Thrombolysis In Myocardial Infarction (TIMI) III antegrade flow. The next day, however, she complained of severe chest pain, and the electrocardiogram showed marked ST-segment elevation in V1-V6, I, and aVL with complete right bundle branch block. Emergent CAG revealed total occlusion of the proximal LAD due to stent thrombosis. She was successfully treated with balloon angioplasty and was discharged with triple anti-platelet therapy.

Hematological profile of Korean very low birth weight infants.

For very low birth weight (VLBW) infants, diagnostic and therapeutic decisions widely depend on hematological values. Although ethnic differences for hematologic parameters have been reported, few studies have been reported for Korean VLBW infants. This study aimed at defining the hematological reference values for medical research and clinical practice. Retrospectively we selected 149 infants confirmed as healthy at birth and had no medical conditions that may have affected the hematological profile. Hematological values obtained within the first 4 h after birth were classified into gestational age and we determined the influence of gender, mode of delivery, sampling site, 1-min and 5-min Apgar scores on these values. Red blood cell (RBC), hemoglobin (Hb) and hematocrit (Hct) values increased, whereas the white blood cell (WBC) and platelets decreased as the gestational age increased. In relation to the mode of delivery and the 5-min Apgar score, WBC, neutrophil, mean corpuscular volume (MCV), RBC, Hb, Hct and the platelets differed selectively. No differences in any hematological values were observed in relation to gender, sampling site, and the 1-min Apgar score. This study should be useful as a guide to the reference range of these hematological values for Korean VLBW infants.

Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha isoform: implications for tumor promotion.

Hypoxia-inducible factor-1 (HIF-1), which is present at higher levels in human tumors, plays important roles in tumor promotion. It is composed of HIF-1alpha and HIF-1beta subunits and its activity depends on the amount of HIF-1alpha, which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1alpha in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1alpha in tumors. On the other hand, phorbol esters such as phorbol-12-myristate-13-acetate (PMA) are known to be potent tumor promoters. Here, we identified a novel HIF-1alpha isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1alpha(785)) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1alpha(785) is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1alpha. HIF-1alpha(785) escapes from lysine acetylation because of the loss of Lys(532) and was stabilized under normoxic conditions. Its expression was blocked by reducing agents and by a mitogen-activated protein/extracellular signal-regulated kinase-1 inhibitor and enhanced by hydrogen peroxide. In addition, HIF-1alpha(785) overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1alpha(785) is induced by PMA under normoxic conditions via a redox-dependent mitogen-activated protein/extracellular signal-regulated kinase-1 pathway and that it plays an important role in tumor promotion.