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Chronic Phase (chronic + phase)
Selected AbstractsComparison between Contrast-Enhanced Magnetic Resonance Imaging and Selvester QRS Scoring System in Estimating Changes in Infarct Size between the Acute and Chronic Phases of Myocardial InfarctionANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2009Daniël A. Geerse M.D. Background: The Selvester QRS score was developed as a method to estimate infarct size (IS) using the ECG and has been validated during the prereperfusion era. Few comparisons exist with contrast-enhanced magnetic resonance imaging (ceMRI) in reperfused patients. This study evaluates the ability of the Selvester QRS score to estimate serial changes in IS during the acute and chronic phases of the infarct evolution in patients who have received reperfusion therapy. Methods: Thirteen patients with acute myocardial infarction underwent serial ceMRI studies in the acute (<1 week) and chronic phase (>2 months) after their initial myocardial infarction. QRS scoring was performed on the corresponding ECGs. The correlation between ceMRI measurement and QRS score estimation of IS was determined at both time points and for the difference between the two phases. Results: The mean IS was 20.1 ± 11.0% of total left ventricular mass (% LV) in the acute phase and 13.3 ± 6.4% LV in the chronic phase ceMRI. The mean IS estimated by Selvester QRS score in the acute and chronic phases were 18.7 ± 8.2% and 16.4 ± 8.5% LV, respectively. A modest correlation was found for the acute (r = 0.57) and chronic phase IS (r = 0.54). However, there was no correlation for the difference in IS between the acute and chronic phases. Conclusions: In this pilot study, the Selvester QRS score correlates modestly to IS by ceMRI during both the acute and chronic phases of the infarction process. The serial changes over time in the Selvester QRS score and IS by ceMRI show no correlation. [source] Human immunodeficiency virus gag and pol-specific CD8 T cells in perinatal HIV infectionCYTOMETRY, Issue 5 2001Thomas W. McCloskey Abstract Background: Binding of fluorochrome-conjugated MHC class I tetramers is a powerful means to detect antigen-specific CD8 T lymphocytes. In human immunodeficiency virus (HIV) infection, cellular immune response is essential in curtailing HIV disease progression but gaps persist in our understanding of HIV-specific cells during the disease course. In this study, we evaluated tetramer binding HIV-specific CD8 T cells in HIV-infected children. Methods: Fluorescently labeled tetramers for HIV gag and pol were utilized to quantify antigen-specific cells by flow cytometry using a whole blood labeling method in a cohort of 19 HLA-A2+ HIV- infected children (age range 1 month to 17 years). Results: Fourteen children had detectable gag (median 0.4%) and pol (median 0.1%) binding CD8 T cells, three children had gag binding cells only, and two had neither. Numbers of gag and pol binding cells correlated with each other and each correlated independently with total CD8 T cells and total CD4 T cells. Conclusions: HIV gag and pol-specific CD8 T cells are maintained during the chronic phase of HIV infection in children and CD4 lymphocytes appear to be important for sustaining their levels. Cytometry (Comm. Clin. Cytometry) 46:265,270, 2001. © 2001 Wiley-Liss, Inc. [source] Novel agents to override imatinib resistance mechanismsDRUG DEVELOPMENT RESEARCH, Issue 7 2008Asumi Yokota Abstract Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr-Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr-Abl kinase inhibitor and is efficacious in treating Ph-chromosome-positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first-line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced-stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr-Abl. In this review, we describe novel Bcr-Abl tyrosine kinase inhibitors, the so-called "Super Gleevec" inhibitors. Drug Dev Res 69:398,406, 2008. © 2008 Wiley-Liss, Inc. [source] Magnetic Resonance Imaging in the Study of the Lithium,Pilocarpine Model of Temporal Lobe Epilepsy in Adult RatsEPILEPSIA, Issue 4 2002Catherine Roch Summary: ,Purpose: In temporal lobe epilepsy, it remains to be clarified whether hippocampal sclerosis is the cause or the consequence of epilepsy. We studied the temporal evolution of the lesions in the lithium,pilocarpine model of epilepsy in the rat with magnetic resonance imaging (MRI) to determine the progressive morphologic changes occurring before the appearance of chronic epilepsy. Methods: MRI was performed on an MR scanner operating at 4.7 T. We followed the evolution of lesions using T2 - and T1 -weighted sequences before and after the injection of gadolinium from 2 h to 9 weeks. Results: At 2 h after status epilepticus (SE), a blood,brain barrier breakdown could be observed only in the thalamus; it had disappeared by 6 h. At 24 h after SE, edema was present in the amygdala and the piriform and entorhinal cortices together with extensive neuronal loss; it disappeared progressively over a 5-day period. During the chronic phase, a cortical signal reappeared in all animals; this signal corresponded to gliosis, which appeared on glial fibrillary acidic protein (GFAP) immunohistochemically stained sections as hypertrophic astrocytes with thickened processes. In the hippocampus, the correlation between histopathology and T2 -weighted signal underscored the progressive constitution of atrophy and sclerosis, starting 2 days after SE. Conclusions: These data show the reactivity of the cortex that characterizes the initial step leading to the development of epilepsy and the late gliosis that could result from the spontaneous seizures. Moreover, it appears that hippocampal sclerosis progressively worsened and could be both the cause and the consequence of epileptic activity. [source] Brain natriuretic peptide in the prediction of recurrence of angina pectorisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2004H. Takase Abstract Background, Circulating levels of brain natriuretic peptide (BNP) provide prognostic information for patients with heart failure, but little is known about its prognostic usefulness in patients with stable angina pectoris. We investigated whether BNP could be used as a marker for the prediction of anginal recurrence after successful treatment. Design, Brain natriuretic peptide levels of 77 patients with stable angina pectoris were measured at enrolment and after confirmation of successful treatment (i.e. no anginal attack for at least 6 months: chronic phase) with percutaneous transluminal coronary angioplasty and/or conventional medication. Then, we prospectively followed them up for 25·9 ± 1·4 months, with the endpoint being a recurrence of anginal attacks. Results, An anginal attack recurred in seven patients. In patients without recurrence, BNP levels in the chronic phase (21 ± 12 [median ± median absolute deviation] pg mL,1) were lower than those measured at enrolment (46 ± 25 pg mL,1, P < 0·0001), whereas the levels in patients with recurrence increased during the same period (from 36 ± 16 to 72 ± 42 pg mL,1, P < 0·05). A univariate analysis revealed that the BNP level measured in the chronic phase was the significant predictor of future anginal recurrence. Analysis of the receiver operating characteristic curve indicated that the cutoff level of BNP in the chronic phase was 68 pg mL,1. The Kaplan-Meier method revealed that the incidence of anginal recurrence was higher in patients with higher (71·4%) than lower levels of BNP (2·9%; P < 0·0001). Conclusions, Measurement of BNP levels after successful therapy is clinically useful for the prediction of recurrence of anginal attacks in patients with angina pectoris. [source] Helicobacter pylori Stimulates a Mixed Adaptive Immune Response with a Strong T-Regulatory Component in Human Gastric MucosaHELICOBACTER, Issue 3 2007Rasmus Goll Abstract Background:, Host factors play an important role in the pathophysiology of Helicobacter pylori infection and development of gastritis and related disease. The established opinion is that the T-cell-mediated immune response to H. pylori infection is of Th1 type. Our earlier immune cell phenotype studies indicate a mixed Th1,Th2 profile of the effector cells. Therefore, an extensive adaptive and regulatory cytokine gene expression profile was conducted by quantitative real-time polymerase chain reaction (qPCR). Materials and Methods:, Biopsies from gastric mucosa of 91 patients diagnosed as H. pylori negative, H. pylori positive with gastritis, or H. pylori positive with peptic ulcer were obtained by endoscopy. Gene expressions of nine cytokines and CagA status were measured by qPCR. Results:, All cytokine genes showed higher expression levels in the presence of H. pylori when compared to H. pylori- negative samples (fold increase: IL8: × 11.2; IL12A: × 2.4; TNF-,: × 5.2; IFN-,: × 4.3; IL4: × 3.6; IL6: × 14.7; and IL10: × 6.7). Patients infected with CagA-positive strains had higher expression of IL1-, and IL18 compared to patients infected with CagA-negative strains (× 1.6 for IL1-, and × 2.0 for IL18). Patients with duodenal ulcer had a lower antral Th1/Th2 ratio than other H. pylori -positive patients. Conclusions:, The cytokine profile of H. pylori -infected gastric mucosa shows a mixed Th1,Th2 profile. Furthermore, a high IL10 expression may indicate that also regulatory T cells play a role in the chronic phase of H. pylori infection. [source] Therapy adapted to molecular response in patients with chronic myelogenous leukaemia in first chronic phase: results of the Duesseldorf study,HEMATOLOGICAL ONCOLOGY, Issue 4 2008Frank Neumann Abstract This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of ,1 log decrease in bcr-abl transcript after 6 or ,2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by ,2 log (n,=,3) or ,3 log (n,=,3) with 800,mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800,mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy. Copyright © 2008 John Wiley & Sons, Ltd. [source] Characterization of cecal gene expression in a differentially susceptible mouse model of bacterial-induced inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 7 2007Matthew H. Myles DVM Abstract Background: A/JCr mice develop typhlitis in response to Helicobacter hepaticus infection, whereas C57BL/6 mice coexist with this bacterium in a "commensal" relationship and do not develop disease even during prolonged colonization. Methods: To determine mechanisms that control this balance between responsiveness and nonresponsiveness, the mucosal response of A/JCr and C57BL/6 mice to acute H. hepaticus colonization was evaluated using genome-wide profiling. Transcription levels for a subset of gene discoveries were then evaluated longitudinally by semiquantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) to identify changes in gene expression that occur during progression from the acute to chronic phase of colonization. To determine whether chronic mucosal inflammation in A/JCr mice was mediated through a Th1 mechanism, as was inferred from the gene expression data, mice with typhlitis were treated with neutralizing antibody targeting IL-12/23p40 or IFN-gamma and the response to treatment was determined by cecal lesion severity and transcription of disease-related genes. Results: A/JCr mice had a biphasic expression of proinflammatory genes that corresponded with the acute and chronic phases of disease. In contrast, C57BL/6 mice exhibited a less robust acute transcriptional response that waned by day 30 postinoculation. Sustained upregulation of proinflammatory signals and responsiveness to anti-IL-12/23p40 and anti-IFN-, antibody suggests that inflammation in A/JCr mice was mediated through a Th1 mechanism. Prolonged upregulation of SOCS3 during the acute response to colonization suggests that C57BL/6 mice maintain mucosal homeostasis, at least in part by attenuating responsiveness to cytokine signaling. Conclusions: Collectively, these findings provide a foundation for understanding the immunological mechanisms that confer resistance or susceptibility to H. hepaticus -induced typhlitis. (Inflamm Bowel Dis 2007) [source] Prolonged imatinib-induced myelosuppression in chronic myeloid leukaemia with an unusually long survivalINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2008D. P. Busuttil Summary A case of Philadelphia chromosome positive chronic myeloid leukaemia (CML) with the longest survival ever reported in the medical literature is presented. The duration of the chronic phase was 29 years, the overall survival being 31 years. The clinical course, when challenged with imatinib in the later stages of the disease, was at variance with what is to be expected from the experience in similar situations. Lifelong myelosuppression resulted that interfered with further therapy and contributed to the demise of the patient from sepsis three years later. Caution is suggested with the use of imatinib in fibrotic CML with a low platelet count. [source] Changes of bladder activity and glycine levels in the lumbosacral cord after partial bladder outlet obstruction in ratsINTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2008Minoru Miyazato Objectives: We investigated the time course of changes in bladder activity as well as in spinal and serum levels of glutamate and glycine after partial bladder outlet obstruction (BOO) in rats. Methods: A total of 36 female rats were divided into six groups: sham operation (control); 3 days, 14 days, and 28 days after BOO; 3 days and 28 days after relief of BOO. Under urethane anesthesia, isovolumetric cystometry was carried out in each group. Then, spinal and serum levels of glutamate and glycine were measured. Results: The interval between bladder contractions was shorter in all of the groups compared with the control group. The amplitude and duration of bladder contractions was decreased at 3 days, 14 days, and 28 days after BOO, and at 3 days after relief of BOO. Spinal and serum glutamate levels showed no changes. However, the spinal glycine level was decreased at 14 days and 28 days after BOO, and at 28 days after relief of BOO. Serum glycine level was also decreased at 28 days after BOO and 28 days after relief of BOO. Conclusions: Detrusor overactivity during the chronic phase of partial BOO is partly caused by a decrease of glycinergic neuronal activity in the lumbosacral cord. A 3-day period of BOO produces detrusor overactivity, which might be due to an irreversible decrease of spinal glycinergic neuronal activity. [source] Postinjury estrogen treatment of chronic spinal cord injury improves locomotor function in ratsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2010Eric A. Sribnick Abstract Spinal cord injury (SCI) causes loss of neurological function and, depending on serverity, may cause paralysis. The only recommended pharmacotherapy for the treatment of SCI is high-dose methylprednisolone, and its use is controversial. We have previously shown that estrogen treatment attenuated cell death, axonal and myelin damage, calpain and caspase activities, and inflammation in acute SCI. The aim of this study was to examine whether posttreatment of SCI with estrogen would improve locomotor function by protecting cells and axons and reducing inflammation during the chronic phase following injury. Moderately severe injury (40 g · cm force) was induced in male Sprague-Dawley rats following laminectomy at T10. Three groups of animals were used: sham (laminectomy only), vehicle (dimethyl sulfoxide; DMSO)-treated injury group, and estrogen-treated injury group. Animals were treated with 4 mg/kg estrogen at 15 min and 24 hr postnjury, followed by 2 mg/kg estrogen daily for the next 5 days. After treatment, animals were sacrificed at the end of 6 weeks following injury, and 1-cm segments of spinal cord (lesion, rostral to lesion, and caudal to lesion) were removed for biochemical analyses. Estrogen treatment reduced COX-2 activity, blocked nuclear factor-,B translocation, prevented glial reactivity, attenuated neuron death, inhibited activation and activity of calpain and caspase-3, decreased axonal damage, reduced myelin loss in the lesion and penumbra, and improved locomotor function compared with vehicle-treated animals. These findings suggest that estrogen may be useful as a promising therapeutic agent for prevention of damage and improvement of locomotor function in chronic SCI. © 2010 Wiley-Liss, Inc. [source] Acute but not chronic macrophage recruitment in filarial infections in mice is dependent on C-C chemokine ligand 2PARASITE IMMUNOLOGY, Issue 8 2007M. RAMESH summary Macrophages play an important role in the formation of granulomas and the clearance of Brugia pahangi infections in mice. However, the factors responsible for the recruitment of these cells to the site of infection are not known. In this study we examined the role of the C-C chemokine ligand 2 (CCL2; also known as macrophage chemotactic factor , MCP1) in macrophage recruitment in intraperitoneal infections with B. pahangi. We observed that CCL2 was expressed by peritoneal exudate cells and was present in the sera of wild-type mice. Serum levels of CCL2 peaked twice during the immune response, once during the early, acute phase and again during the late, chronic phase. To further elucidate the role of this chemokine in the anti-filarial immune response, we compared CCL2 deficient (CCL2,/,) mice to wild-type mice. We observed that macrophage recruitment was impaired only during the acute phase in the former. While macrophage recruitment was unaffected during the chronic phase, increased accumulation of B and T lymphocytes was seen in these mice. We further report that larval clearance and the in vitro adhesion of PECs to larvae were unimpaired in these mice. [source] Reduced apoptosis in BALB/c mice infected with Heligmosomoides polygyrusPARASITE IMMUNOLOGY, Issue 6 2007M. DOLIGALSKA SUMMARY We evaluated levels of apoptosis and the immune response ex vivo in BALB/c mice infected with Heligmosomoides polygyrus. Cell proliferation, apoptosis and cytokine production were measured in mesenteric lymph nodes (MLN) without exposure to H. polygyrus antigens in culture. The inhibited apoptosis and cytokine production reported might reflect a state of cell hyporesponsiveness in the prepatent phase of infection. These changes were accompanied by changes in the percentage of CD4+ cells in MLN and popliteal lymph nodes (PLN). The prolonged reduction in apoptosis coexisted with induced cell proliferation, elevated TNF-,, IL-12p70, IFN-,, IL-6, IL-10 and TGF-, synthesis, but lowered IL-4 and IL-2 levels. In the chronic phase of infection an increasing production of IFN-,, monocyte chemotactic protein-1 (MCP-1), IL-10 and TGF-, with decreasing concentrations of other cytokines resulted in restored apoptosis. The cytokine response in serum showed moderate production of TNF-,, temporary involvement of IL-12p70, induction of IFN-, and IL-10 synthesis, as well as growing IL-6 and MCP-1 production. It is suggested that a synchronized synthesis of distinct cytokines is accompanied by different levels of inhibited apoptosis during the prepatent and chronic phases of H. polygyrus infection in BALB/c mice. We suggest that immunosuppression provoked by the nematode is not the outcome of parasite-induced apoptosis, but rather results from a hyporesponsiveness experienced by cells during H. polygyrus infection. [source] Hearing loss in chronic myeloid leukemiaPEDIATRIC BLOOD & CANCER, Issue 1 2005Rahul Naithani MBBS Abstract A 12-year-old girl presented with abdominal pain, fever, and hearing impairment of 6 months duration. She had massive hepatosplenomegaly and anemia. On the basis of her peripheral blood and bone marrow findings, she was diagnosed as chronic myeloid leukemia (CML) in chronic phase. Her hearing was assessed by brainstem evoked responses (BERA), which showed objective improvement in hearing with hydroxyurea. The rare occurrence of deafness in CML is reviewed and possible pathogenesis is discussed. Pediatr Blood Cancer 2005; 45: 54,56. © 2005 Wiley-Liss, Inc. [source] First-line therapy for chronic myeloid leukemia: Past, present, and future,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2009Carolina Pavlovsky The development of Bcr-Abl tyrosine kinase inhibitors has dramatically changed the prognosis of patients with newly diagnosed chronic myeloid leukemia (CML). Standard-dose imatinib (400 mg/day in chronic phase, 600 mg/day in advanced CML) now dominates the management of this disease, producing considerably higher hematologic, cytogenetic, and molecular response rates than seen with previous drug therapies. However, although many patients respond well to standard-dose imatinib initially, some patients do not achieve adequate levels of response or discontinue therapy because of resistance. One approach to improving treatment response with first-line imatinib may be to increase the imatinib dose (800 mg/day), although recent trial data indicate that overall increases in response rates may be modest. Newer Bcr-Abl tyrosine kinase inhibitors can induce responses in patients with all phases of imatinib-resistant CML, even those with imatinib-resistant mutations in the BCR-ABL gene. Furthermore, in initial studies, first-line dasatinib or nilotinib treatment has produced response rates that compare favorably with historical controls treated with imatinib, although confirmation is required from head-to-head clinical trials. Future clinical approaches may include drug combinations, which may allow quiescent leukemia stem cells to be eradicated. Further improvements in drug treatment for first-line CML are expected during the next few years. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Hepatitis B immunoglobulin in combination with lamivudine for prevention of hepatitis B virus reactivation in children undergoing bone marrow transplantationPEDIATRIC TRANSPLANTATION, Issue 8 2006Betul Tavil Abstract:, There is little information in literature about the use of hepatitis B immunoglobulin (HBIg) in recipients of bone marrow transplantation (BMT). Here, we report two children who received IV HBIg (Hepatect-CP) and lamivudine treatment during BMT course for either patient or donor hepatitis B virus (HBV) viremia. A four-year-old girl underwent a fully human leukocyte antigen-matched allogeneic BMT for thalassemia major from her mother positive for hepatitis B surface antigen (HBsAg). A 12-yr-old boy with chronic myeloid leukemia, positive for HBsAg and HBV-DNA received a fully HLA-matched allogeneic BMT from his sister in the first chronic phase of the disease. HBIg was successfully used in both cases to prevent HBV reactivation of the recipients. The results of our observations are encouraging and we suggest that HBIg in combination with lamivudine may be used in such cases especially in post-transplant early period to prevent HBV reactivation. [source] Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosomeAMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2003Hee Jin Huh Abstract The blast crisis in chronic myelogenous leukemia (CML) is related to the evolution of a Philadelphia chromosome (Ph)-positive clone. Secondary chromosomal abnormalities accompanied by t(9;22) are found in 70,80% of blast crises. Here we describe a patient with Ph-positive CML, who developed Ph-negative acute lymphoblastic leukemia (ALL). A 52-year-old man was diagnosed with CML with the Ph chromosome in the chronic phase. He achieved a partial cytogenetic response after 4 months of imatinib mesylate therapy. After 8 months, common ALL occurred. At that time his karyotype was normal and the Ph chromosome was not noted. Am. J. Hematol. 74:218,220, 2003. © 2003 Wiley-Liss, Inc. [source] Expression of p53 in lesions and unaffected skin of patients with plaque-type and guttate psoriasis: A quantitative comparative studyTHE JOURNAL OF DERMATOLOGY, Issue 6 2007Ayça Cordan YAZICI ABSTRACT Psoriasis is a common inflammatory and hyperproliferative skin disease characterized by hyperproliferation of keratinocytes. The pathogenesis of psoriasis has yet to be determined. The control of cell growth is a delicately balanced process, regulated by external signals or the internal genetic program of an individual cell. In psoriasis, these processes are disturbed and some candidate genes like p53 are suspected of being involved in the pathogenesis of the disease. The p53 protein is essential for the regulation of cell proliferation. The study was performed on 32 patients with psoriasis (24 plaque type, eight guttate type). Biopsy specimens for immunohistochemical determination of p53 protein expression were collected from both the lesional and the nonlesional skin sites that were not exposed to sun in all of the patients (n = 32). Taking the ultraviolet (UV) exposure of the skin into consideration, a third skin sample was taken from each patient (n = 7) who had lesions on the sun-exposed areas. Immunohistochemical assessment of p53 expression in skin was determined as p53 protein expression per 1000 cells (keratinocytes). The statistical analysis revealed that the expressions of p53 per 1000 cells were higher in non-sun-exposed lesional skin than the non-sun-exposed nonlesional skin, also in plaque-type psoriasis than guttate-type psoriasis (P = 0.000, P = 0.046, P = 0.037, respectively). There was a positive correlation between the p53 expression in non-sun-exposed lesional skin versus expression in sun-exposed lesional skin (cubic centimeters = 0.811, P = 0.027). Our results show a stronger association of elevated p53 expression with chronic rather than acute inflammatory psoriasis. This may indicate a mechanistic difference between plaque-type and guttate psoriasis. Alternatively, this could reflect a chronological course as the disease transitions from an acute to a chronic phase. [source] Comparison between Contrast-Enhanced Magnetic Resonance Imaging and Selvester QRS Scoring System in Estimating Changes in Infarct Size between the Acute and Chronic Phases of Myocardial InfarctionANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2009Daniël A. Geerse M.D. Background: The Selvester QRS score was developed as a method to estimate infarct size (IS) using the ECG and has been validated during the prereperfusion era. Few comparisons exist with contrast-enhanced magnetic resonance imaging (ceMRI) in reperfused patients. This study evaluates the ability of the Selvester QRS score to estimate serial changes in IS during the acute and chronic phases of the infarct evolution in patients who have received reperfusion therapy. Methods: Thirteen patients with acute myocardial infarction underwent serial ceMRI studies in the acute (<1 week) and chronic phase (>2 months) after their initial myocardial infarction. QRS scoring was performed on the corresponding ECGs. The correlation between ceMRI measurement and QRS score estimation of IS was determined at both time points and for the difference between the two phases. Results: The mean IS was 20.1 ± 11.0% of total left ventricular mass (% LV) in the acute phase and 13.3 ± 6.4% LV in the chronic phase ceMRI. The mean IS estimated by Selvester QRS score in the acute and chronic phases were 18.7 ± 8.2% and 16.4 ± 8.5% LV, respectively. A modest correlation was found for the acute (r = 0.57) and chronic phase IS (r = 0.54). However, there was no correlation for the difference in IS between the acute and chronic phases. Conclusions: In this pilot study, the Selvester QRS score correlates modestly to IS by ceMRI during both the acute and chronic phases of the infarction process. The serial changes over time in the Selvester QRS score and IS by ceMRI show no correlation. [source] Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in miceARTHRITIS & RHEUMATISM, Issue 7 2010Quan Zhou Objective To develop an in vivo imaging method to assess lymphatic draining function in the K/BxN mouse model of inflammatory arthritis. Methods Indocyanine green, a near-infrared fluorescent dye, was injected intradermally into the footpads of wild-type mice, mouse limbs were illuminated with an 806-nm near-infrared laser, and the movement of indocyanine green from the injection site to the draining popliteal lymph node (LN) was recorded with a CCD camera. Indocyanine green near-infrared images were analyzed to obtain 5 measures of lymphatic function across time. Images of K/BxN arthritic mice and control nonarthritic littermates were obtained at 1 month of age, when acute joint inflammation commenced, and again at 3 months of age, when joint inflammation became chronic. Lymphangiogenesis in popliteal LNs was assessed by immunochemistry. Results Indocyanine green and its transport within lymphatic vessels were readily visualized, and quantitative measures were derived. During the acute phase of arthritis, the lymphatic vessels were dilated, with increased indocyanine green signal intensity and lymphatic pulses, and popliteal LNs became fluorescent quickly. During the chronic phase, new lymphatic vessels were present near the foot. However, the appearance of indocyanine green in lymphatic vessels was delayed. The size and area of popliteal LN lymphatic sinuses progressively increased in the K/BxN mice. Conclusion Our findings indicate that indocyanine green near-infrared lymphatic imaging is a valuable method for assessing the lymphatic draining function in mice with inflammatory arthritis. Indocyanine green,near-infrared imaging of K/BxN mice identified 2 distinct lymphatic phenotypes during the acute and chronic phase of inflammation. This technique can be used to assess new therapies for lymphatic disorders. [source] Spinal tumor necrosis factor , neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: A role for spinal tumor necrosis factor , during induction and maintenance of peripheral inflammationARTHRITIS & RHEUMATISM, Issue 5 2010Michael Karl Boettger Objective In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor , (TNF,) add significantly to both hyperalgesia and maintenance of peripheral inflammation. Methods Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNF,-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. Results Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. Conclusion Our findings indicate that spinal TNF, plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation. [source] Transient Peripheral Immune Response and Central Nervous System Leaky Compartmentalization in a Viral Model for Multiple SclerosisBRAIN PATHOLOGY, Issue 5 2010María José Navarrete-Talloni Abstract Theiler's virus-induced demyelination represents an important animal model to study the chronic-progressive form of multiple sclerosis (MS). The aim of the present study was to identify specific genes and pathways in the deep cervical lymph node (cLN) and spleen of experimentally infected SJL-mice, using DNA microarrays. Analyses identified 387 genes in the deep cLN and only 6 genes in the spleen of infected animals. The lymph node presented 27.4% of genes with fold changes ±1.5 at 14 days post infection (dpi) and a reduced transcription at later time points. K- means clustering analyses resulted in five clusters. Accordingly, functional annotation revealed that the B-cell immune response pathway was the most up-regulated cluster at the early phase. Additionally, an increase of CD68- and lysozyme-positive cells in the deep cLN was observed by immunohistochemistry. Polioencephalitis was most intense at 14 dpi, and the spinal cord demyelinating leukomyelitis started at 42 dpi. In summary, early gene expression is indicative of virus-trigged immune responses in the central nervous system (CNS)-draining lymph node. The decreased gene transcription in the deep cLN during the chronic phase and the low number of spleen genes supports the hypothesis of a compartmentalized inflammation within the CNS, as described in progressive MS. [source] Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intoleranceCANCER, Issue 11 2010Hagop Kantarjian MD Abstract BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society. [source] Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy,CANCER, Issue 11 2010Dushyant Verma MD Abstract BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined. Cancer 2010. © 2010 American Cancer Society. [source] Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion,CANCER, Issue 2 2010Kimmo Porkka MD Abstract BACKGROUND: Dasatinib, a highly potent BCR-ABL inhibitor, is an effective treatment for patients with chronic myeloid leukemia in chronic phase (CML CP) after resistance, suboptimal response, or intolerance to prior imatinib. In a phase 3 dose optimization trial in patients with CML CP (CA180-034), the occurrence of pleural effusion was significantly minimized with dasatinib 100 mg once daily (QD) compared with other treatment arms (70 mg twice daily [twice daily], 140 mg QD, or 50 mg twice daily). METHODS: To investigate the occurrence and management of pleural effusion during dasatinib treatment, and efficacy in patients with or without pleural effusion, data from CA180-034 were analyzed. RESULTS: With 24-month minimum follow-up, 14% of patients treated with dasatinib 100 mg QD incurred pleural effusion (grade 3: 2%; grade 4: 0%) compared with 23% to 26% in other study arms. The pleural effusion rate showed only a minimal increment from 12 to 24 months. In the 100 mg QD study arm, median time to pleural effusion (any grade) was 315 days, and after pleural effusion, 52% of patients had a transient dose interruption, 35% had a dose reduction, 57% received a diuretic, and 26% received a corticosteroid. Three patients in the 100 mg QD study arm discontinued treatment after pleural effusion. Across all study arms, patients with or without pleural effusion demonstrated similar progression-free and overall survival, and cytogenetic response rates were higher in patients with a pleural effusion. CONCLUSIONS: Pleural effusion is minimized with dasatinib 100 mg QD dosing and its occurrence does not affect short- or long-term efficacy. Cancer 2010. © 2010 American Cancer Society. [source] Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemiaCANCER, Issue 13 2009Alfonso Quintás-Cardama MD Abstract BACKGROUND: Although many patients with chronic myeloid leukemia (CML) respond well to imatinib therapy, a significant proportion loses their initial response. Loss of response on imatinib is often because of BCR-ABL mutations. Dasatinib is a 325-fold more potent inhibitor of Bcr-Abl than imatinib and has been associated with high rates of durable responses in patients with CML in chronic phase (CP) after imatinib failure. METHODS: To determine the optimal time for initiating dasatinib after loss of response on imatinib, data from dasatinib trials in CML-CP were analyzed. Patients were grouped according to whether they received early intervention with dasatinib (ie, after cytogenetic recurrence on imatinib), rather than after both cytogenetic and hematologic recurrence. RESULTS: Overall, 72% of patients who received dasatinib after loss of a major cytogenetic response (MCyR) on imatinib achieved a complete cytogenetic response (CCyR) compared with 42% of patients who were treated after loss of both MCyR and complete hematologic response (CHR). Event-free survival (EFS) also was higher after earlier dasatinib treatment (24-month EFS rates: 89% after loss of MCyR on imatinib vs 29% after loss of both MCyR and CHR). Among patients who were treated after loss of CHR on imatinib with no prior MCyR, 26% achieved a CCyR with dasatinib, and the 24-month EFS rate was 64%. In all 3 groups, CCyR rates were similar in patients with or without pre-existing BCR-ABL mutations. CONCLUSIONS: The results of the current study suggested that optimal outcomes are achieved when dasatinib is administered early after imatinib resistance. Cancer 2009. © 2009 American Cancer Society. [source] Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase,,§CANCER, Issue 3 2009Hagop M. Kantarjian MD Abstract BACKGROUND: Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). Treatment guidelines propose dose escalation based on clinical assessments of disease response. METHODS: Response and survival were analyzed in a cohort of patients (n = 106) with newly diagnosed CML-CP who were enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 mg or 800 mg daily. Reasons for dose escalation were evaluated retrospectively based on 2 sets of criteria: the IRIS protocol-defined criteria (n = 39 patients) and the European LeukemiaNet (ELN) recommendations (n = 48 patients). RESULTS: Among all 106 patients who underwent dose escalation, the rates of freedom from progression to accelerated phase or blast phase and overall survival were 89% and 84% at 3 years after dose increase, respectively. A cytogenetic response was obtained in 42% of patients who had their dose escalated based on protocol criteria and in 38% of patients who had their dose escalated according to the ELN recommendations. CONCLUSIONS: The results from this retrospective analysis supported imatinib dose escalation as an appropriate initial option for patients with CML-CP who were experiencing suboptimal cytogenetic response or resistance. Cancer 2009. © 2008 American Cancer Society. [source] Treatment of chronic myeloid leukemia in the imatinib eraCANCER, Issue 6 2007Perspective from a developing country Abstract BACKGROUND There is paucity of data from developing countries on the efficacy and safety of imatinib mesylate in chronic myeloid leukemia (CML). The primary objective of this study was to document complete and partial cytogenetic responses to imatinib in all phases of CML. Secondary objectives included evaluations of complete hematologic response, safety, time to progression, and survival. METHODS Two hundred seventy-five patients in all phases of CML who received treatment with imatinib from January 2001 to December 2005 were included in the study. All patients had on bone marrow or BCR-ABL positive in peripheral blood by polymerase chain reaction. RESULTS After a median follow-up of 18 months, major cytogenetic responses (Ph <35%) in chronic phase (CP), accelerated phase (AP), and blastic phase (BP) were documented in 61%, 57%, and 28% of patients, respectively. A complete cytogenetic response was observed in 39.4%, 35.7%, and 14.3% of patients in CP, AP, and BP, respectively; and a complete hematologic response was observed in 90%, 86%, and 30%, respectively. The median time to progression at 18 months was 91% in CP and 68% in AP. The overall survivals in CP, AP, and BP at 18 months was 92%, 74%, and 38%, respectively. CONCLUSIONS Impressive hematologic, cytogenetic, and molecular responses to imatinib were observed, similar to the responses reported in patients from Western countries. Patients had good compliance, toxicity was limited, and overall quality of life was improved markedly. The results indicated that the biology of CML is not different in patients from developing countries. Cancer 2007 © 2007 American Cancer Society. [source] Results of decitabine (5-aza-2,deoxycytidine) therapy in 130 patients with chronic myelogenous leukemiaCANCER, Issue 3 2003Hagop M. Kantarjian M.D. Abstract BACKGROUND General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m2 over 6 hours every 12 hours × 5 days (1000 mg/m2 per course) in the first 13 patients, 75 mg/m2 in the subsequent 33 patients, and 50 mg/m2 in the remaining 84 patients. RESULTS A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50,75 mg/m2, the median time to granulocyte recovery above 0.5 × 109/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases. Cancer 2003;98:522,8. © 2003 American Cancer Society. DOI 10.1002/cncr.11543 [source] Haploinsufficiency and acquired loss of Bcl11b and H2AX induces blast crisis of chronic myelogenous leukemia in a transgenic mouse modelCANCER SCIENCE, Issue 7 2009Akiko Nagamachi Chronic myelogenous leukemia (CML) is a hematological malignancy that begins as indolent chronic phase (CP) but inevitably progresses to fatal blast crisis (BC). p210BCR/ABL, a chimeric protein with enhanced kinase activity, initiates CML CP, and additional genetic alterations account for progression to BC, but the precise mechanisms underlying disease evolution are not fully understood. In the present study, we investigated the possible contribution of dysfunction of Bcl11b, a zinc-finger protein required for thymocyte differentiation, and of H2AX, a histone protein involved in DNA repair, to the transition from CML CP to BC. For this purpose, we crossed CML CP-exhibiting p210BCR/ABL transgenic (BAtg/,) mice with Bcl11b heterozygous (Bcl11b+/,) mice and H2AX heterozygous (H2AX+/,) mice. Interestingly, p210BCR/ABL transgenic, Bcl11b heterozygous (BAtg/,Bcl11b+/,) mice and p210BCR/ABL transgenic, H2AX heterozygous (BAtg/,H2AX+/,) mice frequently developed CML BC with T-cell phenotype and died in a short period. In addition, whereas p210BCR/ABL was expressed in all of the leukemic tissues, the expression of Bcl11b and H2AX was undetectable in several tumors, which was attributed to the loss of the residual normal allele or the lack of mRNA expression. These results indicate that Bcl11b and H2AX function as tumor suppressor and that haploinsufficiency and acquired loss of these gene products cooperate with p210BCR/ABL to develop CML BC. (Cancer Sci 2009; 100: 1219,1226) [source] | ||||||||||||||||||||||||||||||||||