bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral Fluorescence Molecular Imaging of Lung Metastases Targeting HER2/neu
Authors: Koyama Yoshinori , Hama Yukihiro , Urano Yasuteru , Nguyen Dao M. , Choyke Peter L. , Kobayashi Hisataka
Published: May 2007

Purpose: Surgical resection of pulmonary metastases is now a clinically accepted cancer therapy but its success depends on the accurate localization and removal of all tumor foci. To enhance the detection of pulmonary metastases during surgery, we developed an i.v. administered optical probe that uses a monoclonal antibody, Herceptin (trastuzumab), conjugated to a fluorophore, rhodamine green (RhodG), to specifically detect human epidermal growth factor receptor type 2 (HER2/neu)–expressing pulmonary lesions in an animal model of lung metastases.

Experimental Design: Pulmonary metastases were induced by i.v. injection of gene-transfected murine embryonic fibroblasts (3T3) cells in a murine model to produce a mixed population of HER2+ and HER2− tumors. To image these tumors, an anti-HER2 (Herceptin) or a control (HUT) complementarity-determining region–grafted antibody was conjugated to RhodG and injected i.v. into mice. Spectral fluorescence imaging was done after thoracotomy and images were correlated with gross and microscopic pathology to assess sensitivity and specificity.

Results: HER2+ tumors injected with Herceptin-RhodG were more fluorescent than either HER2− tumors or HER2+ tumors injected with HUT-RhodG at all time points. The maximal fluorescence signal in HER2+ tumors injected with Herceptin-RhodG was observed at 1 day postinjection. The tumors fluoresced primarily at the rim and not their center, reflecting the binding-site barrier that is commonly seen with high-affinity antibodies.

Conclusion: A HER2-targeted optical imaging probe shows the ability to specifically enhance HER2+ pulmonary metastases but not HER2− pulmonary metastases. The high sensitivity and specificity of this probe is encouraging for the development of antigen-targeted optical probes to assist in the resection of pulmonary metastases.
Aurora-A and p16 Polymorphisms Contribute to an Earlier Age at Diagnosis of Pancreatic Cancer in Caucasians
Authors: Chen Jinyun , Li Donghui , Wei Chongjuan , Sen Subrata , Killary Ann M. , Amos Christopher I. , Evans Douglas B. , Abbruzzese James L. , Frazier Marsha L.
Published: May 2007

Purpose: Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer.

Experimental Design: We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender.

Results: Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P = 0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P = 0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found.

Conclusions: Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.
Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma
Authors: Onken Michael D. , Worley Lori A. , Person Erica , Char Devron H. , Bowcock Anne M. , Harbour J. William
Published: May 2007

Purpose: Loss of chromosome 3 is strongly associated with metastasis in uveal melanoma and has been proposed as the basis for clinical prognostic testing. It is not known whether techniques that identify loss of heterozygosity for chromosome 3 predict metastasis more accurately than those that detect only numerical loss of chromosome 3 (monosomy 3).

Experimental Design: Fifty-three uveal melanomas were analyzed by 28 single nucleotide polymorphisms (SNP) across chromosome 3. SNP was compared with fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) for metastasis prediction by sensitivity, specificity, and Kaplan-Meier survival analysis, using our validated gene expression-based classifier as a reference standard.

Results: By Kaplan-Meier analysis, only the gene expression-based classifier (P = 0.001) and SNP-based detection of loss of heterozygosity for chromosome 3 (P = 0.04) were significantly associated with metastasis. Sensitivity and specificity were 95.2% and 80.8%, respectively, for SNP, 77.8% and 64.7%, respectively, for FISH, and 85.0% and 72.0%, respectively, for aCGH. Isodisomy 3 was identified by SNP but undetected by aCGH and FISH in three tumors.

Conclusions: Prognostic tests based on SNP platforms, which detect both chromosomal homologues and their subregions, may be superior to techniques that only detect changes in chromosome number. These observations could have important implications for efforts to detect genetic alterations in cancer genomes with CGH-based approaches.
Epidermal Growth Factor Receptor Expression in High-Grade Osteosarcomas Is Associated with a Good Clinical Outcome
Authors: Kersting Christian , Gebert Carsten , Agelopoulos Konstantin , Schmidt Hartmut , van Diest Paul J. , Juergens Heribert , Winkelmann Winfried , Kevric Matthias , Gosheger Georg , Brandt Burkhard , Bielack Stefan , Buerger Horst
Published: May 2007

Purpose: The expression of the epidermal growth factor receptor (EGFR) in osteosarcomas has repeatedly been described. With the introduction of anti-EGFR–targeted therapies in clinical practice, these findings regain increased attention. Experience with anti-EGFR–targeted therapies in other cancers has made clear that besides the expression status of EGFR, a detailed knowledge about gene mutations is of major predictive power. We therefore aimed to explore the EGFR expression and gene mutation status in high-grade osteosarcomas.

Experimental Design: We investigated tumor samples of osteosarcoma patients of all age groups by means of immunohistochemistry (n = 111) and egfr fluorescence in situ hybridization (n = 39). Sixty-three patients were treated according to the Cooperative Osteosarcoma Study Group protocols and complete clinical follow-up was available in these cases.

Results: Ninety-one of 111 (81%) of osteosarcomas revealed an expression of EGFR. EGFR expression showed a dose-response relation with improved event-free and overall survival. This was independent of the degree of tumor regression due to neoadjuvant chemotherapy. Nine of 39 (23%) osteosarcomas showed egfr amplifications by means of fluorescence in situ hybridization. All these cases expressed EGFR. When comparing EGFR expression between primary biopsy and resection specimen (n = 19), viable residual tumor cells in resection specimens revealed a lower EGFR expression and a tendency toward membranous staining compared with the initial biopsy.

Conclusions: In conclusion, expression and amplification of EGFR are frequently observed in high-grade osteosarcomas and are associated with improved prognosis in a dose-responsive way. This implies that low EGFR expression possibly predicts lack of response to conventional treatment in high-grade osteosarcomas and may warrant a more intensive therapeutic approach, although not based on EGFR targeting.
Increasing Anticarcinoma Activity of an Anti-erbB2 Recombinant Immunotoxin by the Addition of an Anti-EpCAM sFv
Authors: Stish Brad J. , Chen Hua , Shu Yanqun , Panoskaltsis-Mortari Angela , Vallera Daniel A.
Published: May 2007

Purpose: erbB2, the product of the Her2-neu gene, is a well-established therapeutic target for antibody-based biologicals, but anti-erbB2 antibody-toxin fusion proteins are limited in their activity. The goal of this study was to determine if genetically adding an sFv targeting epithelial cell adhesion molecule (EpCAM) to an anti-Her2 sFv immunotoxin would result in enhanced antitumor activity.

Experimental Design: In vitro studies were done in which the new bispecific immunotoxin DTEpCAM23 was compared with monospecific immunotoxins (DTEpCAM and DT23) to quantitate immunotoxin activity. Mixtures of monospecific immunotoxins were tested to determine if they were as effective as the bispecific immunotoxin. Binding and internalization studies were also done. In vivo, bispecific immunotoxins were given i.t. to athymic nude mice bearing HT-29 human colon cancer flank tumors and i.p. to mice with i.p. tumors.

Results: DTEpCAM23 bispecific immunotoxins showed far greater activity than monospecific immunotoxin (sometimes over 2,000-fold) against most tumor lines. Bispecific immunotoxin was superior and selective in its activity against different carcinoma cell lines. Bispecific immunotoxin had greater activity than monospecific immunotoxin indicating an advantage of having both sFv on the same single-chain molecule. Binding and internalization studies did not explain the differences between bispecific immunotoxin and monospecific immunotoxin activity. Orientation of the sFvs on the molecule had a significant effect on in vitro and in vivo properties. The bispecific immunotoxins were more effective than the monospecific immunotoxin in the flank tumor mouse model.

Conclusions: The synthesis of bispecific immunotoxin created a new biological agent with superior in vitro and in vivo activity (over monospecific immunotoxin), more broad reactivity, more efficacy against tumors in vivo, and diminished toxic effects in mice.
Prospective Assessment of XPD Lys751Gln and XRCC1 Arg399Gln Single Nucleotide Polymorphisms in Lung Cancer
Authors: Giachino Daniela F. , Ghio Paolo , Regazzoni Silvia , Mandrile Giorgia , Novello Silvia , Selvaggi Giovanni , Gregori Dario , DeMarchi Mario , Scagliotti Giorgio V.
Published: May 2007

Purpose: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non–small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients.

Experimental Design: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy.

Results: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P = 0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found.

Conclusion: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non–platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.
Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6–Inducible STAT3 Activation
Authors: Bhutani Manisha , Pathak Ashutosh K. , Nair Asha S. , Kunnumakkara Ajaikumar B. , Guha Sushovan , Sethi Gautam , Aggarwal Bharat B.
Published: May 2007

Purpose: Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells.

Experimental Design: The effect of capsaicin on both constitutive and interleukin-6–induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated.

Results: We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6–induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G1 phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice.

Conclusion: Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.
AZD2171 Shows Potent Antitumor Activity Against Gastric Cancer Over-Expressing Fibroblast Growth Factor Receptor 2/Keratinocyte Growth Factor Receptor
Authors: Takeda Masayuki , Arao Tokuzo , Yokote Hideyuki , Komatsu Teruo , Yanagihara Kazuyoshi , Sasaki Hiroki , Yamada Yasuhide , Tamura Tomohide , Fukuoka Kazuya , Kimura Hiroshi , Saijo Nagahiro , Nishio Kazuto
Published: May 2007

Purpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer.

Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo.

Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC50 of 0.15 and 0.37 μmol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus–truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 μmol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar Ki values (∼0.05 μmol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts.

Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.
Enhancement of Docetaxel-Induced Cytotoxicity by Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways in Squamous Cell Carcinoma of the Head and Neck
Authors: Choe Mi Sun , Chen Zhuo , Klass Carmen M. , Zhang Xin , Shin Dong M.
Published: May 2007

Purpose: The addition of molecular targeted agents to enhance the cytotoxicity of chemotherapeutic agents is a promising strategy in cancer treatment. The combination of cyclooxygenase-2 inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors, such as celecoxib and ZD1839 (gefitinib), was reported to achieve synergistic cell growth inhibition in squamous cell carcinoma of the head and neck. Therefore, we postulated that the addition of celecoxib and ZD1839 to docetaxel, a cytotoxic agent, might further increase antitumor activity.

Experimental Design: The combination of celecoxib, ZD1839, and docetaxel was studied for its effect on cell growth and apoptosis by cell growth inhibition and Annexin V assays. The relevant molecular targets of these agents and apoptotic markers were examined by immunoblotting analyses in the presence or absence of these three drugs. Morphologic changes of the microtubule cytoskeleton, a known target of docetaxel, were also evaluated by staining for α-tubulin after the combination treatment.

Results: We showed that this triple combination significantly enhanced cell growth inhibition and docetaxel-induced apoptosis. Docetaxel mainly induced caspase-8 activation, whereas the addition of celecoxib and ZD1839 augmented the caspase-8 activation and enhanced caspase-9 activation. One of the underlying mechanisms for augmentation of docetaxel-induced apoptosis by celecoxib and ZD1839 is to further inhibit the activation of prosurvival pathway molecules, such as extracellular signal-regulated kinase and AKT, and the promotion of aberrant apoptosis.

Conclusions: Our studies suggest that the combination of docetaxel with a cyclooxygenase-2 inhibitor and an epidermal growth factor receptor tyrosine kinase inhibitor may further improve efficacy of docetaxel and other taxane-based therapies in squamous cell carcinoma of the head and neck.
CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity
Authors: Zandvliet Anthe S. , Huitema Alwin D.R. , Copalu William , Yamada Yasuhide , Tamura Tomohide , Beijnen Jos H. , Schellens Jan H.M.
Published: May 2007

Purpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation.

Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, Vmax, Km) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study.

Results: The Michaelis-Menten elimination rate (Vmax) was decreased by 27% (P < 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m2 per mutated allele may be required to normalize this risk.

Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.
KRASMutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer
Authors: Massarelli Erminia , Varella-Garcia Marileila , Tang Ximing , Xavier Ana C. , Ozburn Natalie C. , Liu Diane D. , Bekele Benjamin N. , Herbst Roy S. , Wistuba Ignacio I.
Published: May 2007

Purpose:EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non–small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs.

Experimental Design: Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization.

Results: The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P < 0.0001) but not increased EGFR copy number (P = 0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P = 0.04) and shorter median time to progression (P = 0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a >99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a >96.5% chance of disease progression.

Conclusion:KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.
Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients
Authors: Molenkamp Barbara G. , van Leeuwen Paul A.M. , Meijer Sybren , Sluijter Berbel J.R. , Wijnands Pepijn G.J.T.B. , Baars Arnold , van den Eertwegh Alfons J.M. , Scheper Rik J. , de Gruijl Tanja D.
Published: May 2007

Purpose: A decrease in the frequency and activation state of dendritic cells in the sentinel lymph node (SLN) has been observed in early stages of melanoma development. This may hinder the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Immunopotentiation of the melanoma SLN may therefore be a valuable adjuvant treatment option. One way to achieve this is through the use of bacterially derived unmethylated cytosine-phosphate-guanine (CpG) DNA sequences that bind Toll-like receptor 9 and activate plasmacytoid dendritic cells (PDC). CpG-activated PDC, in turn, release IFNα and may thus boost T-cell and natural killer cell responses as well as activate conventional myeloid dendritic cells (MDC).

Experimental Design: We studied the effects of preoperative local administration of the CpG B-type oligodeoxynucleotide (ODN) PF-3512676 (formerly known as CPG 7909) on dendritic cell and T-cell subsets in the SLN of 23 stage I to III melanoma patients, randomized to receive intradermal injections of either PF-3512676 or saline (NaCl 0.9%).

Results: PF-3512676 administration resulted in bulkier SLN, higher yields of isolated SLN leukocytes, and activation of BDCA-2+CD123+ PDC as well as of CD1a+ MDC. In addition, PF-3512676 administration was associated with the presence of a newly identified CD11chiCD123+CD83+TRAIL+ mature SLN-MDC subset, an increased release of a variety of inflammatory cytokines, and lower frequencies of CD4+CD25hiCTLA-4+FoxP3+ regulatory T cells in the SLN.

Conclusions: These findings point to the possible utility of the conditioning of SLN by PF-3512676 as an adjuvant immunotherapeutic modality for early-stage melanoma.
Accuracy of Serial National Institutes of Health Stroke Scale Scores to Identify Artery Status in Acute Ischemic Stroke
Authors: Mikulik Robert , Ribo Marc , Hill Michael D. , Grotta James C. , Malkoff Marc , Molina Carlos , Rubiera Marta , Delgado-Mederos Raquel , Alvarez-Sabin Jose , Alexandrov Andrei V.
Published: May 2007

Background—

Early recovery after intravenous thrombolysis can be observed in stroke; however, the utility of measuring clinical improvement to assess artery status has not been established. We sought to determine the accuracy of serial National Institutes of Health Stroke Scale (NIHSS) scores to detect complete early recanalization of the middle cerebral artery.

Methods and Results—

Data from the CLOTBUST trial (Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA) were used to determine the most sensitive and specific NIHSS-derived parameter to identify complete recanalization. Then, reproducibility was tested against a separate patient population (Barcelona data set). NIHSS scores were determined before tissue plasminogen activator bolus and at 60 and 120 minutes in both data sets. Receiver operating characteristic curves were used to compare test performance. The accuracy of individual cutoffs was demonstrated by sensitivity, specificity, and positive and negative predictive values. A total of 122 patients in the CLOTBUST data set and 98 in the Barcelona data set received 0.9 mg/kg intravenous tissue plasminogen activator [mean age 69±12 versus 72±12 years, 57% male versus 51% male, median NIHSS 16 versus 17 points, mean time from onset to treatment 140±32 versus 177±59 minutes, and complete recanalization of the middle cerebral artery in 19% versus 17%). For identification of recanalization, an NIHSS score reduction of ≥40% offered the best tradeoff, with sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 85%, 50%, and 91% at 60 minutes and 74%, 80%, 58%, and 89% at 120 minutes, respectively. Test performance was equal in the Barcelona data set.

Conclusions—

Relative changes in serial NIHSS scores can serve as a simple clinical indicator of arterial status after intravenous thrombolysis. Accuracy parameters are affected by the process of recanalization and its varying clinical significance.
Randomized, Double-Blind, Dose-Ranging Study of Otamixaban, a Novel, Parenteral, Short-Acting Direct Factor Xa Inhibitor, in Percutaneous Coronary Intervention
Authors: Cohen Marc , Bhatt Deepak L. , Alexander John H. , Montalescot Gilles , Bode Christoph , Henry Timothy , Tamby Jean-Francois , Saaiman Jan , Simek Stanislas , De Swart Johannes
Published: May 2007

Background—

The optimal anticoagulant regimen for percutaneous coronary intervention (PCI) remains to be determined. Otamixaban, a selective and direct inhibitor of factor Xa, was investigated in patients undergoing nonurgent percutaneous coronary intervention.

Methods and Results—

In this double-blind, double-dummy, parallel-group, dose-ranging trial, 947 patients were randomly assigned to either 1 of 5 weight-adjusted otamixaban regimens or weight-adjusted unfractionated heparin (UFH) before percutaneous coronary intervention. The primary end points were change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity. The main secondary end points were Thrombolysis In Myocardial Infarction (TIMI) bleeding at day 3 or hospital discharge (whichever came first) and 30-day ischemic events. The median change in F1+2 from baseline to the end of infusion was greater with the highest otamixaban dose compared with UFH (−0.3 versus −0.2 ng/mL,
P
=0.008). Anti-factor Xa levels were 65, 155, 393, 571, and 691 ng/mL with otamixaban doses 1 to 5, respectively. Significant TIMI bleeding (major or minor) occurred in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients receiving otamixaban doses 1 to 5, respectively, and in 3.8% of patients receiving UFH. Four TIMI major bleeds were observed. Ischemic events occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of patients receiving otamixaban doses 1 to 5, respectively, and in 5.6% of patients receiving UFH.

Conclusions—

Otamixaban reduced F1+2 significantly more than UFH at the highest dose regimen, whereas no significant difference in the incidence of TIMI bleeding was observed between the otamixaban and UFH groups. These results set the stage for adequately powered clinical outcome trials of selective direct factor Xa inhibition in patients with acute coronary syndromes.
Indicators of Poor Prognosis of Acute Pericarditis
Authors: Imazio Massimo , Cecchi Enrico , Demichelis Brunella , Ierna Salvatore , Demarie Daniela , Ghisio Aldo , Pomari Franco , Coda Luisella , Belli Riccardo , Trinchero Rita
Published: May 2007

Background—

The clinical search for indicators of poor prognosis of acute pericarditis may be useful for clinical triage of patients at high risk of specific causal conditions or complications. The aim of the present article is to assess the relationship between clinical features at presentation and specific causes or complications.

Methods and Results—

A total of 453 patients aged 17 to 90 years (mean age 52±18 years, 245 men) with acute pericarditis (post–myocardial infarction pericarditis was excluded) were prospectively evaluated from January 1996 to August 2004. A specific cause was found in 76 of 453 patients (16.8%): autoimmune in 33 patients (7.3%), neoplastic in 23 patients (5.1%), tuberculous in 17 patients (3.8%), and purulent in 3 patients (0.7%). In multivariable analysis, women (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70;
P
=0.036) and patients with fever >38°C (HR 3.56, 95% CI 1.82 to 6.95;
P
<0.001), subacute course (HR 3.97, 95% CI 1.66 to 9.50;
P
=0.002), large effusion or tamponade (HR 2.15, 95% CI 1.09 to 4.23;
P
=0.026), and failure of aspirin or of nonsteroidal anti-inflammatory drugs (HR 2.50, 95% CI 1.28 to 4.91;
P
=0.008) were at increased risk of specific causal conditions. After a mean follow-up of 31 months, complications were detected in 95 patients (21.0%): recurrences in 83 patients (18.3%), tamponade in 14 patients (3.1%), and constriction in 7 patients (1.5%). In multivariable analysis, women (HR 1.65, 95% CI 1.08 to 2.52;
P
=0.020) and patients with large effusion or tamponade (HR 2.51, 95% CI 1.37 to 4.61;
P
=0.003) and failure of aspirin or of nonsteroidal anti-inflammatory drugs (HR 5.50, 95% CI 3.56 to 8.51;
P
<0.001) were at increased risk of complications.

Conclusions—

Specific clinical features (fever >38°C, subacute course, large effusion or tamponade, and aspirin or NSAID failure) may be useful to identify higher risk of specific causal conditions and complications.
Catheter Ablation of Multiple Ventricular Tachycardias After Myocardial Infarction Guided by Combined Contact and Noncontact Mapping
Authors: Klemm Hanno U. , Ventura Rodolfo , Steven Daniel , Johnsen Christin , Rostock Thomas , Lutomsky Boris , Risius Tim , Meinertz Thomas , Willems Stephan
Published: May 2007

Background—

Insights gained from noncontact mapping of ventricular tachycardia (VT) have not been systematically applied to contact maps. This study sought to unify both techniques for an individualized approach to the patient with multiple ischemic VTs irrespective of cycle length.

Methods and Results—

For 12 consecutive patients with chronic myocardial infarction and recurrent VT, bipolar contact maps were acquired during sinus or paced rhythm. Additional noncontact maps were obtained during 48 induced VTs (cycle length 192 to 579 ms). Endocardial exit sites were superimposed on contact maps and verified by pace-mapping. Radiofrequency lesions were extended for critical borders defined by multiple neighboring exits and followed the isovoltage contour line of contact maps. Nine critical borders were identified in 8 patients and constituted the substrate for 31 VTs. The voltage at exit sites was 0.8 mV (range 0.1 to 2.3). Noncontact maps revealed 23±18% of isthmus conduction. Thirty-seven (77%) of all and 83% of clinically documented VTs were rendered noninducible irrespective of cycle length by application of 27 radiofrequency lesions (range 18 to 56). Spontaneous transitions between distinct VTs along critical borders were demonstrated in 4 patients. Pace-mapping reproduced the QRS morphology of 81% of VTs and was associated with successful ablation (
P
<0.01). Noninducibility of any sustained VT was reached for 8 (67%) patients. During 15 months (range 5 to 28) of follow-up, 8 patients remained without recurrence, and VT episodes were reduced in the other 4 patients (
P
<0.01). VT cycle length was not predictive for acute or long-term success.

Conclusion—

The combined approach of contact and noncontact mapping effectively defines critical borders as the substrate of multiple VTs without limitation for unstable VTs.
View-Synchronized Robotic Image-Guided Therapy for Atrial Fibrillation Ablation
Authors: Reddy Vivek Y. , Neuzil Petr , Malchano Zachary J. , Vijaykumar Ragu , Cury Ricardo , Abbara Suhny , Weichet Jiri , McPherson Christina D. , Ruskin Jeremy N.
Published: May 2007

Background—

A robotic catheter navigation system has been developed that provides a significant degree of freedom of catheter movement. This study examines the feasibility of synchronizing this robotic navigation system with electroanatomic mapping and 3-dimensional computed tomography imaging to perform view-synchronized left atrial (LA) ablation.

Methods and Results—

This study consisted of a porcine experimental validation phase (9 animals) and a clinical feasibility phase (9 atrial fibrillation patients). Preprocedural computed tomography images were reconstructed to provide 3-dimensional surface models of the LA pulmonary veins and aorta. Aortic electroanatomic mapping was performed manually, followed by registration with the corresponding computed tomography aorta image using custom software. The mapping catheter was remotely manipulated with the robotic navigation system within the registered computed tomography image of the LA pulmonary veins. The point-to-surface error between the LA electroanatomic mapping data and the computed tomography image was 2.1±0.7 and 1.6±0.1 mm in the preclinical and clinical studies, respectively. The catheter was remotely navigated into all pulmonary veins, the LA appendage, and circumferentially along the mitral valve annulus. In 7 of 9 animals, circumferential radiofrequency ablation lesions were applied periostially to ablate 11 pulmonary veins. In patients, all of the pulmonary veins were remotely electrically isolated in an extraostial fashion. Adjunctive ablation included superior vena cava isolation in 6 patients, cavotricuspid isthmus ablation in 5 patients, and ablation of sites of complex fractionated activity and atypical LA flutters in 3 patients.

Conclusions—

This study demonstrates the safety and feasibility of an emerging paradigm for atrial fibrillation ablation involving the confluence of 3 technologies: 3-dimensional imaging, electroanatomic mapping, and remote robotic navigation.
Sustained Benefit at 2 Years of Primary Femoropopliteal Stenting Compared With Balloon Angioplasty With Optional Stenting
Authors: Schillinger Martin , Sabeti Schila , Dick Petra , Amighi Jasmin , Mlekusch Wolfgang , Schlager Oliver , Loewe Christian , Cejna Manfred , Lammer Johannes , Minar Erich
Published: May 2007

Background—

Primary stenting with self-expanding nitinol stents of the superficial femoral artery yielded improved morphological and clinical results compared with balloon angioplasty with optional stenting until 12 months in a randomized controlled trial. We now report 2-year data on restenosis and clinical outcomes of these patients.

Methods and Results—

Of 104 patients with chronic limb ischemia and superficial femoral artery obstructions, 98 (94%) could be followed up until 2 years after intervention for occurrence of restenosis (>50%) by duplex ultrasound and for clinical and hemodynamic outcome by treadmill walking distance and ankle brachial index. Restenosis rates at 2 years were 45.7% (21 of 46) versus 69.2% (36 of 52) in favor of primary stenting compared with balloon angioplasty with optional secondary stenting by an intention-to-treat analysis (
P
=0.031). Consistently, stenting (whether primary or secondary; n=63) was superior to plain balloon angioplasty (n=35) with respect to the occurrence of restenosis (49.2% versus 74.3%;
P
=0.028) by a treatment-received analysis. Clinically, patients in the primary stent group showed a trend toward better treadmill walking capacity (average, 302 versus 196 m;
P
=0.12) and better ankle brachial index values (average, 0.88 versus 0.78;
P
=0.09) at 2 years, respectively. Reintervention rates tended to be lower after primary stenting (17 of 46 [37.0%] versus 28 of 52 [53.8%];
P
=0.14).

Conclusions—

At 2 years, primary stenting with self-expanding nitinol stents for the treatment of superficial femoral artery obstructions yields a sustained morphological benefit and a trend toward clinical benefit compared with balloon angioplasty with optional stenting.
Radiofrequency Catheter Ablation of Chronic Atrial Fibrillation Guided by Complex Electrograms
Authors: Oral Hakan , Chugh Aman , Good Eric , Wimmer Alan , Dey Sujoya , Gadeela Nitesh , Sankaran Sundar , Crawford Thomas , Sarrazin Jean F. , Kuhne Michael , Chalfoun Nagib , Wells Darryl , Frederick Melissa , Fortino Jackie , Benloucif-Moore Suzanne , Jongnarangsin Krit , Pelosi Frank , Bogun Frank , Morady Fred
Published: May 2007

Background—

Radiofrequency catheter ablation of atrial fibrillation (AF) guided by complex fractionated atrial electrograms has been reported to eliminate AF in a large proportion of patients. However, only a small number of patients with chronic AF have been included in previous studies.

Methods and Results—

In 100 patients (mean age, 57±11 years) with chronic AF, radiofrequency ablation was performed to target complex fractionated atrial electrograms at the pulmonary vein ostial and antral areas, various regions of the left atrium, and the coronary sinus until AF terminated or all identified complex fractionated atrial electrograms were eliminated. Ablation sites consisted of ≥1 pulmonary vein in 46% of patients; the left atrial septum, roof, or anterior wall in all; and the coronary sinus in 55%. During 14±7 months of follow-up after a single ablation procedure, 33% of patients were in sinus rhythm without antiarrhythmic drugs, 38% had AF, 17% had both AF and atrial flutter, 9% had persistent atrial flutter, and 3% had paroxysmal AF on antiarrhythmic drugs. A second ablation procedure was performed in 44% of patients. Pulmonary vein tachycardia was found in all patients in both previously targeted and nontargeted pulmonary veins. There were multiple macroreentrant circuits in the majority of patients with atrial flutter. At 13±7 months after the last ablation procedure, 57% of patients were in sinus rhythm without antiarrhythmic drugs, 32% had persistent AF, 6% had paroxysmal AF, and 5% had atrial flutter.

Conclusions—

Modest short-term efficacy is achievable with radiofrequency ablation of chronic AF guided by complex fractionated atrial electrograms, but only after a second ablation procedure in >40% of patients. Rapid activity in the pulmonary veins and multiple macroreentrant circuits are common mechanisms of recurrent atrial arrhythmias.
Isolated Systolic Hypertension Is Characterized by Increased Aortic Stiffness and Endothelial Dysfunction
Authors: Wallace Sharon M.L. , Yasmin  , McEniery Carmel M. , Mäki-Petäjä Kaisa M. , Booth Anthony D. , Cockcroft John R. , Wilkinson Ian B.
Published: May 2007

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age±SD: 68±6 years), 30 age-matched control subjects (65±5 years), and 48 young control subjects (37±9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65±2.56 m/s versus 8.26±0.85 m/s;
P
=0.009), and flow-mediated dilatation was lower (2.67±1.64% versus 4.79±3.1%;
P
=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26±0.85 m/s versus 7.09±1.01 m/s and 4.79±3.1% versus 6.94±2.7%;
P
=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (
r
=−0.3;
P
=0.001), which remained significant after adjustment for confounding factors (
P
=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.
NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II
Authors: Gavazzi Gaetan , Deffert Christine , Trocme Candice , Schäppi Michela , Herrmann François R. , Krause Karl-Heinz
Published: May 2007

Oxidative stress leads to vascular damage and participates in the pathomechanisms of aortic dissection and aneurysm formation. Here we study aortic dissection in mice deficient in the superoxide-generating reduced nicotinamide-adenine dinucleotide phosphate oxidase NOX1. Seven days of treatment with the hypertensive agent angiotensin II (3 mg/kg per day) led to aortic dissection in 23% of wild-type C57BL/6J mice but in only 4% of NOX1-deficient mice (
P
=0.05). In contrast, treatment of wild-type C57BL/6J mice with the hypertensive agent norepinephrine (12 mg/kg per day), did not lead to aortic dissection or sudden death, suggesting that hypertension is not sufficient to cause aortic dissection. Interestingly, norepinephrine-dependent blood pressure elevations were conserved in NOX1-deficient mice, demonstrating that, different from angiotensin II, it acts through NOX1-independent hypertensive mechanisms. The resistance of NOX1-deficient mice to angiotensin II-induced aortic dissection suggests a role for NOX1-dependent alterations of the vascular wall. We, therefore, studied gene expression and protease/inhibitor equilibrium. cDNA array analysis demonstrated differential effects of angiotensin II on gene expression in wild-type and NOX1-deficient mice. Tissue inhibitor of metalloproteinase 1 was increased both on the mRNA and the protein level in aortas from NOX1-deficient mice. Thus, our results demonstrate that NOX1 is involved in the mechanisms of angiotensin II-dependent aortic dissection. As one underlying mechanism, we have identified NOX1-dependent suppression of tissue inhibitor of metalloproteinase 1 expression, which could lead to tissue damage through an altered protease/inhibitor balance.
Making Neoliberalism Possible: The State's Organization of Business Support for NAFTA in Mexico
Authors: Fairbrother Malcolm
Published: May 2007

In shifting from nationalist/statist to neoliberal economic policies, states seek out and build alliances with other advocates—especially large capital—and work to disorganize political opponents—including small business. This article examines the politics of the private sector's involvement in trade liberalization in the developing world through a study of Mexico's proposal, negotiation, and ratification of the 1994 North American Free Trade Agreement (NAFTA). The article identifies three instruments that the Mexican state used to construct politically crucial support for NAFTA on the part of domestic business: control over political representation, material concessions to potential critics, and careful strategic framing.
Ethnic Cleavages and Irregular War: Iraq and Vietnam
Authors: Kalyvas Stathis N. , Kocher Matthew Adam
Published: May 2007

The conflict in Iraq has been portrayed as “ethnic” civil war, a radically different conflict from “ideological” wars such as Vietnam. We argue that such an assessment is misleading, as is its theoretical foundation, which we call the “ethnic war model.” Neither Iraq nor Vietnam conforms to the ethnic war model's predictions. The sectarian conflict between Shia and Sunni militias is not simply the outcome of sectarian cleavages in Iraqi society, but to an important extent, a legacy of U.S. occupation. On the other hand, although Vietnam was a society riven by ethnic cleavages, the Vietnam War also fails to conform to the ethnic war model. We show that there is no necessary overlap between ethnic conflict and ethnic war. Some ethnic conflicts evolve into ethnic wars, and others develop dynamics virtually indistinguishable from those of ideological civil wars. We suggest that the state's role is essential in transforming conflicts into either ethnic or irregular wars. We conclude with an analysis of the current situation and future prospects in Iraq.