Magnetic resonance imaging and ultrasound for prediction of residual tumor size in early breast cancer within the ADAPT subtrials.

BACKGROUND: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes. METHODS: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values. RESULTS: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors. CONCLUSIONS: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

How a-Type Anomalies Can Depend on Marginal Couplings.

Even dimensional defects and boundaries in conformal field theory support type a anomalies on their world volume. We show that the one-point functions of marginal operators, in the presence of defects and boundaries, are anomalous, and that the Wess-Zumino consistency condition relates them to the derivative of the a anomaly with respect to the marginal coupling. We also argue that the constant term F for odd dimensional surfaces can depend on marginal parameters.

[Facet infiltration and periradicular therapy]. / Facetteninfiltration und periradikuläre Therapie.

BACKGROUND: Spinal complaints affect a large proportion of the population and lead to numerous doctor visits. PURPOSE: The different techniques of CT-guided infiltration of spinal disorders, taking into account facet infiltration, periradicular infiltration and epidural flooding are demonstrated. MATERIALS AND METHODS: Discussion of basic work and expert recommendations as well as presentation of different treatment steps for everyday clinical practice. RESULTS: The CT-guided application of the different types of infiltration allows precise execution of the therapy. Both facet infiltration and periradicular infiltration and epidural flooding have their place depending on the clinical symptoms. The optimal combination of drugs to administer is still the subject of numerous studies and sometimes controversial discussions. CONCLUSION: An exact clinical and imaging evaluation of the pain symptoms in the back is the basic requirement for a targeted therapy.

Displacement Operators and Constraints on Boundary Central Charges.

Boundary conformal field theories have several additional terms in the trace anomaly of the stress tensor associated purely with the boundary. We constrain the corresponding boundary central charges in three- and four-dimensional conformal field theories in terms of two- and three-point correlation functions of the displacement operator. We provide a general derivation by comparing the trace anomaly with scale dependent contact terms in the correlation functions. We conjecture a relation between the a-type boundary charge in three dimensions and the stress tensor two-point function near the boundary. We check our results for several free theories.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.

OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.

Universal thermal corrections to single interval entanglement entropy for two dimensional conformal field theories.

We consider single interval Rényi and entanglement entropies for a two dimensional conformal field theory on a circle at nonzero temperature. Assuming that the finite size of the system introduces a unique ground state with a nonzero mass gap, we calculate the leading corrections to the Rényi and entanglement entropy in a low temperature expansion. These corrections have a universal form for any two dimensional conformal field theory that depends only on the size of the mass gap and its degeneracy. We analyze the limits where the size of the interval becomes small and where it becomes close to the size of the spatial circle.

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease.

BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120).

This paper reassesses the currently accepted viewpoint that targeting the terminal fields (i.e. striatum) of degenerating nigrostriatal dopamine neurons with neurotrophic factors in Parkinson's disease (PD) is sufficient for achieving an optimal neurotrophic response. Recent insight indicating that PD is an axonopathy characterized by axonal transport deficits prompted this effort. We tested whether a significantly greater neurotrophic response might be induced in SN neurons when the neurotrophic factor neurturin (NRTN) is also targeted to the substantia nigra (SN), compared to the more conventional, striatum-only target. While recognizing the importance of maintaining the integrity of nigrostriatal fibers and terminals (especially for achieving optimal function), we refocused attention to the fate of SN neurons. Under conditions of axonal degeneration and neuronal transport deficits, this component of the nigrostriatal system is most vulnerable to the lack of neurotrophic exposure following striatal-only delivery. Given the location of repair genes induced by neurotrophic factors, achieving adequate neurotrophic exposure to the SN neurons is essential for an optimal neurotrophic response, while the survival of these neurons is essential to the very survival of the fibers. Two separate studies were performed using the 6-OHDA model of nigrostriatal degeneration, in conjunction with delivery of the viral vector AAV2-NRTN (CERE-120) to continuously express NRTN to either striatum or nigra alone or combined striatal/nigral exposure, including conditions of ongoing axonopathy. These studies provide additional insight for reinterpreting past animal neurotrophic/6-OHDA studies conducted under conditions where axon transport deficiencies were generally not accounted for, which suggested that targeting the striatum was both necessary and sufficient. The current data demonstrate that delivering NRTN directly to the SN produces 1) expanded NRTN distribution within the terminal field and cell bodies of targeted nigrostriatal neurons, 2) enhanced intracellular neurotrophic factor signaling in the nigrostriatal neurons, and 3) produced greater numbers of surviving dopamine neurons against 6-OHDA-induced toxicity, particularly under the conditions of active axonopathy. Thus, these data provide empirical support that targeting the SN with neurotrophic factors (in addition to striatum) may help enhance the neurotrophic response in midbrain neurons, particularly under conditions of active neurodegeneration which occurs in PD patients.

Intuitive concepts in internal medicine and their occurrence in undergraduate medical students in different semesters.

Background: Dealing with errors in medical practice is of great importance for patient safety. In the natural sciences, intuitive concepts, so-called misconceptions, are increasingly coming into focus of teaching because they lead to a faulty understanding of contexts and thus to faulty scientific reasoning. In medicine, intuitive concepts still play a subordinate role. However, once intuitive concepts have been memorized, they can become firmly established and, under certain circumstances, lead to diagnostic and treatment errors in medical practice. The aim of this study was to identify potential intuitive concepts in internal medicine and to analyze their occurrence in medical students from different semesters. Methods: Eight internists from different subspecialties were asked about intuitive concepts by means of a structured interview. A total of 17 intuitive concepts were identified. Using these concepts, a multiple-choice test was created with 17 patient cases. For each case, there were four possible answers: the correct answer, an incorrect answer that included the intuitive concept, the answer "both are incorrect", and the answer "I am not sure", which is to be understood in the sense of "I do not know whether one of the three answers is correct". As an online multiple-choice test, these 17 cases were made available to all 2nd, 6th, and 12th semester students (N=1170, n=418 from the 2nd semester, n=425 from the 6th semester, and n=327 from the 12th semester, i.e., the final year) for four weeks in June 2015. The test had to be answered within nine minutes. A mixed logistic regression model was used for evaluation. Results: Of the N=317 participating students (n=97 from the 2nd semester, n=124 from the 6th semester, and n=96 from the internship year, overall response rate 27.1%), on average, students from all three groups chose the intuitive concept most often, approximately 40%, although the correct answer increased toward the final year with simultaneously decreasing uncertainty and decreasing feeling of not knowing, respectively. In the final year, compared to the 2nd semester, the intuitive concept was selected significantly more often for two questions (p<0.01). For four questions, the intuitive concept was selected significantly less frequently in the final year (p<0.01). Conclusion: Intuitive concepts can be identified in internal medicine and do not appear to be significantly reduced in students during the course of their studies. This suggests that this could also be the case for other medical subjects. Therefore, similar studies should be conducted for other medical subjects in order to identify potential sources of error in clinical work. In addition, suitable didactic methods should be developed and tested with which students learn not to succumb to intuitive concepts as far as possible in order to prevent diagnostic or therapeutic errors in later medical practice.

Properly scaled and targeted AAV2-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease.

Recent analyses of autopsied brains from subjects previously administered AAV2-neurturin (NRTN) gene transfer argues that optimizing the effects of neurotrophic factors in Parkinson's disease (PD) likely requires delivery to both the degenerating cell bodies (in substantia nigra) and their terminals (in striatum). Prior to implementing this novel dosing paradigm in humans, we conducted eight nonclinical experiments with three general objectives: (1) evaluate the feasibility, safety and effectiveness of targeting the substantia nigra (SN) with AAV2-NRTN, (2) better understand and appraise recent warnings of serious weight loss that might occur with targeting the SN with neurotrophic factors, and (3) define an appropriate dose of AAV2-NRTN that should safely and effectively cover the SN in PD patients. Toward these ends, we first determined SN volume for rats, monkeys and humans, and employed these values to calculate comparable dose equivalents for each species by scaling each dose, based on relative SN volume. Using this information, we next injected AAV2-GFP to monkey SN to quantify AAV2-vector distribution and confirm reasonable SN coverage. We then selected and administered a ~200-fold range of AAV2-NRTN doses (and a single AAV2-GDNF dose) to rat SN, producing a wide range of protein expression. In contrast to recent warnings regarding nigra targeting, no dose produced any serious side effects or toxicity, though we replicated the modest reduction in weight gain reported by others with the highest AAV2-NRTN and the AAV2-GDNF dose. A dose-related increase in NRTN expression was seen, with the lower doses limiting NRTN to the peri-SN and the highest dose producing mistargeted NRTN well outside the SN. We then demonstrated that the reduction in weight gain following excessive-doses can be dissociated from NRTN in the targeted SN, and is linked to mistargeted NRTN in the diencephalon. We also showed that prior destruction of the dopaminergic SN neurons via 6-OHDA had no impact on the weight loss phenomenon, further dissociating neurotrophic exposure to the SN as the culprit for weight changes. Finally, low AAV2-NRTN doses provided significant neuroprotection against 6-OHDA toxicity, establishing a wide therapeutic index for nigral targeting. These data support targeting the SN with AAV2-NRTN in PD patients, demonstrating that properly targeted and scaled AAV2-NRTN provides safe and effective NRTN expression. They also provided the means to define an appropriate human-equivalent dose for proceeding into an ongoing clinical trial, using empirically-based scaling to account for marked differences in SN volume between species.

Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains.

BACKGROUND: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). METHODS: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated. RESULTS: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons. DISCUSSION: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved.

Accuracy of coronary artery stenosis detection with CT versus conventional coronary angiography compared with composite findings from both tests as an enhanced reference standard.

OBJECTIVE: To prospectively compare the accuracy of coronary CT angiography (CCTA) and conventional coronary angiography (CCA) for stenosis detection using composite findings from both tests as an enhanced reference standard. METHODS: One hundred thirteen patients underwent CCTA and CCA. Per-segment and per-patient accuracy of CCTA compared with initial CCA interpretation were determined. Angiographers were then unblinded to the CCTA results and re-evaluation of the CCA studies was performed with knowledge of CCTA findings, which was used as an enhanced reference standard to compare the diagnostic accuracy of CCTA versus CCA. RESULTS: When using the enhanced reference standard instead of initial CCA interpretation, CCTA accuracy for identifying segments (patients) with ≥50% stenosis increased from 97.7% (96.5%) to 98.1% (98.2%), sensitivity from 90.5% (100%) to 90.8% (100%), and specificity from 98.4% (94.3%) to 98.9% (97.1%). CCTA identified six segments and two patients with stenoses ≥50% missed on initial CCA interpretation. Compared with the enhanced reference standard the accuracies of CCTA and of initial CCA interpretation were not different (p = 0.87). CONCLUSION: CCTA compares favourably with CCA for stenosis detection. Use of a composite reference standard combining findings from both tests can control for the effect of false-negative CCA results when evaluating the accuracy of CCTA.

Dual energy CT for the assessment of reperfused chronic infarction - a feasibility study in a porcine model.

BACKGROUND: Detection of myocardial infarction has been the focus of considerable research over the past few decades. Recently developed dual source computed tomography (DSCT) scanners with dual energy mode have been used to detect myocardial infarction, but the studies on this topic are few. PURPOSE: To evaluate the feasibility and performance of dual energy CT (DECT) during arterial phase in coronary CT angiography for the detection of chronic infarction compared with late enhancement MRI (LE-MRI) and histopathology in a porcine model of reperfused myocardial infarction. MATERIAL AND METHODS: Myocardial infarctions were induced by 30 min occlusion of the proximal left anterior descending coronary artery in eight minipigs. DECT, post-contrast LE-MRI and histopathology were performed 60 days after infarct induction. The CT scan was performed in dual energy mode using a dedicated protocol. Myocardial iodine distribution was superimposed as color maps on grey scale multiplanar reformats of the heart. Two radiologists in consensus interpreted all imaging studies for presence of gadolinium uptake at LE-MRI reduced iodine content at DECT and hypoenhanced areas in the initial 100 kV coronary CT angiography images that were acquired during the DECT-acquisition. Results were compared with histopathology. RESULTS: Based on evaluable segments, DECT showed a sensitivity and specificity of 0.72 and 0.88; LE-MRI showed a sensitivity and specificity of 0.78 and 0.92; and the 100 kV data-set of the DECT scan showed a sensitivity and specificity of 0.60 and 0.93, respectively, for the detection of histological proved ischemia. CONCLUSION: DECT during arterial phase coronary CT angiography, which is ordinarily used for coronary artery evaluation, is feasible for the detection of a chronic reperfused myocardial infarction.

Gene therapy for infantile malignant osteopetrosis: review of pre-clinical research and proof-of-concept for phenotypic reversal.

Infantile malignant osteopetrosis is a devastating disorder of early childhood that is frequently fatal and for which there are only limited therapeutic options. Gene therapy utilizing autologous hematopoietic stem and progenitor cells represents a potentially advantageous therapeutic alternative for this multisystemic disease. Gene therapy can be performed relatively rapidly following diagnosis, will not result in graft versus host disease, and may also have potential for reduced incidences of other transplant-related complications. In this review, we have summarized the past sixteen years of research aimed at developing a gene therapy for infantile malignant osteopetrosis; these efforts have culminated in the first clinical trial employing lentiviral-mediated delivery of TCIRG1 in autologous hematopoietic stem and progenitor cells.

In vitro evaluation of metallic coronary artery stents with 64-MDCT using an ECG-gated cardiac phantom: relationship between in-stent visualization, stent type, and heart rate.

OBJECTIVE: The purpose of this study was to assess the accuracy of 64-MDCT in the visualization of different coronary artery stents and in the appraisal of in-stent stenosis. MATERIALS AND METHODS: Five different coronary stent types with three diameters (2.5, 3.0, and 4.0 mm) were analyzed using anthropomorphic dynamic cardiac phantom. All stents were mounted on polyurethane sticks of defined outer diameter and contained a default concentric stenosis of 50% each. Imaging was performed at four different heart rates (no motion, 60 beats/min, 75 beats/min, and 90 beats/min). Apparent stent diameter, degree of stenosis, in-stent attenuation, and diagnostic accuracy were assessed. RESULTS: A significant (p < 0.05) overestimation of the degree of stenosis (41.1% +/- 41.4%), underestimation of the stent lumen (-42.7% +/- 41.4%), and increase in in-stent attenuation (36.6 +/- 29.2 HU) were observed for all stents and heart rates. In-stent stenosis > 50% was detected with an overall sensitivity of 88.9% (95% CI, 75.9-96.3%) and an overall specificity of 51.1% (95% CI, 35.8-66.3%) by observer 1 and with an overall sensitivity of 86.7% (95% CI, 73.2-94.9%) and an overall specificity of 57.8% (95% CI, 42.2-72.3%) by observer 2. A trend toward higher specificity was observed for increasing stent diameter, however, without reaching statistical significance (p = 0.63). CONCLUSION: In an experimental setting, 64-MDCT allows a reliable detection of instent stenosis but significantly overestimates the actual degree of stenosis. Within the range of physiologic heart rates, diagnostic accuracy is restricted by spatial, not temporal, resolution.

Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease.

Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p<0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p<0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p<0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p<0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.

Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma.

Tobacco smoke consists of numerous carcinogens whose effect on lung tumor development includes the induction of mutations in key genes as well as the induction of chromosome instability (CIN). Consequently, carcinogen-induced mouse lung adenocarcinomas (LAC) display many more recurrent site- and chromosome-specific changes in DNA copy number compared with noninduced LAC. Here we identified the Adenylosuccinate synthetase 1 (Adss1) gene located on distal chromosome 12q as a focus of bi-allelic or homozygous deletion (HD) in LAC. HDs of Adss1 were detected in 10 out of 84 carcinogen-induced mouse primary LAC and mouse LAC cell lines. In only four of these cases did the deletions affect either Siva1 or Inverted-formin 2 (Inf2), which immediately flank the Adss1 locus, indicating that Adss1 is a selective target of deletion in LAC. Losses of Adss1 not meeting the quantitative threshold of HD were detected in 36 out of 84 (42.9%) of the mouse tumors and cell lines. A similar frequency of ADSS1 deletion was observed in human LAC cell lines, suggesting relevance in human lung cancer. Adss1 losses were also found to be significantly associated with a more extensive CIN phenotype in the primary mouse tumors. These results implicate ADSS1 inactivation as a novel somatic alteration in lung carcinogenesis, and suggest that its selective deletion in LAC may be triggered by CIN.

Superconductors from superstrings.

We establish that in a large class of strongly coupled (3+1)-dimensional N=1 quiver conformal field theories with gravity duals, adding a chemical potential for the R charge leads to the existence of superfluid states in which a chiral primary operator of the schematic form O=lambdalambda+W condenses. Here lambda is a gluino and W is the superpotential. Our argument is based on the construction of a consistent truncation of type IIB supergravity that includes a U(1) gauge field and a complex scalar.

Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice MDCT imaging in patients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for Coronary Artery Disease).

This was a prospective, multicenter study designed to evaluate the utility of MDCT in the diagnosis of coronary artery disease (CAD) in patients scheduled for elective coronary angiography (CA) using different MDCT systems from different manufacturers. Twenty national sites prospectively enrolled 367 patients between July 2004 and June 2006. Computed tomography (CT) was performed using a standardized/optimized scan protocol for each type of MDCT system (> or =16 slices) and compared with quantitative CA performed within 2 weeks of MDCT. A total of 284 patients (81%) were studied by 16-slice MDCT systems, while 66 patients (19%) by 64-slice MDCT scanners. The primary analysis was on-site/off-site evaluation of the negative predictive value (NPV) on a per-patient basis. Secondary analyses included on-site evaluation on a per-artery and per-segment basis. On-site evaluation included 327 patients (CAD prevalence 58%). NPV, positive predictive value (PPV), sensitivity, specificity, and diagnostic accuracy (DA) were 0.91 (95% CI 0.85-0.95), 0.91 (95% CI 0.86-0.95), 0.94 (95% CI 0.89-0.97), 0.88 (95% CI 0.81-0.93), and 0.91 (95% CI 0.88-0.94), respectively. Off-site analysis included 295 patients (CAD prevalence 56%). NPV, PPV, sensitivity, specificity, and DA were 0.73 (95% CI 0.65-0.79), 0.93 (95% CI 0.87-0.97), 0.73 (95% CI 0.65-0.79), 0.93 (95% CI 0.87-0.97), and 0.82 (95% CI 0.77-0.86), respectively. The results of this study demonstrate the utility of MDCT in excluding significant CAD even when conducted by centers with varying degrees of expertise and using different MDCT machines.

FoxO3a gene is a target of deletion in mouse lung adenocarcinoma.

Lung adenocarcinomas (LAC) of smokers and never-smokers differ from one another in epidemiology, and clinical and molecular characteristics. The pathogenetic differences between these tumors are potential biomarkers and therapeutic targets. Mouse carcinogenesis models of human LAC are proven tools applicable for the identification of these molecular changes. Allelic loss frequency on human chromosome 6q is higher in LAC of smokers compared with never smokers. We analyzed the orthologous region on mouse chromosome 10 and found this region similarly was a more frequent site of allelic loss in carcinogen-induced LAC compared with non-induced or spontaneous LAC. We then conducted high resolution quantitative PCR-based deletion mapping of this region and identified the FoxO3a gene as the focus of bi-allelic or homozygous deletion (HD). HDs were detected in 5 out of 15 (33.3%) LAC cell lines and in 6 out of 75 (8%) carcinogen-induced primary LAC. FoxO3a was exclusively affected by HD in 7 of the samples examined, as loss of both alleles did extend to the nearest flanking genes of FoxO3a. Deletion of FoxO3a, either by HD or subclonal loss was detected in 38 out of 75 (50.7%) of carcinogen-induced LAC in contrast to only 1 out of 10 (10%) of LAC of untreated mice. Several of the samples also were subjected to direct sequence analysis; however, no intragenic mutations were detected. These results implicate FoxO3a as a selective target of deletion in mouse LAC. Significant association with carcinogenic induction suggests that deletion of FoxO3a contributes to the development of carcinogen-initiated tumors.