Evaluating PET-CT in the detection and management of recurrent cervical cancer: Systematic reviews of diagnostic accuracy and subjective elicitation

Background: Positron emission tomography-computed tomography (PET-CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer. Objective: To evaluate diagnostic accuracy of additional whole body PET-CT compared with CT/magnetic resonance imaging (MRI) alone in women with suspected recurrent/persistent cervical cancer and in asymptomatic women as surveillance. Design: Systematic reviews. Subjective elicitation to supplement diagnostic information. Search strategy/Selection criteria/Data collection and analysis: Searches of electronic databases were performed to June 2013. Studies in women with suspected recurrent/persistent cervical cancer and in asymptomatic women undergoing follow up with sufficient numeric data were included. We calculated sensitivity, specificity and corresponding 95% confidence intervals. Meta-analyses employed a bivariate model that included a random-effects term for between-study variations (CT studies) and univariate random effects meta-analyses (PET-CT studies) for sensitivity and specificity separately. Subjective elicitation: Prevalence of recurrence and the accuracy of imaging elicited using the allocation of points technique. Coherence of elicited subjective probabilities with estimates in the literature examined. Results: We identified 15 relevant studies; none directly compared additional PET-CT with MRI or CT separately. Most CT and MRI studies used older protocols and the majority did not distinguish between asymptomatic and symptomatic women. Meta-analysis of nine PET-CT studies in mostly symptomatic women showed sensitivity of 94.8 (95% CI 91.2-96.9), and specificity of 86.9% (95% CI 82.2-90.5). The summary estimate of the sensitivity of CT for detection of recurrence was 89.64% (95% CI 81.59-94.41) and specificity was 76% (95% CI 43.68-92.82). Meta-analysis for MRI test accuracy studies was not possible because of clinical heterogeneity. The sensitivity and specificity of MRI in pelvic recurrence varied between 82 and 100% and between 78 and 100%, respectively. Formal statistical comparisons of the accuracy of index tests were not possible. Subjective elicitation provided estimates comparable to the literature. Subjective estimates of the increase in accuracy from the addition of PET-CT were less than elicited increases required to justify the use in PET-CT for surveillance. Conclusion: Evidence to support additional PET-CT is scarce, of average quality and does not distinguish between application for surveillance and diagnosis. Guidelines recommending PET-CT in recurrent cervical cancer need to be reconsidered in the light of the existing evidence base

First Results of the Phase II SIMPLE Dark Matter Search

We report results of a 14.1 kgd measurement with 15 superheated droplet detectors of total active mass 0.208 kg, comprising the first stage of a 30 kgd Phase II experiment. In combination with the results of the neutron-spin sensitive XENON10 experiment, these results yield a limit of |a_p| < 0.32 for M_W = 50 GeV/c2 on the spin-dependent sector of weakly interacting massive particle-nucleus interactions with a 50% reduction in the previously allowed region of the phase space formerly defined by XENON, KIMS and PICASSO. In the spin-independent sector, a limit of 2.3x10-5 pb at M_W = 45 GeV/c2 is obtained.Comment: 4 pages, 4 figures; PRL-accepted version with corrected SI contour (Fig. 4

Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling.

© Queen’s Printer and Controller of HMSO 2013. This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising.Cancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging.National Institute for Health Research Health Technology Assessment programm

Final Analysis and Results of the Phase II SIMPLE Dark Matter Search

We report the final results of the Phase II SIMPLE measurements, comprising two run stages of 15 superheated droplet detectors each, the second stage including an improved neutron shielding. The analyses includes a refined signal analysis, and revised nucleation efficiency based on reanalysis of previously-reported monochromatic neutron irradiations. The combined results yield a contour minimum of \sigma_{p} = 4.2 x 10^-3 pb at 35 GeV/c^2 on the spin-dependent sector of WIMP-proton interactions, the most restrictive to date from a direct search experiment and overlapping for the first time results previously obtained only indirectly. In the spin-independent sector, a minimum of 3.6 x 10^-6 pb at 35 GeV/c^2 is achieved, with the exclusion contour challenging the recent CoGeNT region of current interest.Comment: revised, PRL-accepted version with slightly weakened limit contour

The SIMPLE Phase II Dark Matter Search

Phase II of SIMPLE (Superheated Instrument for Massive ParticLe Experiments) searched for astroparticle dark matter using superheated liquid C$_{2}$ClF$_{5}$ droplet detectors. Each droplet generally requires an energy deposition with linear energy transfer (LET) $\gtrsim$ 150 keV/$\mu$m for a liquid-to-gas phase transition, providing an intrinsic rejection against minimum ionizing particles of order 10$^{-10}$, and reducing the backgrounds to primarily $\alpha$ and neutron-induced recoil events. The droplet phase transition generates a millimetric-sized gas bubble which is recorded by acoustic means. We describe the SIMPLE detectors, their acoustic instrumentation, and the characterizations, signal analysis and data selection which yield a particle-induced, "true nucleation" event detection efficiency of better than 97% at a 95% C.L. The recoil-$\alpha$ event discrimination, determined using detectors first irradiated with neutrons and then doped with alpha emitters, provides a recoil identification of better than 99%; it differs from those of COUPP and PICASSO primarily as a result of their different liquids with lower critical LETs. The science measurements, comprising two shielded arrays of fifteen detectors each and a total exposure of 27.77 kgd, are detailed. Removal of the 1.94 kgd Stage 1 installation period data, which had previously been mistakenly included in the data, reduces the science exposure from 20.18 to 18.24 kgd and provides new contour minima of $\sigma_{p}$ = 4.3 $\times$ 10$^{-3}$ pb at 35 GeV/c$^{2}$ in the spin-dependent sector of WIMP-proton interactions and $\sigma_{N}$ = 3.6 $\times$ 10$^{-6}$ pb at 35 GeV/c$^{2}$ in the spin-independent sector. These results are examined with respect to the fluorine spin and halo parameters used in the previous data analysis.Comment: 20 pages, 19 figures; accepted Physical Review

Identification of Genes and Pathways Regulated by Lamin A in Heart

Background Mutations in the LMNA gene, encoding LMNA (lamin A/C), causes distinct disorders, including dilated cardiomyopathies, collectively referred to as laminopathies. The genes (coding and noncoding) and regulatory pathways controlled by LMNA in the heart are not completely defined. Methods and Results We analyzed cardiac transcriptome from wild-type, loss-of-function (Lmna-/-), and gain-of-function (Lmna-/- injected with adeno-associated virus serotype 9 expressing LMNA) mice with normal cardiac function. Deletion of Lmna (Lmna-/-) led to differential expression of 2193 coding and 629 long noncoding RNA genes in the heart (q<0.05). Re-expression of LMNA in the Lmna-/- mouse heart, completely rescued 501 coding and 208 non-coding and partially rescued 1862 coding and 607 lncRNA genes. Pathway analysis of differentially expressed genes predicted activation of transcriptional regulators lysine-specific demethylase 5A, lysine-specific demethylase 5B, tumor protein 53, and suppression of retinoblastoma 1, paired-like homeodomain 2, and melanocyte-inducing transcription factor, which were completely or partially rescued upon reexpression of LMNA. Furthermore, lysine-specific demethylase 5A and 5B protein levels were increased in the Lmna-/- hearts and were partially rescued upon LMNA reexpression. Analysis of biological function for rescued genes identified activation of tumor necrosis factor-α, epithelial to mesenchymal transition, and suppression of the oxidative phosphorylation pathway upon Lmna deletion and their restoration upon LMNA reintroduction in the heart. Restoration of the gene expression and transcriptional regulators in the heart was associated with improved cardiac function and increased survival of the Lmna-/- mice. Conclusions The findings identify LMNA-regulated cardiac genes and their upstream transcriptional regulators in the heart and implicate lysine-specific demethylase 5A and B as epigenetic regulators of a subset of the dysregulated genes in laminopathies

Aquaporin-4 and brain edema.

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury

XUV interferometry using high-order harmonics: Application to plasma diagnostics

In this paper, we present and compare the two different XUV interferometric techniques using high-order harmonics that have been developed so far. The first scheme is based on the interference between two spatially separated phase-locked harmonic sources while the second uses two temporally separated harmonic sources. These techniques have been applied to plasma diagnostics in feasibility experiments where electron densities up to a few 1020 e[minus sign/cm3 have been measured with a temporal resolution of 200 fs. We present the main characteristics of each technique and discuss their respective potentials and limitations

Inhibiting Metastatic Breast Cancer Cell Migration via the Synergy of Targeted, pH-triggered siRNA Delivery and Chemokine Axis Blockade

Because breast cancer patient survival inversely correlates with metastasis, we engineered vehicles to inhibit both the C-X-C chemokine receptor type 4 (CXCR4) and lipocalin-2 (Lcn2) mediated migratory pathways. pH-responsive liposomes were designed to protect and trigger the release of Lcn2 siRNA. Liposomes were modified with anti-CXCR4 antibodies to target metastatic breast cancer (MBC) cells and block migration along the CXCR4-CXCL12 axis. This synergistic approach—coupling the CXCR4 axis blockade with Lcn2 silencing—significantly reduced migration in triple-negative human breast cancer cells (88% for MDA-MB-436 and 92% for MDA-MB-231). The results suggested that drug delivery vehicles engineered to attack multiple migratory pathways may effectively slow progression of MBC

Strong field ionization in arbitrary laser polarizations

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