Potential savings in the diagnosis of vestibular schwannoma.

INTRODUCTION: Magnetic resonance imaging (MRI) is used to screen patients at risk for vestibular schwannoma (VS). These MRIs are costly and have an extremely low yield; only 3% of patients in the screening population has an actual VS. It might be worthwhile to develop a test to predict VS and refer only a subset of all patients for MRI. OBJECTIVE: To examine the potential savings of such a hypothetical diagnostic test before MRI. DESIGN: We built a decision analytical model of the diagnostic strategy of VS. Input was derived from literature and key opinion leaders. The current strategy was compared to hypothetical new strategies, assigning MRI to the following: (i) all patients with pathology, (ii) all patients with important pathology and (iii) only patients with VS. This resulted in potential cost savings for each strategy. We conducted a budget impact analysis to predict nationwide savings for the Netherlands and the United Kingdom (UK), and a probabilistic sensitivity analysis to address uncertainty. RESULTS: Mean savings ranged from €256 (95%CI €250 - €262) or approximately US$284 (95%CI US$277 - US$291) per patient for strategy 1 to €293 (95%CI €290 - €296) or approximately US$325 (95%CI US$322 - US$328) per patient for strategy 3. Future diagnostic strategies can cost up to these amounts per patient and still be cost saving. Annually, for the Netherlands, €2.8 to €3.2 million could be saved and €10.8 to €12.3 million for the UK. CONCLUSIONS: The model shows that substantial savings could be generated if it is possible to further optimise the diagnosis of VS.

Diagnostic accuracy of high-resolution T2-weighted MRI vs contrast-enhanced T1-weighted MRI to screen for cerebellopontine angle lesions in symptomatic patients.

OBJECTIVE: To evaluate diagnostic accuracy of high-resolution T2-weighted MRI (T2w) for detecting cerebellopontine angle (CPA) lesions compared to a combined protocol including gadolinium enhanced T1-weighted MRI (GdT1w). SETTING: Department of Radiology & Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. PARTICIPANTS: A random sample of MRIs from 350 patients (700 CPAs) with asymmetrical audiovestibular complaints was used, acquired between 2013 and 2016. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values of T2w results compared to GdT1w and, in patients with any suggestion of CPA pathology, to the complete examination (T1w, GdT1w and T2w). Inter-rater agreement between an experienced neuroradiologist and a less experienced observer was calculated. RESULTS: Results of 678 CPAs in 340 patients were analysed. On T2w, the neuroradiologist identified all 27 lesions >2 mm in size out of a total of 30 CPA lesions (sensitivity: 90% [95% CI: 73.5%-97.9%]). Negative predictive value reached 99.5% (95% CI: 98.7-99.9). One missed lesion of 2 mm would have been detected in clinical practice, as this was one of 14 patients for which additional GdT1w would have been ordered based on T2w alone, increasing sensitivity to 93% (95% CI: 77.9%-99.2%) and negative predictive value to 99.7% (95% CI: 98.9%-100%). Inter-rater agreement for T2w was 98% (95% CI: 96.4-98.8). CONCLUSION: T2w has a very high diagnostic accuracy for the presence of CPA lesions in patients with asymmetrical audiovestibular complaints. However, in a screening protocol with T2w only, smallest vestibular schwannomas as well as rare differential diagnoses that probably only would be detected on GdT1w may remain unnoticed.

The diagnostic accuracy of non-imaging screening protocols for vestibular schwannoma in patients with asymmetrical hearing loss and/or unilateral audiovestibular dysfunction: a diagnostic review and meta-analysis.

BACKGROUND: Currently, all patients presenting with asymmetrical sensorineural hearing loss and/or unilateral audiovestibular dysfunction (i.e. tinnitus, dizziness) undergo MRI, leading to a substantial amount of MRIs with negative findings as the incidence of vestibular schwannoma (VS) in this screening population varies between 1% and 4.7% (i.e. more than 95% of MRIs are negative for VS). OBJECTIVE OF REVIEW: The aim was to assess the diagnostic accuracy of different non-imaging screening protocols that can be used prior to MRI to select patients at high risk of VS. TYPE OF REVIEW: Diagnostic review and meta-analysis. SEARCH STRATEGY: We systematically searched MEDLINE, Embase and The Cochrane Library as from inception up to 28 July 2016. We included studies that compared non-imaging screening protocols to MRI as gold reference standard. EVALUATION METHOD: Methodological quality was assessed by two independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies tool. Data necessary to complete 2 × 2 tables were obtained, and patient, study, screening and imaging characteristics were extracted. We calculated sensitivity and specificity of all tests and obtained pooled estimates using a bivariate random effects model. RESULTS: We analysed 12 studies (4969 patients) of poor to moderate quality according to the quality assessment. Most studies tested diagnostic accuracy of multiple screening protocols. Five pure-tone audiometry (PTA) protocols were studied by multiple authors; pooled estimates for sensitivity ranged from 88% [95% CI: 84-91] to 91% [95% CI: 52-99] and specificity from 31% [95% CI: 10-66] to 58% [95% CI: 49-65]. Due to heterogeneity, we were unable to pool other tests. In five studies testing auditory brainstem response, sensitivity values ranged from 37% [95% CI: 23-52] to 100% [95% CI: 40-100] and specificity from 57% to 96% [95% CI: 87-100]. Two authors studied PTA shape as a screening test. Presenting symptoms, electronystagmography, caloric irrigation and hyperventilation test were assessed by one study each. All reported low diagnostic accuracy. CONCLUSIONS: All identified studies had a moderate-to-high risk of bias, and none of the currently available non-imaging screening protocols appear to be accurate in detecting VSs.

Spin-orbit coupling of light in asymmetric microcavities.

When spinning particles, such as electrons and photons, undergo spin-orbit coupling, they can acquire an extra phase in addition to the well-known dynamical phase. This extra phase is called the geometric phase (also known as the Berry phase), which plays an important role in a startling variety of physical contexts such as in photonics, condensed matter, high-energy and space physics. The geometric phase was originally discussed for a cyclically evolving physical system with an Abelian evolution, and was later generalized to non-cyclic and non-Abelian cases, which are the most interesting fundamental subjects in this area and indicate promising applications in various fields. Here, we enable optical spin-orbit coupling in asymmetric microcavities and experimentally observe a non-cyclic optical geometric phase acquired in a non-Abelian evolution. Our work is relevant to fundamental studies and implies promising applications by manipulating photons in on-chip quantum devices.

Positron emission mammography in the diagnosis of breast cancer. Is maximum PEM uptake value a valuable threshold for malignant breast cancer detection?

AIM: To evaluate the diagnostic value (sensitivity, specificity) of positron emission mammography (PEM) in a single site non-interventional study using the maximum PEM uptake value (PUVmax). PATIENTS, METHODS: In a singlesite, non-interventional study, 108 patients (107 women, 1 man) with a total of 151 suspected lesions were scanned with a PEM Flex Solo II (Naviscan) at 90 min p.i. with 3.5 MBq 18F-FDG per kg of body weight. In this ROI(region of interest)-based analysis, maximum PEM uptake value (PUV) was determined in lesions, tumours (PUVmaxtumour), benign lesions (PUVmaxnormal breast) and also in healthy tissues on the contralateral side (PUVmaxcontralateral breast). These values were compared and contrasted. In addition, the ratios of PUVmaxtumour / PUVmaxcontralateral breast and PUVmaxnormal breast / PUVmaxcontralateral breast were compared. The image data were interpreted independently by two experienced nuclear medicine physicians and compared with histology in cases of suspected carcinoma. RESULTS: Based on a criteria of PUV>1.9, 31 out of 151 lesions in the patient cohort were found to be malignant (21%). A mean PUVmaxtumour of 3.78 ± 2.47 was identified in malignant tumours, while a mean PUVmaxnormal breast of 1.17 ± 0.37 was reported in the glandular tissue of the healthy breast, with the difference being statistically significant (p < 0.001). Similarly, the mean ratio between tumour and healthy glandular tissue in breast cancer patients (3.15 ± 1.58) was found to be significantly higher than the ratio for benign lesions (1.17 ± 0.41, p < 0.001). CONCLUSION: PEM is capable of differentiating breast tumours from benign lesions with 100% sensitivity along with a high specificity of 96%, when a threshold of PUVmax >1.9 is applied.

A dedicated compression device for high resolution X-ray tomography of compressed gas diffusion layers.

We present an experimental approach to study the three-dimensional microstructure of gas diffusion layer (GDL) materials under realistic compression conditions. A dedicated compression device was designed that allows for synchrotron-tomographic investigation of circular samples under well-defined compression conditions. The tomographic data provide the experimental basis for stochastic modeling of nonwoven GDL materials. A plain compression tool is used to study the fiber courses in the material at different compression stages. Transport relevant geometrical parameters, such as porosity, pore size, and tortuosity distributions, are exemplarily evaluated for a GDL sample in the uncompressed state and for a compression of 30 vol.%. To mimic the geometry of the flow-field, we employed a compression punch with an integrated channel-rib-profile. It turned out that the GDL material is homogeneously compressed under the ribs, however, much less compressed underneath the channel. GDL fibers extend far into the channel volume where they might interfere with the convective gas transport and the removal of liquid water from the cell.

Three-dimensional imaging of magnetic domains.

Magnetic domains have been the subject of much scientific investigation since their theoretical existence was first postulated by P.-E. Weiss over a century ago. Up to now, the three-dimensional (3D) domain structure of bulk magnets has never been observed owing to the lack of appropriate experimental methods. Domain analysis in bulk matter thus remains one of the most challenging tasks in research on magnetic materials. All current domain observation methods are limited to studying surface domains or thin magnetic films. As the properties of magnetic materials are strongly affected by their domain structure, the development of a technique capable of investigating the shape, size and distribution of individual domains in three dimensions is of great importance. Here, we show that the novel technique of Talbot-Lau neutron tomography with inverted geometry enables direct imaging of the 3D network of magnetic domains within the bulk of FeSi crystals.

False-positive radio-iodinated metaiodobenzylguanidine (123I-MIBG) accumulation in a mast cell-infiltrated infantile haemangioma.

Radio-iodinated metaiodobenzylguanidine ((123)I-MIBG) is used for the detection and staging of neuroblastoma, pheochromcytoma and other neuroendocrine tumours in diagnostic nuclear medicine. A specific uptake and storage mechanism provides the basis for imaging with (123)I-MIBG. Nevertheless, cases of false-positive (123)I-MIBG scintigraphy with accumulation in non-chromaffin tumours have been described. Here, we present a case of a false-positive (123)I-MIBG scan in a case of a mast-cell infiltrated infantile haemangioma and discuss the possible uptake mechanism.

Impact of FDG-PET for staging of oesophageal cancer.

BACKGROUND AND AIMS: Treatment of oesophageal cancer depends on staging and the general health of the patient. In stages I-II b, as well as in some stage III diseases, surgical resection remains the therapy of choice for cure, but a curative approach is not possible in stage IV. In our hospital we give preoperative radio-chemotherapy to all patients with an oesophageal cancer T>1, Nx, M0. Therefore, the main purpose of the clinical staging of oesophageal cancer is the exclusion of M1 and T4 disease with infiltration into the tracheobronchial system or the aorta. The aim of the investigation was the assessment of positron emission tomography for detection of M1 disease. PATIENTS/METHODS: Between 1998 and 2002, 84 patients with oesophageal cancer (64% squamous cell carcinoma and 36% adenocarcinoma) were enrolled into the study. Of these, 48.8% were operated on; 35.7% of the patients were not operated on, for oncological reasons, 7.1% for medical reasons, 3.6% chose not to be operated on, and, for unknown reasons, 4.8% were not operated on. RESULTS: Twenty-five patients had stage IV disease or additional, synchronous cancer of the head and neck ( n=2). As the only investigational procedure, positron emission tomography revealed M1 stage in 11 of 25 patients (44%). In 13/25 (52%) both computed tomography and positron emission tomography revealed stage IV disease. False positive results by positron emission tomography were observed in three patients. The sensitivity and specificity of positron emission tomography (PET) was 0.96 and 0.95, respectively. Most of the metastases detected by PET only, were localised within the neck, liver and bone. With regard to the 66 of 84 patients deemed medically fit for operation and without local infiltration into the tracheobronchial system (T4) PET as the only imaging procedure changed the therapeutic strategy in 11 of 66 (16.6%) patients with to M1 disease. CONCLUSION: Our results demonstrated clearly the impact of the PET scan for decision-making in patients with oesophageal carcinoma. PET should be performed prior to therapy with curative intention. However, addition of a computed tomography scan of the neck might reduce the rate of unexpected metastases detected by PET.

Effects of neoadjuvant radio-chemotherapy on 18F-FDG-PET in esophageal carcinoma.

AIM: To investigate whether results of [F-18]-fluorodeoxy-d-glucose (FDG) positron emission tomography (PET) of esophageal cancer (EC) before and after neoadjuvant radio-chemotherapy correlate with histopathology after esophageal resection. METHODS: Twenty consecutive patients with EC without distant metastases were examined twice with 18F-FDG-PET during primary staging and after neoadjuvant radio-chemotherapy. FDG standardised uptake values (SUV) were correlated with the histopathological findings (percentage of viable tumour cells, tumour regression grade 1-5). RESULTS: Regression analysis revealed a slight (not significant) positive correlation between SUV(pre) (R=0.41, p=0.08) and SUV(post) (R=0.37, p=0.11) and the percentage of viable tumour cells in the resectate. Although all patients showed a significant decrease in SUV after radio-chemotherapy (p < 0.01) the percentual decrease of the SUV after therapy (DeltaSUV%) did not significantly differ between the TRG-groups. In 12 of 20 patients (60%), therapy-induced esophagitis was detected in post-therapeutic PET images. CONCLUSION: In EC, a higher pre-therapeutic SUV might be correlated with a higher fraction of vital tumour cells remaining after radio-chemotherapy. Applying the neoadjuvant therapy protocol and the study design used in this examination, there is no correlation between decrease in SUV and histopathology.

[Appropriate uptake period for myocardial PET imaging with 18F-FDG after oral glucose loading]. / Optimaler Akquisitionszeitpunkt für die Herz-PET mit 18F-FDG nach oraler Glukosebelastung.

AIM: Identification of a rationale for the appropriate uptake period for myocardial (18)F-FDG-PET imaging of patients with and without diabetes mellitus. METHODS: In a subset of 27 patients, static 2D-PET examination was performed of patients with chronic coronary artery disease and known myocardial infarction. The patients fasted (at least 4 h) before examination. (18)F-FDG (330 +/- 20 MBq) was injected intravenously. The image quality was semiquantitativly determined by ROI-analysis and the myocardium-to-blood pool activity ratio (M/B) was calculated. I.) Scans 30, 60, and 90 min p. i. of 10 non-diabetic patients (60 g oral glucose loading one hour before FDG-injection, low-dose intravenous insulin bolus if necessary). II.) Scans 30, 60, and 90 min p. i. of 10 patients with known non-insulin dependent diabetes (20 g glucose, insulin bolus). III.) Scans 90 min p. i. of 7 patients with known non-insulin dependent diabetes and elevated fasting serum glucose level (140-200 mg/dl; insulin bolus, no glucose). RESULTS: I.) The M/B ratio significantly increases in nondiabetic patients with the uptake time (30 min 1.95 +/- 0.20; 60 min 2.96 +/- 0.36; 90 min 3.78 +/- 0.43). II.) In patients with non-insulin dependent diabetes the M/B ratio also significantly increases with uptake time. Compared to non-diabetic patients group II reached smaller M/B values (30 min 1.56 +/- 0.10; 60 min 2.15 +/- 0.14; 90 min 2.71 +/- 0.19). III.) In the group of patients with elevated fasting serum glucose level (who only got insulin but no glucose loading) the M/B activity ratio 90 min p. i. was clearly inferior compared with diabetic patients after oral glucose loading and insulin administration (M/B 2.71 +/- 0.19 versus 2.16 +/- 0.07). CONCLUSIONS: In static myocardial viability PET studies with (18)F-FDG an uptake time of 90 min yields image quality superior to that obtained after shorter uptake time.

Attosecond control of electronic processes by intense light fields.

The amplitude and frequency of laser light can be routinely measured and controlled on a femtosecond (10(-15) s) timescale. However, in pulses comprising just a few wave cycles, the amplitude envelope and carrier frequency are not sufficient to characterize and control laser radiation, because evolution of the light field is also influenced by a shift of the carrier wave with respect to the pulse peak. This so-called carrier-envelope phase has been predicted and observed to affect strong-field phenomena, but random shot-to-shot shifts have prevented the reproducible guiding of atomic processes using the electric field of light. Here we report the generation of intense, few-cycle laser pulses with a stable carrier envelope phase that permit the triggering and steering of microscopic motion with an ultimate precision limited only by quantum mechanical uncertainty. Using these reproducible light waveforms, we create light-induced atomic currents in ionized matter; the motion of the electronic wave packets can be controlled on timescales shorter than 250 attoseconds (250 x 10(-18) s). This enables us to control the attosecond temporal structure of coherent soft X-ray emission produced by the atomic currents--these X-ray photons provide a sensitive and intuitive tool for determining the carrier-envelope phase.

Time-resolved atomic inner-shell spectroscopy.

The characteristic time constants of the relaxation dynamics of core-excited atoms have hitherto been inferred from the linewidths of electronic transitions measured by continuous-wave extreme ultraviolet or X-ray spectroscopy. Here we demonstrate that a laser-based sampling system, consisting of a few-femtosecond visible light pulse and a synchronized sub-femtosecond soft X-ray pulse, allows us to trace these dynamics directly in the time domain with attosecond resolution. We have measured a lifetime of 7.9(-0.9)(+1.0) fs of M-shell vacancies of krypton in such a pump-probe experiment.

Steering attosecond electron wave packets with light.

Photoelectrons excited by extreme ultraviolet or x-ray photons in the presence of a strong laser field generally suffer a spread of their energies due to the absorption and emission of laser photons. We demonstrate that if the emitted electron wave packet is temporally confined to a small fraction of the oscillation period of the interacting light wave, its energy spectrum can be up- or downshifted by many times the laser photon energy without substantial broadening. The light wave can accelerate or decelerate the electron's drift velocity, i.e., steer the electron wave packet like a classical particle. This capability strictly relies on a sub-femtosecond duration of the ionizing x-ray pulse and on its timing to the phase of the light wave with a similar accuracy, offering a simple and potentially single-shot diagnostic tool for attosecond pump-probe spectroscopy.

[Effects of a high intensity training program on patients with chronic obstructive airways disease (COAD)]. / Nutzen eines intensiven Trainingsprogrammes bei Patienten mit obstruktiver Atemwegskrankheit.

UNLABELLED: In a controlled/prospective clinical trial we examined 125 patients with moderate COAD, 84 of which performed a high-intensity training program on cycle ergometers. METHODS: All participants (controls n = 39, training-group n = 84, age 48.7 versus 48.1 years, FEV1 62.3 % vs. 63.1 % of predicted) were examined spiroergometrically (ramp protocol, increment 10 W/min), the anaerobic threshold (AT) determined and a training intensity calculated (AT + 40 % of the difference to peak exercise). Training was carried out on cycle ergometers with 5 training units weekly at 40 minutes each. We aimed at a minimum of 22 training units during 4 weeks. RESULTS: Both groups improved in the lung function at rest (FEV1 + 11 % versus + 12 % in the controls). Only for the training group we found a statistically significant improvement in maximum exercise capacity (O2 uptake + 286.4 ml vs. + 72.4 ml, maximum workrate + 20.0 watts vs. + 5.7 W), of the anaerobic threshold (AT improved by 8.4 watts vs. 5.1 W) as well as in the metabolic load (lactate decreased by 1.3 mmol vs. 0.2 mmol, ventilation decreased by 3.8 l/min vs. 2.3 l/min). In most subscales of the SF-36 questionnaire quality of living improved more clearly in the training group, whereas the LAQ questionnaire showed no group-specific differences and no improvement after training. CONCLUSION: We conclude from the result that a high intensity training program can be recommended as a useful and low-risk component in pulmonary rehabilitation programs.

Attosecond metrology.

The generation of ultrashort pulses is a key to exploring the dynamic behaviour of matter on ever-shorter timescales. Recent developments have pushed the duration of laser pulses close to its natural limit-the wave cycle, which lasts somewhat longer than one femtosecond (1 fs = 10-15 s) in the visible spectral range. Time-resolved measurements with these pulses are able to trace dynamics of molecular structure, but fail to capture electronic processes occurring on an attosecond (1 as = 10-18 s) timescale. Here we trace electronic dynamics with a time resolution of

Quantum transport in nonuniform magnetic fields: Aharonov-Bohm ring as a spin switch.

We study spin-dependent magnetoconductance in mesoscopic rings subject to an inhomogeneous in-plane magnetic field. We show that the polarization direction of transmitted spin-polarized electrons can be controlled via an additional magnetic flux such that spin flips are induced at half a flux quantum. This quantum interference effect is independent of the strength of the nonuniform field applied. We give an analytical explanation for one-dimensional rings and numerical results for corresponding ballistic microstructures.

X-ray pulses approaching the attosecond frontier.

Single soft-x-ray pulses of approximately 90-electron volt (eV) photon energy are produced by high-order harmonic generation with 7-femtosecond (fs), 770-nanometer (1.6 eV) laser pulses and are characterized by photoionizing krypton in the presence of the driver laser pulse. By detecting photoelectrons ejected perpendicularly to the laser polarization, broadening of the photoelectron spectrum due to absorption and emission of laser photons is suppressed, permitting the observation of a laser-induced downshift of the energy spectrum with sub-laser-cycle resolution in a cross correlation measurement. We measure isolated x-ray pulses of 1.8 (+0.7/-1.2) fs in duration, which are shorter than the oscillation cycle of the driving laser light (2.6 fs). Our techniques for generation and measurement offer sub-femtosecond resolution over a wide range of x-ray wavelengths, paving the way to experimental attosecond science. Tracing atomic processes evolving faster than the exciting light field is within reach.

Multiple beam interference in a quadrupolar glass fiber.

Motivated by the recent observation of periodic filter characteristics of an oval-shaped microcavity, we study the possible interference of multiple beams in the far field of a laser-illuminated quadrupolar glass fiber. From numerical ray-tracing simulations we obtain the interference-relevant length-difference spectrum and compare it with data extracted from the experimental filter results. Our analysis reveals that different polygonal cavity modes that are refractively output coupled in the high-curvature region of the fiber contribute to the observed far-field interference.

Femtosecond X-Ray fluorescence

Using few-cycle-driven coherent laser harmonics, K-shell vacancies have been created in light elements, such as boron (E(B) = 188 eV) and carbon (E(B) = 284 eV), on a time scale of a few femtoseconds for the first time. The capability of detecting x-ray fluorescence excited by few-femtosecond radiation with an accuracy of the order of 1 eV paves the way for probing the evolution of the microscopic environment of selected atoms in chemical and biochemical reactions on previously inaccessible time scales (<100 fs) by tracing the temporal evolution of the "chemical shift" of peaks associated with inner-shell electronic transitions in time-resolved x-ray fluorescence and photoelectron spectra.