Pembrolizumab Achieves a Complete Response in an NF-1 Mutated, PD-L1 Positive Malignant Peripheral Nerve Sheath Tumor: A Case Report and Review of the Benchmarks.

Malignant peripheral nerve sheath tumors (MPNSTs) represent a rare subtype of neural crest cell-derived soft tissue sarcomas (STS). Standard of care therapy comprises surgical resection followed by adjuvant radiation, and most clinical studies have demonstrated finite survival benefit of radiation and chemotherapy. In metastatic disease, palliative chemotherapy provides very limited efficacy. We report a 60-year-old male patient with a primary para vertebral tumor at T7-T8 with lung metastases who recurred after surgical resection and later progressed on epirubicin plus ifosfamide. He was an international patient and referred to the phase 1 clinic. Molecular profiling and immunohistochemistry of the tumor revealed a PD-L1 expression of 70% (2+) and pathogenic genetic alterations by next-generation sequencing in ARID1A, CDKN2A, KMT2A, NF1, and TP53. Immune checkpoint therapy (ICT) with pembrolizumab was commenced, and interval computed tomography revealed a complete remission by cycle 6. Randomized clinical trials illustrate that ICTs such as anti-PD-1 and anti-CTLA4 monoclonal antibodies in STS cohorts display low or modest response rates by variable PD-L1 expression. This and 3 other case reports of disparate PD-L1 expression demonstrate complete responses in PD-L1 positive MPNSTs treated with ICT. These case reports necessitate further study of ICT in neural crest cell subtype of STS.

A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation.

Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low-level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entrée into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material.

A geographical study of thyroid cancer incidence in north-west England following the Windscale nuclear reactor fire of 1957.

The Windscale nuclear reactor fire at Sellafield, United Kingdom, in October 1957 led to an uncontrolled release of iodine-131 (radioactive half-life, 8 d) into the atmosphere. Contamination from the accident was most pronounced in the counties of Cumbria and Lancashire, north-west England. Radioiodine concentrates in the thyroid gland producing an excess risk of thyroid cancer, notably among those exposed as children, which persists into later life. For an initial investigation of thyroid cancer incidence in north-west England, data were obtained on cases of thyroid cancer among people born during 1929-1973 and diagnosed during 1974-2012 while resident in England, together with corresponding populations. Incidence rate ratios (IRRs), with Poisson 95% confidence intervals (CIs), compared thyroid cancer incidence rates in Cumbria and in Lancashire with those in the rest of England. For those aged <20 years in 1958, a statistically significantly increased IRR was found for those diagnosed during 1974-2012 while living in Cumbria (IRR = 1.29; 95% CI 1.09-1.52), but the equivalent IRR for Lancashire was marginally non-significantly decreased (IRR = 0.91; 95% CI 0.80-1.04). This pattern of IRRs was also apparent for earlier births, and the significantly increased IRR in Cumbria extended to individuals born in 1959-1963, who would not have been exposed to iodine-131 from the Windscale accident. Moreover, significant overdispersion was present in the temporal distributions of the IRRs, so that Poisson CIs substantially underestimate statistical uncertainties. Consequently, although further investigations are required to properly understand the unusual patterns of thyroid cancer IRRs in Cumbria and Lancashire, the results of this preliminary study are not consistent with an effect of exposure to iodine-131 from the Windscale accident.

Breaking free from chemical spreadsheets.

Drug discovery scientists often consider compounds and data in terms of groups, such as chemical series, and relationships, representing similarity or structural transformations, to aid compound optimisation. This is often supported by chemoinformatics algorithms, for example clustering and matched molecular pair analysis. However, chemistry software packages commonly present these data as spreadsheets or form views that make it hard to find relevant patterns or compare related compounds conveniently. Here, we review common data visualisation and analysis methods used to extract information from chemistry data. We introduce a new framework that enables scientists to work flexibly with drug discovery data to reflect their thought processes and interact with the output of algorithms to identify key structure-activity relationships and guide further optimisation intuitively.

Evaluation of six TPS algorithms in computing entrance and exit doses.

Entrance and exit doses are commonly measured in in vivo dosimetry for comparison with expected values, usually generated by the treatment planning system (TPS), to verify accuracy of treatment delivery. This report aims to evaluate the accuracy of six TPS algorithms in computing entrance and exit doses for a 6 MV beam. The algorithms tested were: pencil beam convolution (Eclipse PBC), analytical anisotropic algorithm (Eclipse AAA), AcurosXB (Eclipse AXB), FFT convolution (XiO Convolution), multigrid superposition (XiO Superposition), and Monte Carlo photon (Monaco MC). Measurements with ionization chamber (IC) and diode detector in water phantoms were used as a reference. Comparisons were done in terms of central axis point dose, 1D relative profiles, and 2D absolute gamma analysis. Entrance doses computed by all TPS algorithms agreed to within 2% of the measured values. Exit doses computed by XiO Convolution, XiO Superposition, Eclipse AXB, and Monaco MC agreed with the IC measured doses to within 2%-3%. Meanwhile, Eclipse PBC and Eclipse AAA computed exit doses were higher than the IC measured doses by up to 5.3% and 4.8%, respectively. Both algorithms assume that full backscatter exists even at the exit level, leading to an overestimation of exit doses. Despite good agreements at the central axis for Eclipse AXB and Monaco MC, 1D relative comparisons showed profiles mismatched at depths beyond 11.5 cm. Overall, the 2D absolute gamma (3%/3 mm) pass rates were better for Monaco MC, while Eclipse AXB failed mostly at the outer 20% of the field area. The findings of this study serve as a useful baseline for the implementation of entrance and exit in vivo dosimetry in clinical departments utilizing any of these six common TPS algorithms for reference comparison.

Calculation of exit dose for conformal and dynamically-wedged fields, based on water-equivalent path length measured with an amorphous silicon electronic portal imaging device.

In this study, we use the quadratic calibration method (QCM), in which an EPID image is converted into a matrix of equivalent path lengths (EPLs) and, therefore, exit doses, so as to model doses in conformal and enhanced dynamic wedge (EDW) fields. The QCM involves acquiring series of EPID images at a reference field size for different thicknesses of homogeneous solid water blocks. From these, a set of coefficients is established that is used to compute the EPL of any other irradiated material. To determine the EPL, the irradiated area must be known in order to establish the appropriate scatter correction. A method was devised for the automatic calculation of areas from the EPID image that facilitated the calculation of EPL for any field and exit dose. For EDW fields, the fitting coefficients were modified by utilizing the linac manufacturer's golden segmented treatment tables (GSTT) methodology and MU fraction model. The nonlinear response of the EPL with lower monitor units (MUs) was investigated and slight modification of the algorithm performed to account for this. The method permits 2D dose distributions at the exit of phantom or patient to be generated by relating the EPL with an appropriate depth dose table. The results indicate that the inclusion of MU correction improved the EPL determination. The irradiated field areas can be accurately determined from EPID images to within ± 1% uncertainty. Cross-plane profiles and 2D dose distributions of EPID predicted doses were compared with those calculated with the Eclipse treatment planning system (TPS) and those measured directly with MapCHECK 2 device. Comparison of the 2D EPID dose maps to those from TPS and MapCHECK shows that more than 90% of all points passed the gamma index acceptance criteria of 3% dose difference and 3 mm distance to agreement (DTA), for both conformal and EDW study cases. We conclude that the EPID QCM is an accurate and convenient method for in vivo dosimetry and may, therefore, complement existing techniques.

Reconstructing the abundance of Dounreay hot particles on an adjacent public beach in Northern Scotland.

Following the discovery of a number of hot particles in the offshore environment of Dounreay on the North Coast of Scotland in 1997, the Dounreay site operator was required to introduce rapid and extensive beach monitoring. Since the introduction of vehicular based beach monitoring in 1999 there have been two further generations of beach monitoring equipment, developed to satisfy regulatory requirements for particle detection and in response to the recommendations of the Dounreay Particles Advisory Group (DPAG). This paper reports the results of DPAG's review of beach monitoring capabilities, evaluating the factors influencing detection capability, assessing the likely monthly particle abundance and whether there has been any real change in particle arrivals with time. The incorporation of real time kinematic GPS has enabled changes in beach elevation to be mapped, and thus allowed the assessment of whether particles detected have recently arrived or may have been buried undisturbed for extended periods of time. The results focus on Sandside Beach from which, between 1984 and December 2009, 150 particles have been recovered. This is by far the largest number of particles found on a Caithness Beach with the exception of the Foreshore of the Dounreay site. The results suggested that there is no evidence for a change in the rate of particle arrivals and DPAG estimated that there is a 1 in 20 million chance of encountering a relevant particle via contact with the skin on Sandside Beach.

A novel method for patient exit and entrance dose prediction based on water equivalent path length measured with an amorphous silicon electronic portal imaging device.

In vivo dosimetry is one of the quality assurance tools used in radiotherapy to monitor the dose delivered to the patient. Electronic portal imaging device (EPID) images for a set of solid water phantoms of varying thicknesses were acquired and the data fitted onto a quadratic equation, which relates the reduction in photon beam intensity to the attenuation coefficient and material thickness at a reference condition. The quadratic model is used to convert the measured grey scale value into water equivalent path length (EPL) at each pixel for any material imaged by the detector. For any other non-reference conditions, scatter, field size and MU variation effects on the image were corrected by relative measurements using an ionization chamber and an EPID. The 2D EPL is linked to the percentage exit dose table, for different thicknesses and field sizes, thereby converting the plane pixel values at each point into a 2D dose map. The off-axis ratio is corrected using envelope and boundary profiles generated from the treatment planning system (TPS). The method requires field size, monitor unit and source-to-surface distance (SSD) as clinical input parameters to predict the exit dose, which is then used to determine the entrance dose. The measured pixel dose maps were compared with calculated doses from TPS for both entrance and exit depth of phantom. The gamma index at 3% dose difference (DD) and 3 mm distance to agreement (DTA) resulted in an average of 97% passing for the square fields of 5, 10, 15 and 20 cm. The exit dose EPID dose distributions predicted by the algorithm were in better agreement with TPS-calculated doses than phantom entrance dose distributions.

Investigation of 18F-FDG 3D mode PET image quality versus acquisition time.

OBJECTIVE: Three-dimensional (3D) mode positron emission tomography (PET) is being used increasingly for clinical PET imaging. However, as yet, optimal acquisition parameters have not been established. The aim of this study was to investigate the effect of varying acquisition time on 3D image quality using standard clinical activities of F-fluorodeoxyglucose (FDG). METHODS: F-FDG phantom and patient PET images were acquired with varying acquisition times on a GE Discovery-STE PET/CT system. The NEMA Image-Quality phantom was imaged with four hot lesions in a uniform background. Images were acquired for 1, 2, 3, 4, and 5-min frames with three different lesion-to-background contrast ratios. Patient data were investigated using list mode acquisition to obtain comparable 2, 3, and 4-min frames. Qualitative analysis involved grading image quality and lesion detectability. Quantitative analysis of phantom images involved assessing the coefficient of variation (COV) of background areas as a measure of noise, and lesion over background variability as a measure of image quality. Patient data were also assessed using COV analysis of liver uptake. RESULTS: Qualitative and quantitative analysis showed no significant difference in image quality between 4 and 5-min acquisition frames for 3D mode F-FDG PET imaging with standard clinical activities. The observers noted no difference in perceived image quality. This finding was supported by COV analysis. CONCLUSION: This study shows that GE Discovery-STE acquisition frame time can be reduced to 3 min for standard 3D mode imaging at standard clinical activities of F-FDG.

Issues in medical exposures.

Medical exposures account, on average, for some 14% of the background ionising radiation exposure in the UK and form the great majority of the non-natural component. In the United States of America, medical exposures comprised over 50% of the total in 2006. This is due primarily to an increase in x-ray computed tomography (CT) and positron emission tomography (PET) procedures. This paper highlights the potential problems in the use of CT scanning to investigate the asymptomatic individual, where the traditional risk/benefit considerations are less clear-cut than in conventional clinical situations. It draws on a recent COMARE report which examined the use of CT for whole body, heart, lung and colon studies. The number of PET facilities is increasing rapidly in the UK and, in addition to considerations of radiation dose to subjects, careful planning is necessary to limit doses to staff. In non-ionising radiation, a topic of keen interest at present is the use of increasingly powerful sunbeds, particularly by those aged under 18. Legislation and regulation vary widely across Europe and the Scottish Parliament has recently introduced the first UK regulation. It is suggested that further research is required into the effects of current UV systems and the reasons why tanning is thought so desirable by Caucasians. Lastly, a number of issues requiring radiobiological and epidemiological input are considered and actions to satisfy these identified.

Assessment of dosimetrical performance in 11 Varian a-Si-500 electronic portal imaging devices.

Dosimetrical characteristics of 11 Varian a-Si-500 electronic portal imaging devices (EPIDs) in clinical use for periods ranging between 10 and 86 months were investigated for consistency of performance and portal dosimetry implications. Properties studied include short-term reproducibility, signal linearity with monitor units, response to reference beam, signal uniformity across the detector panel, signal dependence on field size, dose-rate influence, memory effects and image profiles as a function of monitor units. The EPID measurements were also compared with those of the ionization chambers' to ensure stability of the linear accelerators. Depending on their clinical installation date, the EPIDs were interfaced with one of the two different acquisition control software packages, IAS2/IDU-II or IAS3/IDU-20. Both the EPID age and image acquisition system influenced the dosimetric characteristics with the newer version (IAS3 with IDU-20) giving better data reproducibility and linearity fit than the older version (IAS2 with IDU-II). The relative signal response (uniformity) after 50 MU was better than 95% of the central value and independent of detector. Sensitivity for all EPIDs reduced continuously with increasing dose rates for the newer image acquisition software. In the dose-rate range 100-600 MU min(-1), the maximum variation in sensitivity ranged between 1 and 1.8% for different EPIDs. For memory effects, the increase in the measured signal at the centre of the irradiated field for successive images was within 1.8% and 1.0% for the older and newer acquisition systems, respectively. Image profiles acquired at a lower MU in the radial plane (gun-target) had gradients in measured pixel values of up to 25% for the older system. Detectors with software/hardware versions IAS3/IDU-20 have a high degree of accuracy and are more suitable for routine quantitative IMRT dosimetrical verification.

Determination of left ventricular long-axis orientation using MRI: changes during the respiratory and cardiac cycles in normal and diseased subjects.

BACKGROUND: It has previously been shown that magnetic resonance imaging (MRI) can be used to accurately determine left ventricular (LV) long-axis orientation in healthy individuals. However, the inter- and intra-observer variability in patients with acute coronary syndrome (ACS) and chronic heart failure (CHF) has not been explored. Furthermore, the changes in LV long-axis orientation because of respiration and during the cardiac cycle remain to be determined. METHODS: LV long-axis orientation was determined by MRI in the frontal and transverse planes in 44 subjects with no cardiac disease, 20 ACS patients and 13 CHF patients. Changes in LV long-axis orientation because of respiration were assessed in a subset of 25 subjects. Changes during the cardiac cycle were assessed in six subjects from each subject group. Reproducibility was assessed by a re-examination of 17 subjects after 28 days. RESULTS: The inter- and intra-observer variability for LV long-axis orientation was low for all subject groups. The difference between the baseline and the 28 days examinations was -1.4+/-5.9 degrees and -0.8+/-4.4 degrees in the frontal and transverse planes, respectively. No significant change in LV long-axis orientation was found between end-expiration and end-inspiration (frontal plane, P=0.63 and transverse plane, P=0.42; n=25). No significant difference in change of the LV long-axis orientation during the cardiac cycle was found between the subject groups (frontal plane, chi-square 1.8, P=0.40 and transverse plane, chi-square 5.7, P=0.06). CONCLUSIONS: There is a low inter-and intra-observer variability and a high reproducibility for determining LV long-axis orientation in patients with no cardiac disease as well as in patients with ACS or CHF. There is no significant change in LV long-axis orientation due to respiration, and only small changes during the cardiac cycle in these groups.

Investigation of the effect of subcutaneous fat on image quality performance of 2D conventional imaging and tissue harmonic imaging.

Tissue harmonic imaging (THI) has been reported to improve contrast resolution, tissue differentiation and overall image quality in clinical examinations. However, a study carried out previously by the authors (Brown et al. 2004) found improvements only in spatial resolution and not in contrast resolution or anechoic target detection. This result may have been due to the homogeneity of the phantom. Biologic tissues are generally inhomogeneous and THI has been reported to improve image quality in the presence of large amounts of subcutaneous fat. The aims of the study were to simulate the distortion caused by subcutaneous fat to image quality and thus investigate further the improvements reported in anechoic target detection and contrast resolution performance with THI compared with 2D conventional imaging. In addition, the effect of three different types of fat-mimicking layer on image quality was examined. The abdominal transducer of two ultrasound scanners with 2D conventional imaging and THI were tested, the 4C1 (Aspen-Acuson, Siemens Co., CA, USA) and the C5-2 (ATL HDI 5000, ATL/Philips, Amsterdam, The Netherlands). An ex vivo subcutaneous pig fat layer was used to replicate beam distortion and phase aberration seen clinically in the presence of subcutaneous fat. Three different types of fat-mimicking layers (olive oil, lard and lard with fish oil capsules) were evaluated. The subcutaneous pig fat layer demonstrated an improvement in anechoic target detection with THI compared with 2D conventional imaging, but no improvement was demonstrated in contrast resolution performance; a similar result was found in a previous study conducted by this research group (Brown et al. 2004) while using this tissue-mimicking phantom without a fat layer. Similarly, while using the layers of olive oil, lard and lard with fish oil capsules, improvements due to THI were found in anechoic target detection but, again, no improvements were found for contrast resolution for any of the layer combinations. Therefore, it was felt that the lack of improvement in contrast resolution performance may be due to the test phantom design and not to whether a layer was present that caused beam distortion and phase aberrations.

Long-lived radiopharmaceuticals: dispensing from multidose vials.

We report the use of broth simulation as a means of validating the practice of sub-dispensing from stock vials of long-lived sterile radiopharmaceuticals. 'Matched' vials of nutrient broth accompanied the stock vials of long-lived sterile radiopharmaceuticals during their time in use and were subject to the same handling and storage procedures. At the end of the life of each radiopharmaceutical stock vial, the matching broth residue was sent for incubation and reporting. The results to date have yielded no reports of microbial contamination in any of the simulated broths (0 in 256).

Validation of a sensitivity performance index test protocol and evaluation of colour Doppler sensitivity for a range of ultrasound scanners.

The ability to detect flow is the most crucial aspect of an ultrasound (US) system because, if flow cannot be detected, no other aspect of performance matters. The objectives of this study were to validate a Doppler "sensitivity performance index," a figure of merit, and to determine if it could be used to differentiate colour Doppler sensitivity performance in scanners of varying complexity. The sensitivity performance index was developed to give a combined measure of related aspects of sensitivity, such as the lowest detectable velocity, the vessel size and the penetration depth. The colour Doppler sensitivity was evaluated objectively as the lowest detectable velocity signal from the deepest achievable point within the Doppler sensitivity phantom free from extraneous noise in a small diameter vessel (3.2 mm inner diameter). The effect of vessel size and mean velocity on the sensitivity performance index were investigated and it was found that the index was not proportional to vessel size, but this may be accounted for by considering the effect of the acoustic properties of the vessel material, the clutter filter and beam shape. The results obtained using flow phantoms with vessel sizes different from those used in this study are, therefore, not directly comparable to the results found in this study; however, a similar trend should be found in the results for the effect of control settings and a similar range of US scanners. It was found that the Doppler sensitivity performance index was a robust challenging test because none of the US scanners evaluated was capable of achieving the highest sensitivity performance index score, which would be limited by the lowest pump velocity and the deepest point of the vessel within the flow phantom. Therefore, this suggests that this method of determining Doppler sensitivity performance is valuable in the absence of other suitable methods, despite the fact that the relationship between the sensitivity performance index and vessel size is not proportional. Furthermore, use of the Doppler sensitivity performance index for the evaluation of a range of scanners demonstrated that curvilinear transducers have higher sensitivity performance indices than higher-frequency linear transducers, due to the higher achievable penetration depth. The effect of instrument settings was assessed for two transducers, the 4C3 curvilinear general-purpose transducer (Aspen) and the PVM375AT curvilinear general-purpose transducer (Nemio). The colour Doppler sensitivity performance was found to be significantly dependent on the clutter filter setting and the output power setting for both transducers tested. Users need to be aware of the effect of these settings on the colour Doppler sensitivity performance of their US scanner when interpreting the clinical significance of the colour Doppler information.