Synthese

Some fallibilist knowledge: Questioning knowledge-attributions and open knowledge Abstract We may usefully distinguish between one's having fallible knowledge and having a fallibilist stance on some of one's knowledge. A fallibilist stance could include a concessive knowledge-attribution (CKA). But it might also include a questioning knowledge-attribution (QKA). Attending to the idea of a QKA leads to a distinction between what we may call closed knowledge that p and open knowledge that p. All of this moves us beyond Elgin's classic tale of the epistemic capacities of Holmes and of Watson, and towards a way of resolving Kripke's puzzle about dogmatism and knowing.

What we cannot learn from analogue experiments Abstract Analogue experiments have attracted interest for their potential to shed light on inaccessible domains. For instance, 'dumb holes' in fluids and Bose–Einstein condensates, as analogues of black holes, have been promoted as means of confirming the existence of Hawking radiation in real black holes. We compare analogue experiments with other cases of experiment and simulation in physics. We argue—contra recent claims in the philosophical literature—that analogue experiments are not capable of confirming the existence of particular phenomena in inaccessible target systems. As they must assume the physical adequacy of the modelling framework used to describe the inaccessible target system, arguments to the conclusion that analogue experiments can yield confirmation for phenomena in those target systems, such as Hawking radiation in black holes, beg the question.

Error possibility, contextualism, and bias Abstract A central theoretical motivation for epistemic contextualism is that it can explain something that invariantism cannot. Specifically, contextualism claims that judgments about "knowledge" are sensitive to the salience of error possibilities and that this is explained by the fact that salience shifts the evidential standard required to truthfully say someone "knows" something when those possibilities are made salient. This paper presents evidence that undermines this theoretical motivation for epistemic contextualism. Specifically, it demonstrates that while error salience does sometimes impact "knowledge" judgments as contextualism predicts, it does so in ways that are consistent with invariantism and does not require positing any additional contextualist semantics to explain. These results advance our understanding of the pathways by which error possibility affects "knowledge" judgments, answer a major challenge to invariantism, and suggest several methodological improvements for the study of knowledge attribution.

Explaining the behaviour of random ecological networks: the stability of the microbiome as a case of integrative pluralism Abstract Explaining the behaviour of ecosystems is one of the key challenges for the biological sciences. Since 2000, new-mechanism has been the main model to account for the nature of scientific explanation in biology. The universality of the new-mechanist view in biology has been however put into question due to the existence of explanations that account for some biological phenomena in terms of their mathematical properties (mathematical explanations). Supporters of mathematical explanation have argued that the explanation of the behaviour of ecosystems is usually provided in terms of their mathematical properties, and not in mechanistic terms. They have intensively studied the explanation of the properties of ecosystems that behave following the rules of a non-random network. However, no attention has been devoted to the study of the nature of the explanation in those that form a random network. In this paper, we cover that gap by analysing the explanation of the stability behaviour of the microbiome recently elaborated by Coyte and colleagues, to determine whether it fits with the model of explanation suggested by the new-mechanists or by the defenders of mathematical explanation. Our analysis of this case study supports three theses: (1) that the explanation is not given solely in terms of mechanisms, as the new-mechanists understand the concept; (2) that the mathematical properties that describe the system play an essential explanatory role, but they do not exhaust the explanation; (3) that a non-previously identified appeal to the type of interactions that the entities in the network can exhibit, as well as their abundance, is also necessary for Coyte and colleagues' account to be fully explanatory. From the combination of these three theses we argue for the necessity of an integrative pluralist view of the nature of behaviour explanation when this is given by appealing to the existence of a random network.

Causal concepts and temporal ordering Abstract Though common sense says that causes must temporally precede their effects, the hugely influential interventionist account of causation makes no reference to temporal precedence. Does common sense lead us astray? In this paper, I evaluate the power of the commonsense assumption from within the interventionist approach to causal modeling. I first argue that if causes temporally precede their effects, then one need not consider the outcomes of interventions in order to infer causal relevance, and that one can instead use temporal and probabilistic information to infer exactly when X is causally relevant to Y in each of the senses captured by Woodward's interventionist treatment. Then, I consider the upshot of these findings for causal decision theory, and argue that the commonsense assumption is especially powerful when an agent seeks to determine whether so-called "dominance reasoning" is applicable.

An ecumenical notion of entailment Abstract Much has been said about intuitionistic and classical logical systems since Gentzen's seminal work. Recently, Prawitz and others have been discussing how to put together Gentzen's systems for classical and intuitionistic logic in a single unified system. We call Prawitz' proposal the Ecumenical System, following the terminology introduced by Pereira and Rodriguez. In this work we present an Ecumenical sequent calculus, as opposed to the original natural deduction version, and state some proof theoretical properties of the system. We reason that sequent calculi are more amenable to extensive investigation using the tools of proof theory, such as cut-elimination and rule invertibility, hence allowing a full analysis of the notion of Ecumenical entailment. We then present some extensions of the Ecumenical sequent system and show that interesting systems arise when restricting such calculi to specific fragments. This approach of a unified system enabling both classical and intuitionistic features sheds some light not only on the logics themselves, but also on their semantical interpretations as well as on the proof theoretical properties that can arise from combining logical systems.

Hinge epistemology and the prospects for a unified theory of knowledge Abstract I defend two theses here. First, I argue that at least many of the commitments that Wittgenstein identifies as "hinge commitments" are plausibly what cognitive psychology and artificial intelligence call "procedural knowledge." Procedural knowledge can be implemented in cognitive systems in a variety of ways, and these modes of implementation, I argue, predict several properties of Wittgensteinian hinge commitments, including their functional profile, as well as other of their characteristic features. Second, I argue that thinking of hinge commitments as a kind of procedural knowledge allows a unified virtue-theoretic treatment of the generation of knowledge, the transmission of knowledge, and Wittgensteinian "hinge knowledge." This last thesis is noteworthy, in that Wittgenstein and his defenders have so far failed to offer any unified epistemology of hinge commitments and the knowledge that such commitments are supposed to make possible.

Infinitesimal idealization, easy road nominalism, and fractional quantum statistics Abstract It has been recently debated whether there exists a so-called "easy road" to nominalism. In this essay, I attempt to fill a lacuna in the debate by making a connection with the literature on infinite and infinitesimal idealization in science through an example from mathematical physics that has been largely ignored by philosophers. Specifically, by appealing to John Norton's distinction between idealization and approximation, I argue that the phenomena of fractional quantum statistics bears negatively on Mary Leng's proposed path to easy road nominalism, thereby partially defending Mark Colyvan's claim that there is no easy road to nominalism.

Combining finite and infinite elements: Why do we use infinite idealizations in engineering? Abstract This contribution sheds light on the role of infinite idealization in structural analysis, by exploring how infinite elements and finite element methods are combined in civil engineering models. This combination, I claim, should be read in terms of a 'complementarity function' through which the representational ideal of completeness is reached in engineering model-building. Taking a cue from Weisberg's definition of multiple-model idealization, I highlight how infinite idealizations are primarily meant to contribute to the prediction of structural behavior in Multiphysics approaches.

Minimal approximations and Norton's dome Abstract In this note, I apply Norton's (Philos Sci 79(2):207–232, 2012) distinction between idealizations and approximations to argue that the epistemic and inferential advantages often taken to accrue to minimal models (Batterman in Br J Philos Sci 53:21–38, 2002) could apply equally to approximations, including "infinite" ones for which there is no consistent model. This shows that the strategy of capturing essential features through minimality extends beyond models, even though the techniques for justifying this extended strategy remain similar. As an application I consider the justification and advantages of the approximation of a inertial reference frame in Norton's dome scenario (Philos Sci 75(5):786–798, 2008), thereby answering a question raised by Laraudogoitia (Synthese 190(14):2925–2941, 2013).

Environmental Monitoring and Assessment

Risk assessment of heavy metal contamination of paddy soil and rice ( Oryza sativa ) from Abakaliki, Nigeria Abstract The study assessed the concentration and bioavailability of Pb, Cd, Zn, Cr and Fe metals in soil from rice fields in Abakaliki, Nigeria. The concentrations of these heavy metals in rice grains were also determined, with a view to assessing their human health risk on consumers. Heavy metal concentrations in soil and rice were determined using FAAS after digestion with 5:1 HNO3:HClO4 while Tessier's sequential extraction method was used to obtain the fractionated soil digests. The mean concentrations (μg/g) of the total heavy metal ranged from 1.036 ± 1.86 (Cd) to 6900.537 ± 734.82 (Fe) in soil while that of rice grains ranged from 0.024 ± 0.07 (Cd) to 101.446 ± 75.26 (Fe).The concentrations of Fe and Cd in most of the soil samples and Pb in rice grains exceeded some Nigerian and International standards. The heavy metal sequential extractions of soil samples showed that lead and zinc were less mobile in the soil and are bioavailable for plant uptake. The estimated daily intake of the metals was below the tolerable daily intake. The hazard quotient and the total hazard index were less than one showing that at present, there is no possible adverse health effect on rice consumers.

Optimization of treating phenol from wastewater through the TiO 2 -catalyzed advanced oxidation process and response surface methodology Abstract The use of dispersed catalysts in aqueous medium inside reactors in advanced oxidative processes is common among researchers. However, due to the difficult separation of these species after treatment, in many cases, the treatment process is unfeasible. In this context, the main target of the work was the evaluation of degradation of the phenolic solution by ozonation titanium dioxide (TiO2/P25), supported on zeolite spheres. The process was investigated through the response surface methodology (RSM) and optimized by the generalized reduced gradient (GRG) algorithm. The effects of various operating parameters including pH, power ozone (O3) generation, flow rate, and treatment time were investigated, using as a response to removal of chemical oxygen demand (COD). It was made in optimum conditions the ratio of biochemical oxygen demand (BOD)/chemical oxygen demand to check the increasing biodegradability, aiming ozonation as preliminary treatment, with the possibility of subsequent biological treatments. There was an increase in this ratio from 0.17 to 0.50 in 48 min, which would facilitate the use of the subsequent biological process. The proposed model showed good fit to the experimental data with R2 and R2adj correlation coefficients of 0.9964 and 0.9932, respectively.

Assessing water-quality changes in US rivers at multiple geographic scales using results from probabilistic and targeted monitoring Abstract Two commonly used approaches for water quality monitoring are probabilistic and targeted. In a probabilistic approach like the US Environmental Protection Agency's National Rivers and Streams Assessment, monitoring sites are selected using a statistically representative approach. In a targeted approach like that used by many monitoring organizations, monitoring sites are chosen individually to answer specific questions. One important goal of both approaches is documenting long-term changes in water quality. Here, we compare chloride change results in US rivers and streams between the early 2000s and early 2010s from both approaches. The probabilistic approach provided an unbiased representation of change in all US rivers and streams, but was designed to measure low-streamflow conditions within a spring/summer index period during periodic survey years. The targeted approach was focused on larger, more developed watersheds but samples were collected frequently throughout the assessment period in different seasons and streamflows. The probabilistic results showed a small decrease in chloride concentrations in rivers and streams with the lowest concentrations, but no consistent increase or decrease in the remainder. The increased granularity of the targeted results showed that there was, in fact, a mix of changes occurring, with increases at 132 sites, decreases at 112 sites, and relatively stable conditions at 55 sites. The combined results suggest that chloride is not responding to a widespread, common driver across the USA and that management of chloride would be most effective when targeted regionally or locally.

Assessment of Typha capensis for the remediation of soil contaminated with As, Hg, Cd and Pb Abstract The use of macrophytes has been identified as one of the eco-friendly means of remediating soils contaminated with heavy metal(loid)s. This study sought to ascertain the synergistic influences of Hg, As, Cd and Pb on the uptake capacity of Typha capensis in remediating soils contaminated with these pollutants. Uptake of Hg, As, Cd and Pb by this aquatic plant species in metal(loid)-contaminated water and soil was studied in batch culture experiment. The plants were irrigated with standard heavy metal(loid)-simulated solutions. After 20, 40 and 60 days, plant samples were subjected to heavy metal(loid) analysis by a Unicam 969 atomic absorption spectrometer (AAS). The macrophytes were able to remediate all the four selected heavy metal(loid)s when they either existed as individual or when all the four were in the solution; however, the level of uptake by the plant was inhibited when either two of the heavy metals existed in the solution. Typha capensis performs better in the absorption of mercury, arsenic, cadmium and lead in large quantities from polluted water and soil.

Multi-criteria decision model for assessing groundwater pollution risk in the urban-rural interface of Mar del Plata City (Argentina) Abstract In developing countries, conflict between the objectives of environmental policies and those focused on economic development, a low availability of human resources and infrastructure, and the lack of continuity and incentives, contribute to the inability to successfully implement environmental policies. Moreover, in these countries, population growth in the peri-urban areas has resulted in serious water pressures, poor water management, and severe non-point source pollution. The aim of this paper is to implement a procedure of aquifer pollution risk assessment for identifying priority areas in an urban-rural interface based on multi-criteria decision tools. In this sense, a multi-criteria decision model was designed, in terms of environmental and socio-economic criteria and sub-criteria relevant to water resource management, by using the software Criterium Decision Plus 4.0. This model was applied to the northwestern peri-urban area of Mar del Plata City, Argentina, which is embedded in the second most important fruit-horticultural belt of the country. Here, groundwater is the only source of water supply. The proposed decision model allowed establishing a ranking of priority areas for defining action guidelines in order to minimize the risk of pollution of the aquifer. Aquifer pollution hazard criterion mainly contributes to alternatives classified as very high priority whilst in the case of low and very low priority classes, social vulnerability criterion mostly influences the final results. The first alternatives will require an intervention in a short-term time horizon, and the last ones must be monitored in order to avoid their shift to a worse environmental condition.

Distribution characteristics and health risk assessment of heavy metals and PAHs in the soils of green spaces in Shanghai, China Abstract The environmental sustainability of megacities is a global problem, and megacities are experiencing increasing pressure and challenges with regard to providing a suitable living environment for people. Urban green space plays a crucial role in protecting urban ecological environments and in maintaining the physical and mental health of residents. In this study, a total of 94 soil samples from green spaces in Shanghai, including park green spaces and road green spaces in the eight central urban districts, were collected, and the contents of heavy metals and polycyclic aromatic hydrocarbons (PAHs) were analyzed to determine the distribution characteristics and influencing factors and to assess the associated health risks. The accumulation of heavy metals was greater in park green space soils than in road green space soils, although the variation coefficient of the former was lower than that of the latter. Conversely, the accumulation of PAHs was lower in park green space soils than that in road green space soils, although the variation coefficient of the former was higher than that of the latter. In particular, Cu, Zn, Pb, Cd, As, and PAHs have accumulated in Shanghai green space soils. With increasing soil depth (0–2 cm, 2–5 cm, 5–10 cm, and 10–30 cm), the PAH content increased in the park green space soils but decreased in the road green space soils. According to the "Technical guidelines for risk assessment of contaminated sites (MEP of China 2014)," the overall health risk posed by green space soils in urban areas in Shanghai can be considered safe, except at individual sampling sites. The PAH, Cu, and Zn contents of park green space soils might be related to the application of organic materials and to traffic and industry emissions. However, the soil pollutants in road green spaces are predominantly related to traffic and industrial emissions. Therefore, the monitoring and management of soil environmental quality must be strengthened.

Runoff simulation of two typical urban green land types with the Stormwater Management Model (SWMM): sensitivity analysis and calibration of runoff parameters Abstract The characteristics of surface runoff and the infiltration properties of urban green land are important to determine the effects of runoff reduction by low-impact development (LID) facilities. In this paper, two typical types of urban green land (lawn and shrub) in Shanghai were selected to study the runoff characteristics under eight rainfall events. The sensitivity of the runoff parameters was analyzed, and then, the optimal parameters were determined using the Stormwater Management Model (SWMM). The results showed that the interception and infiltration capacities of shrub were greater than those of lawn. The rainfall intensity and rainfall pattern were the major factors that influenced the interception and infiltration of rainwater. The threshold value that generates runoff varied across the eight rainfall events ranged from 1.6 to 28.5 mm for lawn and 4.5 to 32.0 mm for shrub. The maximum reduction ratios of runoff and peak flow for shrub were 52 and 57% higher than them for lawn, respectively. The parameters for shrub were more sensitive to runoff and peak flow compared with those for lawn. Under light rainfalls with a short duration, the maximum infiltration rate and depression storage were more sensitive than those under heavy rainfalls with a long duration. Antecedent dry weather period was not found to be a sensitive parameter except for the shrub under light rainfalls. The relative errors of runoff and dynamic mean runoff (60 min) for lawn and shrub were within ± 9.5%. The errors of peak flow ranged between − 21 and 16.6%. The dynamic runoff characteristics and the parameters for lawn and shrub determined in this study can provide references for simulating urban runoff and planning LID areas.

Effects of intercropping with Bidens species plants on the growth and cadmium accumulation of Ziziphus acidojujuba seedlings Abstract To study the effects of intercropping with accumulator plants on heavy metal accumulation of fruit trees, plants of three Bidens species (Bidens pilosa, Bidens biternata, and Bidens parviflora) were intercropped with Ziziphus acidojujuba seedlings under cadmium (Cd)-contaminated conditions (5 mg kg−1). Intercropping with Bidens species increased the biomass and chlorophyll b content of Z. acidojujuba seedlings compared with monoculture, but decreased their carotenoid content. Intercropping with Bidens species also improved the activity of superoxide dismutase, peroxidase, and catalase in Z. acidojujuba seedlings compared with monoculture. Intercropping with Bidens species decreased the Cd content in the roots of Z. acidojujuba seedlings compared with monoculture. Conversely, when intercropped with B. pilosa, B. biternata, and B. parviflora, the Cd content in the shoots of Z. acidojujuba seedlings increased by 62.18%, 60.10%, and 62.18%, respectively, compared with that of those monocultured. When intercropped with Z. acidojujuba seedlings, the Cd accumulation amount of three Bidens species plants were ranked B. parviflora > B. biternata > B. pilosa. Therefore, intercropping with plants of three Bidens species is not suitable for Cd-contaminated jujube orchards.

Optimizing stormwater low-impact development strategies in an urban watershed considering sensitivity and uncertainty Abstract Stormwater management in an urban environment is beset by uncertainties about future development. Dynamic strategies must be devised to cope with such uncertain environment. This work proposes a simulation–optimization model that minimizes the costs of low-impact development (LID) measures for mitigating impacts of future urban development on runoff. This paper's methodology is tested in an urban watershed in Tehran, Iran, relying on the stormwater management model (SWMM) coupled with the genetic algorithm (GA) to function as a simulation–optimization method for urban–runoff control by means of LID stormwater control measures. A sensitivity analysis of the calculated optimal solution revealed the impacts the most sensitive LIDs would have on runoff considering a set of plausible future development scenarios in the urban catchment. A comparison of the results from two different scenarios of future development with the existing stormwater system's performance shows the cost increase in redesigning the existing system to make it LID sensitive would equal 20% of the existing system's cost. The additional cost of redesigning the existing system without LID features would be 45% of the existing system's cost. These results demonstrate the importance of assessing the sensitivity of designed units in a stormwater management system and studying the trade-offs between possible decisions and future uncertainties concerning development in the watershed.

Magnetic cobalt particle–assisted solid phase extraction of tellurium prior to its determination by slotted quartz tube-flame atomic absorption spectrophotometry Abstract The emergence of magnetic materials has opened up doors to numerous applications including their use as sorbents for preconcentration of trace elements. Magnetic materials exhibit many unique advantages in sample preparation such as easy separation from the sample, high preconcentration factor, and short operation period. In the present study, magnetic cobalt material was synthesized, characterized, and used as an effective sorbent in a solid phase extraction process. Experimental variables of the extraction process including pH and volume of buffer solution, eluent concentration and volume, mixing type and period, and sorbent amount were optimized to achieve maximum extraction efficiency. Instrumental variables of flame atomic absorption spectrophotometry and the type of slotted quartz tube were also investigated. Under the optimum conditions, the combined method provided a wide linear range between 50 and 200 ng/mL with detection and quantification limits of 15.4 ng/mL and 51.3 ng/mL, respectively. Relative standard deviations of the proposed method were less than 5.0% and a high enrichment factor of 86.7 was obtained. The proposed method was successfully applied to soil samples for the determination of trace tellurium.

La radiologia medica

National guidelines for dental diagnostic imaging in the developmental age

Radiologists' recommendations for additional imaging (RAI) in the inpatient setting Abstract Objective The aim of our study was to measure the rate of radiologists' additional recommended imaging examinations (RAI) at a hospital-based inpatient setting and to estimate the influence on RAI of clinical variables. Materials and methods This retrospective study was approved by the institutional review board. Inpatients CT and US examinations interpreted by fifteen radiologists between October and December 2016 were studied. Information about RAI from radiology report texts was extracted manually. The analytic data set included the interpreting radiologists' years of experience, patient age, patient gender, radiologist gender, ordering service and "clinical question to be answered" as collected from the radiology request forms. Results Of the 1996 US and CT examinations performed between October and December 2016 in the inpatient setting, 34% (683 examinations) had a radiologists' RAI. The largest proportion of RAI was for chest CT, followed by PET-CT, abdominal CT and abdominal MRI. Patient age and gender had no impact on RAI. Radiologists' years of experience were inversely correlated to RAI. "Pneumonia" showed the highest rate of RAI due to follow-up of lung nodules. Conclusion A high percentage of RAI resulted from CT and US radiologists' reports. The largest proportion of RAI was for chest CT, followed by PET-CT, abdominal CT, and abdominal MRI. Radiologists' years of experience play an important role in the number of the requested RAI. Further studies with a larger cohort of radiologists are needed to confirm the role of radiologists' experience in RAI. Also, follow-up studies are warranted to assess the number of RAI that are actually acted upon by the referring physicians.

MRI findings and utility of DWI in the evaluation of solid parathyroid lesions Abstract Purpose To evaluate the MRI findings of solid parathyroid lesions and to elaborate on a possible improvement of MRI detection of parathyroid lesions by the use of additional DWI. Materials and methods MRI and DWI properties of pathologically proven 20 solid parathyroid lesions were retrospectively reviewed. Mean ADC values (b50 + b400 + b800/3) of parathyroid lesions were compared with that of normal appearing thyroid parenchyma (TP), sternocleidomastoid muscle (SCM) and jugulodigastric lymph nodes (JDLN). Results Of lesions, 4 were parathyroid hyperplasia, 13 parathyroid adenoma and 3 parathyroid adenocarcinoma. All parathyroid lesions were very bright on fat-saturated T2W images. Parathyroid hyperplasia and adenoma were small sized, homogenous, well-defined and low on T1W, high on T2W and avidly enhancing. Parathyroid carcinoma was large sized, ill-defined and very heterogeneous on MRI including DWI. Means ADC values of parathyroid hyperplasia, adenoma, and adenocarcinoma, TP, SCM and JDLN were measured as 2.3 ± 0.14 × 10−3, 1.7 ± 0.45 × 10−3, 1.5 ± 1.48 × 10−3, 0.87 ± 0.40 × 10−3, 0.55 ± 0.21 × 10−3 and 0.96 ± 0.33 × 10−3 mm2/s, respectively. All parathyroid lesions had high diffusion properties comparing other soft tissue structures of head and neck region. By increasing strength (b value) of diffusion tensor on DWI, solid parathyroid lesions still kept their brightness comparing other soft tissue structures of head and neck region because of their high T2 properties. Conclusion Solid parathyroid lesions had higher diffusion properties comparing other soft tissues structures of head and neck region. This feature makes them easily differentiate from nearby structures on fat-saturated T2W and DWI.

Dynamic contrast-enhanced magnetic resonance imaging in locally advanced rectal cancer: role of perfusion parameters in the assessment of response to treatment Abstract Purpose To correlate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters to tumor grading and to assess their reliability in predicting pathological complete response (pCR) before neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Materials and methods Forty patients (24 male; mean age, 67.3 ± 8.1 years) with histologically proven LARC who had undergone 3-Tesla DCE-MRI before (MRI_1) and after CRT (MRI_2) between August 2015 and February 2016 were included in this retrospective study. DCE-MRI parameters at MRI_1 and MRI_2 were extracted by two board certified radiologists in consensus reading with Olea Sphere 2.3 software using the extended Tofts model. Based on DCE-MRI results, patients were divided in complete responders (CR) and non-complete responders (nCR) and the perfusion parameters were correlated to tumor grading and pCR. Results Wash-out and Kep at MRI_1 showed significant correlation with LARC grading (P = 0.004 and 0.01, respectively). Ve showed a significant increase between MRI_1 (0.47 ± 0.27) and MRI_2 (0.63 ± 0.23; P = 0.007). Ktransmeasured at MRI_1 was significantly higher in CR (0.66 ± 0.48) compared to nCR (0.53 ± 0.34, P = 0.02). Conclusion Wash-out and Kep measured before CRT correlate with LARC grading. Ve changes during CRT, while Ktrans measured before CRT may predict the response to therapy. Therefore, DCE-MRI parameters can predict tumor aggressiveness and CRT efficacy, playing a role as imaging biomarkers in patients with LARC.

Overcoming metallic artefacts from orthopaedic wrist volar plating on a low-field MRI scanner Abstract Purpose To quantitatively compare the artefact reduction between standard and metallic artefact reduction (MAR) fast spin echo (FSE) T2 sequences in a low-field magnetic resonance imaging (MRI) scanner (0.3 T) in patients with titanium volar wrist plating. Materials and methods Sixteen patients with fractures of the distal radius, treated with titanium volar wrist plating and screws, were examined using a dedicated 0.3 T MRI scanner. Coronal standard FSE T2, FSE T2 high bandwidth (HiBW) and FSE T2 view angle tilting (VAT) sequences were performed. Metallic artefact volume, consisting of both "black" and "bright" artefacts, was calculated for each sequence. Quantitative differences were compared using repeated measures ANOVA test (P < 0.05). Results FSE T2 HiBW and FSE T2 VAT showed a significant reduction in artefact volume compared to the standard sequence. Differences between the artefact volume of the standard FSE T2, HiBW and VAT sequences were statistically significant for both the "black" and "bright" artefacts (P < 0.0001). Differences between the 1.5 HiBW and VAT sequences were statistically significant (black P < 0.0001, bright P < 0.0302). Conclusions MAR sequences significantly reduced metallic artefacts in vivo using a 0.3 T MRI scanner.

Role of pretreatment 18F-FDG PET/CT parameters in predicting outcome of non-endemic EBV DNA-related nasopharyngeal cancer (NPC) patients treated with IMRT and chemotherapy Abstract Purpose To evaluate the prognostic role of pretreatment 18F-FDG PET/CT metabolic parameters in non-endemic Epstein–Barr Virus (EBV DNA)-related nasopharyngeal cancer (NPC) patients treated with curative intensity-modulated radiation therapy (IMRT) with or without chemotherapy (CHT). Materials/methods We retrospectively reviewed clinical data of 160 consecutive non-metastatic NPC patients who received IMRT with or without CHT. Forty-nine out of 160 patients that underwent whole body 18F-FDG PET/CT at our institution for disease staging with a minimum follow-up to 12 months were included in this study. We evaluated the relationship between maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume and total lesion glycolysis (TLG) of primary tumor and cervical lymph nodes with disease-free survival (DFS) and overall survival (OS). We also investigated the prognostic role of clinical variables such as age, disease stage, plasma EBV DNA load (copies/ml), gross tumor volume of primary tumor and lymph nodes. Results Median follow-up was 55 months. Two- and 5-year OS were 95.8% and 90.5%, respectively, while DFS was 83.4% at both time points. SUVmax of primary tumor ≥ 18.8 g/ml and primary tumor TLG ≥ 203.1 g were significant prognostic factors of worse OS. Furthermore, stages IVB and EBV DNA load ≥ 3493 copies/ml were significantly associated with lower DFS. No correlation was found between PET parameters and plasma EBV DNA load. Conclusion Even in a limited series, our data suggested that SUVmax, SUVmean and TLG of primary tumor could predict a poor outcome in NPC patients also in non-endemic area hypothesizing their use for refinement of prognostication.

Diagnostic efficacy of model-based iterative reconstruction algorithm in an assessment of coronary artery in comparison with standard hybrid-Iterative reconstruction algorithm: dose reduction and image quality Abstract Purpose To evaluate the image quality and radiation dose exposure of low-dose coronary CTA (cCTA) study, reconstructed with the new model-based iterative reconstruction algorithm (IMR), compared with standard hybrid-iterative reconstruction (iDose4) cCTA in patients with suspected coronary artery disease. Materials and methods Ninety-eight patients with an indication for coronary CT study were prospectively enrolled. Fifty-two patients (study group) underwent 256-MDCT low-dose cCTA (80 kV; automated-mAs; 60 mL of CM, 350 mgL/mL) with prospective ECG-triggering acquisition and IMR. A control group of 46 patients underwent 256-MDCT standard prospective ECG-gated protocol (100 kV; automated-mAs; 70 mL of CM, 400 mgL/mL; iDose4). Subjective and objective image quality (attenuation value, SD, SNR and CNR) were evaluated by two radiologists subjectively. Radiation dose exposure was quantified as DLP, CTDIvol and ED. Results Mean values of mAs were significantly lower for IMR-cCTA (167 ± 62 mAs) compared to iDose-cCTA (278 ± 55 mAs), p < 0.001. With a significant reduction of 38% in radiation dose exposure (DLP: IMR-cCTA 91.7 ± 26 mGy cm vs. iDose-cCTA 148.6 ± 35 mGy cm; p value < 0.001), despite the use of different CM, we found higher mean attenuation values of the coronary arteries in IMR group compared to iDose4 (mean density in LAD: 491HU IMR-cCTA vs. 443HU iDose-cCTA; p = 0.03). We observed a significant higher value of SNR and CNR in study group due to a lower noise level. Qualitative analysis did not reveal any significant differences between the two groups (p = 0.23). Conclusions Low-dose cCTA study combined with IMR reconstruction allows to correctly evaluate coronary arteries disease, offering high-quality images and significant radiation dose exposure reduction (38%), as compared to standard cCTA protocol.

Evaluation of US and MRI techniques for carotid stenosis: a novel phantom approach Abstract Carotid atherosclerosis is very important in the pathogenesis of cerebral ischemia. Ultrasonography (US) and magnetic resonance imaging (MRI) are the predominant noninvasive techniques capable to identify the presence and stage of intra-plaque hemorrage. In this work, we propose a novel dedicated phantom that can be used for both US and MRI scanners to evaluate carotid atherosclerotic lesions. The phantom consists of a polymethyl metacrylate (PMMA) diagonally crossed by a PMMA hollow cylinder simulating a blood vessel. To simulate a stenosis, we inserted a plastic hollow tube inside the cylinder. Quantitative image analysis, based on accuracy measurements, was performed on two US and two MRI scanners. The accuracy measurements have highlighted the use of the 3.0 T MRI scanner to characterize the vessel stenosis. However, no significant difference between US and MRI techniques was found in Fisher exact test and inter-rater agreement. The concordance correlation coefficient showed a moderate agreement between some methods. Agreement between 3.0 T and other methods results poor, and this could be due to the fact that the 3.0 T has a better resolution compared to a US and MR 1.5 T. These methods seem to have similar efficacies for the evaluation of vessel stenosis, legitimizing the use of the developed phantom as a versatile and reproducible instrument that could be used during quality controls programs.

Lumbosacral transitional vertebra in the young men population with low back pain: anatomical considerations and degenerations (transitional vertebra types in the young men population with low back pain) Abstract Introduction To evaluate the prevalence of subtypes of congenital lumbosacral transition vertebra (LSTV) in young male populations with low back pain (LBP) and their relationship to lumbar disc and facet degeneration. Materials and methods 1875 patients (male, aged; 18–40 years) with LBP were investigated retrospectively. Standard lumbar MRI protocol of sagittal, and axial T1 weighted images (WI) and T2 WI and coronal short tau inversion recovery (STIR) T2 WI were obtained. Castellvi classification of LSTV were used for subtyping. The level and above the level of LSTV were evaluated for the lumbar disc space and facet degeneration based on grading methods which compares subtype groups with each other. Results Prevalence of LSTV was 32% (600 of 1875). The most frequent LSTV types were type I (dysplastic enlarged transverse process; 66.5%) and type II (pseudoarticulation; 21.8%). Eight percent of the patients were type III (fusion) and 3.6% patients type IV (one transverse process fused and one with pseudoarticulation). The most commonly detected LSTV types were type I + II (88%) and all bilateral LSTV types were seen much more than unilateral types (bilateral versus unilateral 63.2%, 33.2%). The LSTV type I highly correlated with the disc degeneration and facet arthrosis. But the groups with higher grade of disc degeneration were type IV and III. Conclusion In young male patients with LBP, LSTV was found to be high in frequency and mostly occurred to be subtype I. LSTV type I and associated disk and facet degeneration were found to be remarkable in this group. Coronal T2 STIR images are useful in showing lumbosacral region anomalies and variants, and should be included in the routine lumbar MRI protocol.

Evaluation of CSF flow metrics in patients with communicating hydrocephalus and idiopathic intracranial hypertension Abstract Purpose To search for CSF dynamics of idiopathic intracranial hypertension (IIH) and communicating hydrocephalus and any correlation between MRI findings, CSF metrics and CSF opening pressure in IIH. Materials and methods Healthy subjects (30) and subjects with IIH (29) and high-pressure communicating hydrocephalus (43) were enrolled. Nonparametric Kruskal–Wallis test (p = 0.05) was used to compare three groups, Mann–Whitney U test with Bonferroni correction to compare two groups (p = 0.016). Correlation of MRI findings of IIH with CSF metrics and CSF opening pressure was analyzed by Spearman's Rank correlation coefficient (p = 0.05). Results In IIH, no correlation between MRI findings and aqueductal stroke volume (ASV) but statistically significantly CSF opening pressure in the presence of transverse sinus compression was noted. Comparing with healthy subjects, ASV was nonsignificantly lower and standardized diastolic and sum and difference of systolic and diastolic flow durations were statistically significantly lower. Comparing with hydrocephalus, the width of prepontine cistern (PPC)/the width of aqueductus sylvii (AS) was significantly higher and other CSF metrics with standardized systolic and sum of systolic and diastolic flow durations were significantly lower. In hydrocephalus, ASV and peak velocities were significantly higher. Compared with normal group, PPC/AS and reverse/forward flow duration were significantly lower and other CSF metrics were significantly higher. Conclusion In hydrocephalus, significant increase in ASV and peak velocities were noted. In IIH, CSF opening pressure was statistically significantly high in the presence of transverse sinus compression and standardized diastolic flow durations were statistically significantly short that are probably effects of increased impedance of CSF flow against increased intracranial pressure and unchanged or even decreased intraventricular CSF volume.

Breast Cancer Research and Treatment

Efficacy of a web-based women's health survivorship care plan for young breast cancer survivors: a randomized controlled trial Abstract Purpose Breast cancer survivorship care plans (SCP) have limited content addressing women's health issues. This trial tested if young breast cancer survivors who receive a web-based, women's health SCP were more likely to improve on at least one of the four targeted issues (hot flashes, fertility-related concerns, contraception, and vaginal symptoms) compared to attention controls. Methods A randomized controlled trial recruited female survivors ages 18–45 at diagnosis, 18–50 at enrollment, completed primary cancer treatment, and had a significant women's health issue: moderate or higher fertility-related concerns; ≥ 4 hot flashes/day with ≥ 1 of moderate severity; ≥ 1 moderate vaginal atrophy symptoms; or not contracepting/using less effective methods. Survivors underwent stratified, block randomization with equal allocation to intervention and control groups. The intervention group accessed the online SCP; controls accessed curated resource lists. In intention-to-treat analysis, the primary outcome of improvement in at least one issue by 24 weeks was compared by group. Results 182 participants (86 intervention, 96 control), mean age 40.0 ± 5.9 and 4.4 ± 3.2 years since diagnosis, were randomized. 61 intervention group participants (70.9%) improved, compared to 55 controls (57.3%) (OR 1.82, 95% CI 0.99–3.4, p = 0.057). The following issue-specific improvements were observed in the intervention versus control arms: fertility-related concerns (27.9% vs. 14.6%, OR 2.3, 95% CI 1.1–4.8); hot flashes (58.5% vs. 55.8%, OR 1.1, 95% CI 0.57–2.2); vaginal symptoms (42.5% vs. 40.7%, OR 1.1, 95% CI 0.6–2.0); contraception (50% vs. 42.6%, OR 1.4, 95% CI 0.74–2.5). Conclusions In young breast cancer survivors, a novel, web-based SCP did not result in more change in the primary outcome of improvement in at least one of the four targeted women's health issues, than the attention control condition. The intervention was associated with improved infertility concerns, supporting efficacy of disseminating accessible, evidence-based women's health information to this population.

Elevated serum levels of sialyl Lewis X (sLe X ) and inflammatory mediators in patients with breast cancer Abstract Purpose The carbohydrate sialyl LewisX (sLeX) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLeX and inflammatory cytokines/chemokines in breast cancer sera. Methods We retrospectively measured sLeX and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLeX and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLeX using a cut-off of 8 U/mL as previously defined. Results Median serum sLeX was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLeX > 8 U/mL have a significantly shorter progression-free survival (PFS) (P = 0.0074) and overall survival (OS (P = 0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P = 0.001 and P < 0.001, respectively) and PFS (P = 0.010 and P < 0.001, respectively). sLeX, MCP-1 and IP-10 remained significant in multivariate survival analysis. Conclusion Elevated serum sLeX was associated with invasive cancer but not DCIS. High serum sLeX levels were associated with inflammatory mediators and may play a role in facilitating local invasion of breast tumor. Furthermore, serum MCP-1, IP-10 and sLeX may have prognostic value in breast cancer.

Noncompliance with palliative systemic therapy in patients with distant metastatic breast cancer: a blind spot for oncologists? Abstract Purpose The goal of our study was to provide a general overview of noncompliance with palliative systemic therapy in distant metastatic breast cancer (MBC). Methods We analyzed an unselected cohort of 339 patients who were diagnosed with MBC over a 22-year period (1990–2011, age restriction: ≥ 85 years old). Results Forty patients (11.8%) rejected the offered or recommended systemic therapy (age distribution of this noncompliance subgroup: ≤60 years at MBC diagnosis: 7.9%; 60–70 years: 13.2%; > 70 years: 15.6%). The rate of noncompliance was equally distributed over time (1990–1999: 12.2% vs. 2000–2011: 11.5%, p = 0.87). Compared to patients who had received palliative antineoplastic systemic therapy, those who remained untreated were significantly older (70 vs. 61 years, p = 0.015), had shorter metastatic disease survival (2 vs. 27 months, p < 0.001), had more often an aggressive tumor subtype (hormone-receptor negative carcinomas: 48.7% vs. 22.2%, p < 0.001), and had more often secondary MBC (95.0% vs. 73.6%, p = 0.001). Conclusions Although the high rate of noncompliance in the subgroup of elderly patients was not unexpected, it is noticeable that even in the subgroup of patients who were younger than 60 years, approximately 8% also rejected any systemic therapy before a MBC-related death occurred This group of younger women rarely had any relevant comorbidities, were potential candidates for chemotherapy and knowingly declined the therapy options. Such patients are never or seldom seen by oncologists in their daily practice and therefore play a minor role in their personal perception of disease. Nevertheless, these under-reported cases make up a significant proportion of MBC.

HER2 positive breast cancer patients having HER2 loss after neoadjuvant chemotherapy should still be treated with adjuvant anti-HER2 treatment

Change in study randomization allocation needs to be included in statistical analysis: comment on 'Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study'

Atypical ductal hyperplasia in men with gynecomastia: what is their breast cancer risk? Abstract Purpose Atypical ductal hyperplasia (ADH) significantly increases the risk of breast cancer in women. However, little is known about the implications of ADH in men. Methods Review of 932 males with breast pathology was performed to identify cases of ADH. Patients were excluded if ADH was upgraded to cancer on excision, or if they had contralateral breast cancer. Cases were reviewed to determine whether any male with ADH developed breast cancer. Results Nineteen males were diagnosed with ADH from June 2003 to September 2018. All had gynecomastia. Surgical procedure was mastectomy in 8 patients and excision/reduction in 11. One patient had their nipple areola complex removed, and 1 required a free nipple graft. Median patient age at ADH diagnosis was 25 years (range 18–72 years). Of the 14 patients with bilateral gynecomastia, 10 had bilateral ADH and 4 had unilateral. Five cases of ADH were described as severe, bordering on ductal carcinoma in situ. No patient reported a family history of breast cancer. No patient took tamoxifen. At a mean follow-up of 75 months (range 4–185 months), no patient developed breast cancer. Conclusion Our study is the first to provide follow-up information for males with ADH. With 6 years of mean follow-up, no male in our series has developed breast cancer. This suggests that either ADH in men does not pose the same risk as ADH in women or that surgical excision of symptomatic gynecomastia in men effectively reduces the risk of breast cancer.

Correction to: Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated. The original article has been corrected.

Tamoxifen and pregnancy: an absolute contraindication? Abstract Purpose Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy. Methods A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy. Results A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen. Conclusion There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated.

The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer Abstract Purpose Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p < 0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the high SLC cluster (p < 0.001). When different BC subtypes were considered, the association with the poor outcome was observed in the ER+ high proliferation/luminal B class only (p = 0.003). In multivariate analysis, SLC clusters were independent risk factor for shorter BC-specific survival (p = 0.001). Conclusion The co-operative expression of SLC1A5, SLC7A5, and SLC3A2 appears to play a role in the aggressive subclass of ER+ high proliferation/luminal BC, driven by c-MYC, and therefore have the potential to act as therapeutic targets, particularly in synergism.

Customized breast cancer risk assessment in an ambulatory clinic: a portal for identifying women at risk Abstract Purpose Existing high-risk clinic models focus on patients with known risk factors, potentially missing many high-risk patients. Here we describe our experience implementing universal risk assessment in an ambulatory breast center. Methods Since May 2017, all breast center patients completed a customized intake survey addressing known breast cancer risk factors and lifestyle choices. Patient characteristics, family history, risk scores, and lifestyle factors were examined; patients with high-risk breast lesions were excluded. Patients were considered at increased risk by model thresholds Gail 5-year risk > 1.7% (35–59 years), Gail 5-year risk > 5.5% (≥ 60 years), or Tyrer–Cuzick (T–C) v7 lifetime risk > 20% (any age). Results From May 2017–April 2018, there were 874 eligible patients—420 (48%) referred for risk assessment (RA) and 454 (52%) for non-specific breast complaints (NSBC). Overall, 389 (45%) were at increased risk of breast cancer. Gail 5-year risks were similar between RA and NSBC patients. However, RA patients more frequently met criteria by T–C score (P = 0.02). Of all patients at increased risk, 149 (39%) were overweight (BMI > 25) or obese (BMI > 30) and only 159 (41%) met recommended exercise standards. NSBC patients who met criteria were more frequently smokers (8% vs 1%, P < 0.01); all other demographic/lifestyle factors were similar among high-risk patients regardless of referral reason. Conclusions Universal risk assessment in a comprehensive breast health center identified 45% of our population to be at increased risk of breast cancer. This clinical care model provides a unique opportunity to identify and address modifiable risk factors among women at risk.

Brain Tumor Pathology

High-grade glioneuronal tumor with an ARHGEF2 – NTRK1 fusion gene Abstract Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)–NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.

Clinicopathological characteristics of circumscribed high-grade astrocytomas with an unusual combination of BRAF V600E, ATRX , and CDKN2A/B alternations Abstract We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3–46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

Reviewers in 2018

Preface

Pilomyxoid astrocytomas: a short review Abstract Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma

Pathologic and molecular aspects of anaplasia in circumscribed gliomas and glioneuronal tumors Abstract Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality, and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. Recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review the current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas, with a focus on their anaplastic counterparts.

Overview of DNA methylation in adult diffuse gliomas Abstract Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 (IDH1) and IDH2, and H3 histone family member 3A, which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.

Novel concept of the border niche: glioblastoma cells use oligodendrocytes progenitor cells (GAOs) and microglia to acquire stem cell-like features Abstract Glioblastoma (GBM) is a major malignant brain tumor developing in adult brain white matter, characterized by rapid growth and invasion. GBM cells spread into the contralateral hemisphere, even during early tumor development. However, after complete resection of tumor mass, GBM commonly recurs around the tumor removal cavity, suggesting that a microenvironment at the tumor border provides chemo-radioresistance to GBM cells. Thus, clarification of the tumor border microenvironment is critical for improving prognosis in GBM patients. MicroRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass was compared, and five miRNAs showing characteristically higher expression in the tumor border were identified, with the top three related to oligodendrocyte differentiation. Pathologically, oligodendrocyte lineage cells increased in the border, but were rare in tumors. Macrophages/microglia also colocalized in the border area. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, suggesting that OPCs and macrophages/microglia constitute a special microenvironment for GBM cells at the tumor border. The supportive function of OPCs for GBM cells has not been discussed previously. OPCs are indispensable for GBM cells to establish special niches for chemo-radioresistance outside the tumor mass.

Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors Abstract The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

The emerging clinical potential of circulating extracellular vesicles for non-invasive glioma diagnosis and disease monitoring Abstract Diffuse gliomas (grades II–IV) are amongst the most frequent and devastating primary brain tumours of adults. Currently, patients are monitored by clinical examination and radiographic imaging, which can be challenging to interpret and insensitive to early signs of treatment failure and tumour relapse. While brain biopsy and histologic analysis can evaluate disease progression, serial biopsies are invasive and impractical given the cumulative surgical risk, and may not capture the complete molecular landscape of an evolving tumour. The availability of a minimally invasive 'liquid biopsy' that could assess tumour activity and molecular phenotype in situ has the potential to greatly enhance patient care. Circulating extracellular vesicles (EVs) hold significant promise as robust disease-specific biomarkers accessible in the blood of patients with glioblastoma and other diffuse gliomas. EVs are membrane-bound nanoparticles shed from most if not all cells of the body, and carry DNA, RNA, protein, and lipids that reflect the identity and molecular state of their cell-of-origin. EVs can cross the blood–brain barrier and their release is upregulated in neoplasia. In this review, we describe the current knowledge of EV biology, the role of EVs in glioma biology and the current experience and challenges in profiling glioma-EVs from the circulation.