Multiple staging investigations may not change management in patients with high-grade dysplasia or early esophageal adenocarcinoma.

The clinical value of multiple staging investigations for high-grade dysplasia or early adenocarcinoma of the esophagus is unclear. A single-center prospective cohort of patients treated for early esophageal cancer between 2000 and 2019 was analyzed. This coincided with a transition period from esophagectomy to endoscopic mucosal resection (EMR) as the treatment of choice. Patients were staged with computed tomography (CT), endoscopic ultrasound (EUS) and 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography(PET)/CT. The aim of this study was to assess their accuracy and impact on clinical management. 297 patients with high-grade dysplasia or early adenocarcinoma were included (endoscopic therapy/EMR n = 184; esophagectomy n = 113 [of which a 'combined' group had surgery preceded by endoscopic therapy n = 23]). Staging accuracy was low (accurate staging EMR: CT 40.1%, EUS 29.6%, FDG-PET/CT 11.0%; Esophagectomy: CT 43.3%, EUS 59.7%, FDG-PET/CT 29.6%; Combined: CT 28.6%, EUS46.2%, FDG-PET/CT 30.0%). Staging inaccuracies across all groups that could have changed management by missing T2 disease were CT 12%, EUS 12% and FDG-PET/CT 1.6%. The sensitivity of all techniques for detecting nodal disease was low (CT 12.5%, EUS 12.5%, FDG-PET/CT0.0%). Overall, FDG-PET/CT and EUS changed decision-making in only 3.2% of patients with an early cancer on CT and low-risk histology. The accuracy of staging with EUS, CT and FDG-PET/CT in patients with high-grade dysplasia or early adenocarcinoma of the esophagus is low. EUS and FDG-PET/CT added relevant staging information over standard CT in very few cases, and therefore, these investigations should be used selectively. Factors predicting the need for esophagectomy are predominantly obtained from EMR histology rather than staging investigations.

Occurrence of a human-associated microbial source tracking marker and its relationship with faecal indicator bacteria in an urban estuary.

One of the main impacts of urban sprawl in rapidly growing countries has been contamination of coastal environments by waterborne pathogens, posing a critical risk to ecosystem and human health. Microbial source tracking (MST) has been a robust tool to identify the origin of these pathogens globally. This study compared the occurrence of a human-associated Bacteroides marker (BT-α) with faecal indicator bacteria (FIB) in an urban estuary (Golden Horn, Istanbul, Turkey). Faecal coliform (culture method), enterococci (both culture and qPCR method) concentrations and physicochemical variables were compared with the BT-α concentrations in monthly collected samples for a year (n = 108). Enterococci concentrations detected by culture and qPCR were positively correlated (r = 0·86, P < 0·01) suggesting that qPCR can be an alternative method for monitoring. BT-α marker was positive for 30% of the samples and positively correlated with enterococci (r = 0·61 and r = 0·64 for culture and qPCR methods respectively, P < 0·01). Rainfall had a moderate positive correlation with all faecal/MST indicators suggesting combined sewer overflows also severely impacted estuarine water quality. The high FIB and BT-α concentrations at upper estuary suggested that faecal pollution mainly originated from the peri-urban settlements around two creeks entering the estuary.

Prediction of a positive circumferential resection margin at surgery following neoadjuvant chemotherapy for adenocarcinoma of the oesophagus.

Background: A positive circumferential resection margin (CRM) has been associated with higher rates of locoregional recurrence and worse survival in oesophageal cancer. The aim of this study was to establish if clinicopathological and radiological variables might predict CRM positivity in patients who received neoadjuvant chemotherapy before surgery for oesophageal adenocarcinoma. Methods: Multivariable analysis of clinicopathological and CT imaging characteristics considered potentially predictive of CRM was performed at initial staging and following neoadjuvant chemotherapy. Prediction models were constructed. The area under the curve (AUC) with 95% confidence intervals (c.i.) from 1000 bootstrapping was assessed. Results: A total of 223 patients were included in the study. Poor differentiation (odds ratio (OR) 2·84, 95 per cent c.i. 1·39 to 6·01) and advanced clinical tumour status (T3-4) (OR 2·93, 1·03 to 9·48) were independently associated with an increased CRM risk at diagnosis. CT-assessed lack of response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3·38, 1·43 to 8·50). Additional CT evidence of local invasion and higher CT tumour volume (14 cm3) improved the performance of a prediction model, including all the above parameters, with an AUC (c-index) of 0·76 (0·67 to 0·83). Variables associated with significantly higher rates of locoregional recurrence were pN status (P = 0·020), lymphovascular invasion (P = 0·007) and poor response to chemotherapy (Mandard score 4-5) (P = 0·006). CRM positivity was associated with a higher locoregional recurrence rate, but this was not statistically significant (P = 0·092). Conclusion: The presence of advanced cT status, poor tumour differentiation, and CT-assessed lack of response to chemotherapy, higher tumour volume and local invasion can be used to identify patients at risk of a positive CRM following neoadjuvant chemotherapy.

Antecedentes: Un margen de resección circunferencial (circumferential resection margin, CRM) positivo se ha asociado con tasas más elevadas de recidiva locorregional y peor supervivencia en el cáncer de esófago. El objetivo de este estudio fue establecer si las variables clínico­patológicas y radiológicas podrían predecir la positividad del CRM en el adenocarcinoma de esófago tras quimioterapia neoadyuvante antes de la cirugía. Métodos: Se realizó un análisis multivariable de las características clínico­patológicas y de la tomografía computarizada (computed tomography, CT) que se consideraron potencialmente predictivas de CRM en la estadificación inicial y tras la quimioterapia neoadyuvante. Se construyeron modelos de predicción. Se evaluó el área bajo la curva (area under curve, AUC) con el i.c. del 95% a partir de 1.000 muestras bootstrap. Resultados: Se incluyeron 223 pacientes en el estudio. Una pobre diferenciación (razón de oportunidades, odds ratio, OR 2,84, i.c. del 95% 1,39­6,01) y un estadio clínico T avanzado (T3­4) (OR 2,93, i.c. del 95% 1,03­9,48) se asociaron de forma independiente con un riesgo aumentado de CRM en el diagnóstico. La falta de respuesta en la CT (estable o enfermedad en progresión) tras la quimioterapia se correspondía de forma independiente con un riesgo aumentado de CRM positivo (OR 3,38, i.c. del 95% 1,43­8,50). Además, la evidencia por CT de invasión local y un mayor volumen del tumor en CT (14 cm3) mejoraron el funcionamiento del modelo predictivo, incluyendo todos los parámetros previamente señalados; con AUC (índice c) de 0,76 (0,68­0,83). Las variables asociadas de forma significativa con tasas más elevadas de recidiva locorregional fueron el estado de los ganglios linfáticos patológicos (P = 0,002), la invasión linfovascular (P = 0,007) y la respuesta pobre a la quimioterapia (Mandard 4 y 5 (P = 0,006)). La positividad del CRM se asoció con una tasa de recidiva locorregional más elevada pero sin alcanzar significación estadística (P = 0,09). Conclusión: La presencia de un estadio clínico T avanzado, tumor pobremente diferenciado, falta de respuesta a la quimioterapia en la TC, mayor volumen del tumor en la TC e invasión local pueden ser utilizados para identificar pacientes en riesgo de un CRM positivo tras quimioterapia neoadyuvante.

A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

Endoscopic management of dysplasia and early oesophageal cancer.

In the past decade there have been technological advances in Endoscopic Eradication Therapy (EET) for the management of patients with oesophageal neoplasia and early cancer. Multiple endoscopic techniques now exist for both squamous and Barrett's oesophagus associated neoplasia or early cancer. A fundamental aspect of endotherapy is removal of the target lesion by endoscopic mucosal resection, or endosopic submucosal dissection. Residual tissue is subsequently ablated to remove the risk of recurrence. The most validated technique for Barrett's oesophagus is radiofrequency ablation, but other techniques such as hybrid-APC and cryotherapy also show good results. This chapter will discuss the evolution of EET, and which patients are most likely to benefit. It will also explore the evidence behind the success of different techniques and provide practical advice on how to carry out the endoscopic techniques with a focus on radiofrequency ablation and endoscopic mucosal resection in particular.

The brain's specialized systems for aesthetic and perceptual judgment.

We recorded brain activity when 21 subjects judged the beauty (aesthetic or affective judgment) and brightness (perceptual or cognitive judgment) of simultaneously presented paintings. Aesthetic judgments engaged medial and lateral subdivisions of the orbitofrontal cortex as well as subcortical stations associated with affective motor planning (globus pallidus, putamen-claustrum, amygdala, and cerebellar vermis), whereas the motor, premotor and supplementary motor areas, as well as the anterior insula and the dorsolateral prefrontal cortex, were engaged by both kinds of judgment. The results lead us to conclude: (i) that there is a functional specialization for judgment, with aesthetic judgments engaging distinct systems, in addition to those that they share with perceptual judgments; (ii) that the systems engaged by affective judgments are those in which activity correlates with polar experiences (e.g. love-hate, beauty-ugliness, and attraction-repulsion); and (iii) that there is also a functional specialization in the motor pathways, with aesthetic judgments engaging motor systems not engaged by perceptual judgments, in addition to those engaged by both kinds of judgment.

Natural vision reveals regional specialization to local motion and to contrast-invariant, global flow in the human brain.

Visual changes in feature movies, like in real-live, can be partitioned into global flow due to self/camera motion, local/differential flow due to object motion, and residuals, for example, due to illumination changes. We correlated these measures with brain responses of human volunteers viewing movies in an fMRI scanner. Early visual areas responded only to residual changes, thus lacking responses to equally large motion-induced changes, consistent with predictive coding. Motion activated V5+ (MT+), V3A, medial posterior parietal cortex (mPPC) and, weakly, lateral occipital cortex (LOC). V5+ responded to local/differential motion and depended on visual contrast, whereas mPPC responded to global flow spanning the whole visual field and was contrast independent. mPPC thus codes for flow compatible with unbiased heading estimation in natural scenes and for the comparison of visual flow with nonretinal, multimodal motion cues in it or downstream. mPPC was functionally connected to anterior portions of V5+, whereas laterally neighboring putative homologue of lateral intraparietal area (LIP) connected with frontal eye fields. Our results demonstrate a progression of selectivity from local and contrast-dependent motion processing in V5+ toward global and contrast-independent motion processing in mPPC. The function, connectivity, and anatomical neighborhood of mPPC imply several parallels to monkey ventral intraparietal area (VIP).

The neurobiology of love.

Romantic and maternal love are highly rewarding experiences. Both are linked to the perpetuation of the species and therefore have a closely linked biological function of crucial evolutionary importance. The newly developed ability to study the neural correlates of subjective mental states with brain imaging techniques has allowed neurobiologists to learn something about the neural bases of both romantic and maternal love. Both types of attachment activate regions specific to each, as well as overlapping regions in the brain's reward system that coincide with areas rich in oxytocin and vasopressin receptors. Both deactivate a common set of regions associated with negative emotions, social judgment and 'mentalizing' that is, the assessment of other people's intentions and emotions. Human attachment seems therefore to employ a push-pull mechanism that overcomes social distance by deactivating networks used for critical social assessment and negative emotions, while it bonds individuals through the involvement of the reward circuitry, explaining the power of love to motivate and exhilarate. Yet the biological study of love, and especially romantic love, must go beyond and look for biological insights that can be derived from studying the world literature of love, and thus bring the output of the humanities into its orbit.

The sightless view: neural correlates of occluded objects.

The relationship between neural activity and object perception has received considerable attention using stimulus manipulations such as masking or dichoptic presentation. Here we investigate the same problem by occluding objects with an opaque screen that acts to dissociate the direct perception of the object from the awareness of its presence. We used functional magnetic resonance imaging to measure brain activity when subjects viewed objects (faces and houses) that underwent occlusion and found that the response of the majority of the fusiform face area (FFA) and lateral occipital cortex is the same whether the object is visible or occluded. This suggests that when objects are directly viewed, activity within object-selective regions may reflect the awareness of presence, not the direct perception, of the object. Additionally, we identify a region of premotor cortex that is selectively activated by occlusion of either object type, suggesting its generic involvement with processing occluded objects.

The temporal order of binding visual attributes.

The brain processes distinct attributes such as colour and motion in anatomically largely segregated systems. Moreover, these two attributes are perceived with different latencies. Here, we show that the time required to bind these two attributes differs too. In psychophysical experiments, we determined minimal presentation times required to perceptually pair spatially separate pairs of stimuli consisting of colour or motion. Binding two colours required longer presentation times than binding the directions of two moving stimuli. Cross-attribute binding between colour and motion took longer than within-attribute binding. This was so even when the relative perceptual delay between colour and motion was compensated for, which accelerated colour-motion binding. Moreover, stimuli could be discriminated but not bound at fast presentation rates. Our results thus show that spatial binding is an attribute-specific process and faster within the same than across different attributes. Furthermore, the time required to bind attributes is independent of that required to process them, since colour is perceived before motion but requires longer time for binding. Finally, our results suggest that binding acts on attribute-specific neural representations of the stimuli at a late, perceptually explicit stage. These results lead us to conclude that spatial binding is separate from, and subsequent to, stimulus processing and that it is an attribute-dependent and post-conscious process.

The integration of colour and motion by the human visual brain.

Objects in the visual scene are defined by different cues such as colour and motion. Through the integration of these cues the visual system is able to utilize different sources of information, thus enhancing its ability to discriminate objects from their backgrounds. In the following experiments, we investigate the neural mechanisms of cue integration in the human. We show, using functional magnetic resonance imaging (fMRI), that both colour and motion defined shapes activate the lateral occipital complex (LOC) and that shapes defined by both colour and motion simultaneously activate the anterior-ventral margins of this area more strongly than shapes defined by either cue alone. This suggests that colour and motion cues are integrated in the LOC and possibly a neighbouring, more anterior, region. We support this result using an fMR adaptation technique, demonstrating that a region of the LOC adapts on repeated presentations of a shape regardless of the cue that is used to define it and even if the cue is varied. This result raises the possibility that the LOC contains cue-invariant neurons that respond to shapes regardless of the cue that is used to define them. We propose that such neurons could integrate signals from different cues, making them more responsive to objects defined by more than one cue, thus increasing the ability of the observer to recognize them.

The disunity of consciousness.

Attempts to decode what has become known as the (singular) neural correlate of consciousness (NCC) suppose that consciousness is a single unified entity, a belief that finds expression in the term 'unity of consciousness'. Here, I propose that the quest for the NCC will remain elusive until we acknowledge that consciousness is not a unity, and that there are instead many consciousnesses that are distributed in time and space.

The processing of kinetic contours in the brain.

This work investigates whether the brain assigns special cortical areas for the processing of kinetic contours. In human imaging experiments, we compared the brain activity produced in the so-called 'kinetic occipital' area ('KO') when humans perceive shapes generated from kinetic boundaries or from equiluminant colors. 'KO' was activated whenever subjects perceived shapes, no matter how they were derived; it is therefore not specialized for the processing of kinetic contours. The application of independent component analysis (ICA) to imaging data obtained when subjects viewed 22 min of an action movie showed that the time course of activity in 'KO' correlates better with activity in area V3 than with activity in two adjacent areas, V5 and LO. We thus consider 'KO' to be part of the V3 family of areas, and use the terminology of Smith et al. (J Neurosci 18:3816-3830, 1998), to refer to it as area V3B. Recordings from orientation-selective cells in the macaque V3 complex show that the great majority have the same orientational specificity when tested with oriented lines generated from kinetic stimuli or from luminance differences. We conclude that there is no present evidence for a visual area specialized for the processing of kinetic contours in the primate visual brain.

The relationship between cortical activation and perception investigated with invisible stimuli.

The aim of this work was to study the relationship between cortical activity and visual perception. To do so, we developed a psychophysical technique that is able to dissociate the visual percept from the visual stimulus and thus distinguish brain activity reflecting the perceptual state from that reflecting other stages of stimulus processing. We used dichoptic color fusion to make identical monocular stimuli of opposite color contrast "disappear" at the binocular level and thus become "invisible" as far as conscious visual perception is concerned. By imaging brain activity in subjects during a discrimination task between face and house stimuli presented in this way, we found that house-specific and face-specific brain areas are always activated in a stimulus-specific way regardless of whether the stimuli are perceived. Absolute levels of cortical activation, however, were lower with invisible stimulation compared with visible stimulation. We conclude that there is no terminal "perceptual" area in the visual brain, but that the brain regions involved in processing a visual stimulus are also involved in its perception, the difference between the two being dictated by a higher level of activity in the specific brain region when the stimulus is perceived.

Responses of spectrally selective cells in macaque area V2 to wavelengths and colors.

We have recorded from wavelength-selective cells in macaque monkey visual area V2, interposed between areas V1 and V4 of the color-specialized pathway, to learn whether their responses correlate with perceived colors or are determined by the wavelength composition of light reflected from their receptive fields. All the cells we recorded from were unselective for the orientation and direction of motion of the stimulus, and all were histologically identified to be in the thin cytochrome oxidase stripes. Using multi-colored "Mondrian" scenes of the appropriate spatial configuration, areas of different color were placed in the receptive field of each cell and the entire scene illuminated by three projectors, passing long-, middle-, and short-wave light, respectively, in various combinations. Our results show that wavelength-selective cells in V2 respond to an area of any color depending on whether or not it reflects a sufficient amount of light of their preferred wavelength. In addition, the responses of a third of the cells tested were also influenced by the wavelength composition of their immediate surrounds, thus signaling the result of a local spatial comparison with respect to the amount of their preferred wavelength present. The responses of all also depended on the sequence with which their receptive fields were illuminated with light of the three different wavebands: cells were activated when there was an increase (and inhibited when there was a decrease) in the amount of their preferred wavelength with respect to the other two; the temporal route taken was therefore a determining factor, and, depending on it, cells would either respond or not to a particular combination of wavelengths. We conclude that although spatiotemporal wavelength comparisons are taking place in the color-specialized subdivisions of area V2, the determination of complete color-constant behavior at the neuronal level requires further processing, in other areas.

Functional organization of macaque V3 for stereoscopic depth.

Recordings were made from single and small groups of cells in prestriate area V3 of the visual cortex of the Cynomolgus macaque (Macaca fascicularis). The majority of cells in V3 were selective for orientation and stereoscopic depth, these cells being segregated into two sets of functionally distinct columns. Orientation columns in V3 have been previously demonstrated; here we show that V3 also contains columns of segregated disparity-selective cells. On the basis of its cellular properties, functional organization, and intra-cortical connections, we propose that V3 contributes to the processing of stereoscopic depth information and that the parietal areas to which it projects use this information for the analysis of object depth and three-dimensional form.

Hepatocellular oxidative DNA injury induced by macrophage-derived nitric oxide.

Previous studies have indicated that splenic macrophages migrate into the liver and play a role in endotoxin-induced hepatic damage. The present study was designed to elucidate the mechanisms of hepatocyte injury induced by activated splenic macrophages, focusing especially on endogenously released NO and oxidative DNA alterations in hepatocytes. Splenic macrophages isolated from Wistar rats were incubated with either lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and cocultured with hepatocytes. Nitrite and nitrate levels in the culture medium were measured, and inducible-type NO synthase (iNOS) and nitrotyrosine were determined by immunofluorescence staining. The ratio of 8-hydroxy-deoxyguanosine (8-OH-dG) to deoxyguanosine (dG) was measured by high-performance liquid chromatography, and single-stranded DNA in hepatocytes was detected with acridine orange. NO release and nitrotyrosine expression in hepatocytes increased after 8 h of coculture with activated macrophages, and this coculture also induced increases in the 8-OH-dG/dG ratio and single-stranded DNA in the hepatocytes. These alterations were attenuated by superoxide dismutase (SOD) and NO synthesis inhibitors. A similar pattern of alterations was observed in hepatocytes incubated with SIN-1, and these changes were also prevented by SOD. These results suggest that activated macrophage-derived NO and its oxidative metabolite, peroxynitrite, play key roles in hepatocyte injury during inflammation, and cause subsequent DNA damage in surviving hepatocytes.