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[Therapeutic strategies in superior sulcus tumors: a model for combined modality therapy in non-small cell lung cancer].

Superior sulcus tumors have been individualized among other non-small cell lung cancers because of their characteristic clinical presentation in connection with their local extension to the chest wall and the brachial plexus. For a long time considered as marginally resectable, superior sulcus tumors have been treated since the early 1960's, with a combined approach including preoperative radiotherapy and curative-intent surgery. Surgical resection includes both thoracic, cervical and neurosurgical approach, and aims at obtaining complete resection, which has been identified as a determining prognostic factor in most reported series. Two recent phase II trials showed the benefit, both regarding resectability and local control rates, and survival of combined therapeutic strategies including induction platinum-based chemoradiation, extensive surgical resection, and adjuvant chemotherapy. Adjuvant radiotherapy is not recommended at the time, but needs to be re-evaluated regarding its recent technical optimisation. Similarly to other locally advanced non-small cell lung cancers, exclusive chemoradiation is the standard treatment of unresectable superior sulcus tumors. In this way, radiotherapy has shown to offer a prolonged analgesia in more than 75% of cases, and is associated with concurrent or sequential chemotherapy, with comparable results to those observed in stage III lung cancer. These developments make superior sulcus tumors a therapeutic model for locally advanced non-small cell lung cancer, whereby the benefit of combined multimodal strategies including induction chemoradiation and surgical resection are currently evaluated in phase III trials.

Carcinoma, Non-Small-Cell Lung↗

Dorfman-Berbaum-Metz method for statistical analysis of multireader, multimodality receiver operating characteristic data: validation with computer simulation.

RATIONALE AND OBJECTIVES: The authors examined the relationship between the critical P value (alpha) and the empirical type I error rate when using the Dorfman-Berbaum-Metz (DMB) method for analysis of variance in multireader, multimodality receiver operating characteristic (ROC) data. METHODS: The authors developed a linear mixed-effect model to generate continuous, normally distributed random decision variables containing multiple sources (components) of variation. A range of magnitudes for these variance components was used to stimulate experiments in which multiple readers (three or five) read imaged obtained with two modalities from the same set of cases with no re-reading. Three binormal population ROC curves, with areas of 0.962, 0.855, and 0.702, were included. Case-sample sizes ranged from 50 to 400, and either 50% or 10% of cases were actually positive. For each experiment, 2,000 data sets were analyzed by the computer program, and the proportion of 2,000 modality differences that was found to be statistically significant at an alpha level of .05 was tubulated. RESULTS: The test for modality difference performed well for the low and intermediate ROC curves, even with small case samples. For the high ROC curve, the small-sample results were conservative. No relationship between observed type I error rate and the magnitude of data correlation was evident. CONCLUSION: For typical ROC curves, the DBM method is robust in testing for modality effects in the null case, given a sufficient sample size. Instructions for obtaining a free copy of the software are given.

Analysis of Variance↗

Control of the refractive index in photopolymerizable materials for (2+1)D solitary wave guide formation.

We report an experimental and theoretical study on the optimization of (2+1)D self-written waveguide formation inside a photopolymerizable material. The accurate control of the refractive index value inside the bulk of the material during the polymerization process gives us the opportunity to define a virtual core and a virtual cladding for the system. The V value which characterizes the guidance properties of a fiber can be applied to this propagation. The control of the V value allows us to propagate single mode or multimode waveguides on a few centimeters. Numerical simulations of these waveguides based on a paraxial model including both photopolymerization and Kerr effect give very good agreement with our experimental results.

Journal Article↗

A least-squares parameter estimation algorithm for switched hammerstein systems with applications to the VOR.

A "Multimode" or "switched" system is one that switches between various modes of operation. When a switch occurs from one mode to another, a discontinuity may result followed by a smooth evolution under the new regime. Characterizing the switching behavior of these systems is not well understood and, therefore, identification of multimode systems typically requires a preprocessing step to classify the observed data according to a mode of operation. A further consequence of the switched nature of these systems is that data available for parameter estimation of any subsystem may be inadequate. As such, identification and parameter estimation of multimode systems remains an unresolved problem. In this paper, we 1) show that the NARMAX model structure can be used to describe the impulsive-smooth behavior of switched systems, 2) propose a modified extended least squares (MELS) algorithm to estimate the coefficients of such models, and 3) demonstrate its applicability to simulated and real data from the Vestibulo-Ocular Reflex (VOR). The approach will also allow the identification of other nonlinear bio-systems, suspected of containing "hard" nonlinearities.

Algorithms↗

Noninvasive imaging of oral premalignancy and malignancy.

Early detection of cancer and its precursors remains the best way to ensure patient survival and quality of life. Our specific aim is to test a multimodality approach to noninvasive diagnostics of oral premalignancy and malignancy. In the hamster cheek pouch model (120 hamsters), in vivo optical coherence tomography (OCT) and optical Doppler tomography (ODT) map epithelial, subepithelial, and vascular change throughout carcinogenesis. In vivo multiwavelength multiphoton (MPM) and second-harmonic generated (SHG) fluorescence techniques provided parallel data on surface and subsurface tissue structure, specifically collagen presence and structure, cellular presence, and vasculature. Images are diagnosed by two blinded, prestandardized investigators using a scale from 0 to 6 for all modalities. After sacrifice, histopathology is evaluated on a scale of 0 to 6. Imaging data are reproducibly obtained with good accuracy. Carcinogenesis-related structural and vascular changes are clearly visible to tissue depths of 2 mm. Sensitivity (OCT/ODT alone, 71 to 88%; OCT+MPMSHG, 79 to 91%) and specificity (OCT alone, 62 to 83%; OCT+MPMSHG, 67 to 90%) compare well with conventional techniques. Our conclusions are that OCT/ODT and MPM/SHG are promising noninvasive in vivo diagnostic modalities for oral dysplasia and malignancy.

Animals↗

GICPIdb: an archival repository of multimodal data focusing on pathological images for gastrointestinal cancers.

INTRODUCTION: Deep learning (DL) shows great potential for predicting biomarkers from routine histopathological slides of gastrointestinal (GI) cancers. Yet most existing models are validated on limited patient cohorts, while pathological image annotation and molecular marker standardization demand substantial professional expertise. To address these gaps, we constructed the Gastrointestinal Cancer Pathological Image Archive (GICPIdb, gicpidb.shubuzuo.top), a dedicated database and web platform covering seven major GI cancer types. METHODS: High-quality hematoxylin and eosin (H&E)-stained whole-slide images were collected from multiple sources and uniformly processed. Image annotations were performed by board-certified pathologists following standardized protocols. GICPIdb offers five interactive web modules for data uploading, quality control, feature extraction, online annotation and AI-based prediction. Its intuitive interface supports data browsing, retrieval, visualization and downloading. RESULTS: The database houses 2,863 pathologist-annotated, uniformly processed, high-quality H&E stained images collected from 2,655 patients. Of these, 1,699 patients were sourced from The Cancer Genome Atlas (TCGA), 182 from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and 424 from China-Japan Friendship Hospital and 350 from Chifeng Municipal Hospital in Inner Mongolia, China. It also integrates data on over 50 key molecular markers (e.g., MSI, TMB) and prognostic labels related to survival, recurrence and metastasis. DISCUSSION: GICPIdb aims to promote the development of DL-driven AI tools for cancer research and clinical translation. The multi-institutional data collection and standardized annotation pipeline are expected to enhance the generalizability and reproducibility of AI-based prediction models across diverse patient populations.

deep learning↗

Crossmodal integration in the identification of consonant segments.

Although speechreading can be facilitated by auditory or tactile supplements, the process that integrates cues across modalities is not well understood. This paper describes two "optimal processing" models for the types of integration that can be used in speechreading consonant segments and compares their predictions with those of the Fuzzy Logical Model of Perception (FLMP, Massaro, 1987). In "pre-labelling" integration, continuous sensory data is combined across modalities before response labels are assigned. In "post-labelling" integration, the responses that would be made under unimodal conditions are combined, and a joint response is derived from the pair. To describe pre-labelling integration, confusion matrices are characterized by a multidimensional decision model that allows performance to be described by a subject's sensitivity and bias in using continuous-valued cues. The cue space is characterized by the locations of stimulus and response centres. The distance between a pair of stimulus centres determines how well two stimuli can be distinguished in a given experiment. In the multimodal case, the cue space is assumed to be the product space of the cue spaces corresponding to the stimulation modes. Measurements of multimodal accuracy in five modern studies of consonant identification are more consistent with the predictions of the pre-labelling integration model than the FLMP or the post-labelling model.

Attention↗

Multimodal integration of EEG, MEG and fMRI data for the solution of the neuroimage puzzle.

In this paper, advanced methods for the modeling of human cortical activity from combined high-resolution electroencephalography (EEG), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) data are presented. These methods include a subject's multicompartment head model (scalp, skull, dura mater, cortex) constructed from magnetic resonance images, multidipole source model and regularized linear inverse source estimates of cortical current density. Determination of the priors in the resolution of the linear inverse problem was performed with the use of information from the hemodynamic responses of the cortical areas as revealed by block-designed (strength of activated voxels) fMRI. Examples of the application of these methods to the estimation of the time varying cortical current density activity in selected region of interest (ROI) are presented for movement-related high-resolution EEG data.

Algorithms↗

The evolution of acute stroke recorded by multimodal magnetic resonance imaging.

Events associated with an evolving cerebral infarction were studied using multiple magnetic resonance imaging (MRI) techniques at 4.7 T in a rat model of middle cerebral artery occlusion. High resolution perfusion images revealed a core of absent perfusion surrounded by a zone of slow, but measurable perfusion. Only the core of severest perfusion deficit demonstrated restricted water diffusion as early as 1 hr, consistent with "cytotoxic" cellular edema in the most vulnerable region. Within 24 hours, the area of restricted diffusion encompassed the entire region destined to become infarcted. In spin-echo images, hypointensity, likely reflecting deoxygenated hemoglobin, was visible in the ischemic hemisphere. Edema accumulated over 72 hr primarily in the surrounding slowly perfused rim, consistent with the concept of "vasogenic" edema. These studies demonstrate that multimodal MRI can visualize events which define the ischemic penumbra--deoxygenation, maintenance of transmembrane ionic gradients, reduced flow, and delayed cell death. These experiments noninvasively visualized differential hemodynamic and biochemical processes within the core and perifocal penumbra and will allow quantitation over time of the relationship between blood flow, cytotoxicity and edema in stroke.

Acute Disease↗

Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma.

OBJECT: Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas. METHODS: A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm. Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size. CONCLUSIONS: Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

Adenoma↗

[Prediction of postoperative nausea and vomiting using an artificial neural network].

OBJECTIVE: Postoperative nausea and vomiting (PONV) are still frequent side-effects after general anaesthesia. These unpleasant symptoms for the patients can be sufficiently reduced using a multimodal antiemetic approach. However, these efforts should be restricted to risk patients for PONV. Thus, predictive models are required to identify these patients before surgery. So far all risk scores to predict PONV are based on results of logistic regression analysis. Artificial neural networks (ANN) can also be used for prediction since they can take into account complex and non-linear relationships between predictive variables and the dependent item. This study presents the development of an ANN to predict PONV and compares its performance with two established simplified risk scores (Apfel's and Koivuranta's scores). METHODS: The development of the ANN was based on data from 1,764 patients undergoing elective surgical procedures under balanced anaesthesia. The ANN was trained with 1,364 datasets and a further 400 were used for supervising the learning process. One of the 49 ANNs showing the best predictive performance was compared with the established risk scores with respect to practicability, discrimination (by means of the area under a receiver operating characteristics curve) and calibration properties (by means of a weighted linear regression between the predicted and the actual incidences of PONV). RESULTS: The ANN tested showed a statistically significant ( p<0.0001) and clinically relevant higher discriminating power (0.74; 95% confidence interval: 0.70-0.78) than the Apfel score (0.66; 95% CI: 0.61-0.71) or Koivuranta's score (0.69; 95% CI: 0.65-0.74). Furthermore, the agreement between the actual incidences of PONV and those predicted by the ANN was also better and near to an ideal fit, represented by the equation y=1.0x+0. The equations for the calibration curves were: KNN y=1.11x+0, Apfel y=0.71x+1, Koivuranta 0.86x-5. CONCLUSION: The improved predictive accuracy achieved by the ANN is clinically relevant. However, the disadvantages of this system prevail because a computer is required for risk calculation. Thus, we still recommend the use of one of the simplified risk scores for clinical practice.

Artificial Intelligence↗

Identification of degenerate neuronal systems based on intersubject variability.

Group studies implicitly assume that all subjects activate one common system to sustain a particular cognitive task. Intersubject variability is generally treated as well-behaved and uninteresting noise. However, intersubject variability might result from subjects engaging different degenerate neuronal systems that are each sufficient for task performance. This would produce a multimodal distribution of intersubject variability. We have explored this idea with the help of Gaussian Mixture Modeling and Bayesian model comparison procedures. We illustrate our approach using a crossmodal priming paradigm, in which subjects perform a semantic decision on environmental sounds or their spoken names that were preceded by a semantically congruent or incongruent picture or written name. All subjects consistently activated the superior temporal gyri bilaterally, the left fusiform gyrus and the inferior frontal sulcus. Comparing a One and Two Gaussian Mixture Model of the unexplained residuals provided very strong evidence for two groups with distinct activation patterns: 6 subjects exhibited additional activations in the superior temporal sulci bilaterally, the right superior frontal and central sulcus. 11 subjects showed increased activation in the striate and the right inferior parietal cortex. These results suggest that semantic decisions on auditory-visual compound stimuli might be accomplished by two overlapping degenerate neuronal systems.

Acoustic Stimulation↗

Modeling global and focal hyperarticulation during human-computer error resolution.

When resolving errors with interactive systems, people sometimes hyperarticulate--or adopt a clarified style of speech that has been associated with increased recognition errors. The primary goals of the present study were: (1) to provide a comprehensive analysis of acoustic, prosodic, and phonological adaptations to speech during human-computer error resolution after different types of recognition error; and (2) to examine changes in speech during both global and focal utterance repairs. A semi-automatic simulation method with a novel error-generation capability was used to compare speech immediately before and after system recognition errors. Matched original-repeat utterance pairs then were analyzed for type and magnitude of linguistic adaption during global and focal repairs. Results indicated that the primary hyperarticulate changes in speech following all error types were durational, with increases in number and length of pauses most noteworthy. Speech also was adapted toward a more deliberate and hyperclear articulatory style. During focal error repairs, large durational effects functioned together with pitch and amplitude to provide selective prominence marking of the repair region. These results corroborate and generalize the computer-elicited hyperarticulate adaptation model (CHAM). Implications are discussed for improved error handling in next-generation spoken language and multimodal systems.

Computers↗

Multimodal pattern formation in phenotype distributions of sexual populations.

During bouts of evolutionary diversification, such as adaptive radiations, the emerging species cluster around different locations in phenotype space. How such multimodal patterns in phenotype space can emerge from a single ancestral species is a fundamental question in biology. Frequency-dependent competition is one potential mechanism for such pattern formation, as has previously been shown in models based on the theory of adaptive dynamics. Here, we demonstrate that also in models similar to those used in quantitative genetics, phenotype distributions can split into multiple modes under the force of frequency-dependent competition. In sexual populations, this requires assortative mating, and we show that the multimodal splitting of initially unimodal distributions occurs over a range of assortment parameters. In addition, assortative mating can be favoured evolutionarily even if it incurs costs, because it provides a means of alleviating the effects of frequency dependence. Our results reveal that models at both ends of the spectrum between essentially monomorphic (adaptive dynamics) and fully polymorphic (quantitative genetics) yield similar results. This underscores that frequency-dependent selection is a strong agent of pattern formation in phenotype distributions, potentially resulting in adaptive speciation.

Animals↗

Interaction of vestibular, somatosensory and visual signals for postural control and motion perception under terrestrial and microgravity conditions--a conceptual model.

This article considers the intersensory interaction mechanisms and biomechanical aspects of human spatially oriented behavior and asks to what extent these are interrelated on earth by gravity and how they might be affected under microgravity. The interactions between vestibular, somatosensory and visual inputs for postural control are obscured by several complications (biomechanics, multi-body dynamics, multimodal feedback control, cognition etc.). However, they can be revealed in psychophysical studies on human self-motion perception. Based on such studies, we present a conceptual model, which we think is valid also for postural control. It accounts for the multi-segmental structure of the body, allowing local control of inter-segmental joints, but uses one global reference system for all segments, which is derived from the intersensory interactions. We hold that, at a sensory level, the system is tied together by linkages between vestibular, visual and somatosensory information which develop through experience of inertial and gravitational reaction forces. On earth these linkages are established even in the absence of active behavior by gravity, allowing the incorporation of one's body and its support into a notion (Gestalt) of ourselves in the environment. Under microgravity, in contrast, the linkages have to be actively established for postural and perceptual stability in the environment (e.g., by grasping a handle on the wall). From this work we recommend that future research under altered gravity conditions should be guided by models that include biomechanics, considerations of intersensory interaction and dynamic control mechanisms. Such an integrative conceptual framework will be helpful for reaching a general understanding of spatially oriented behavior.

Gravitation↗

Molecular imaging reveals skeletal engraftment sites of transplanted bone marrow cells.

Molecular imaging holds great promise for the in vivo study of cell therapy. Our hypothesis was that multimodality molecular imaging can identify the initial skeletal engraftment sites post-bone marrow cell transplantation. Utilizing a standard mouse model of bone marrow (BM) transplantation, we introduced a combined bioluminescence (BLI) and positron emission tomography (PET) imaging reporter gene into mouse bone marrow cells. Bioluminescence imaging was used for monitoring serially the early in vivo BM cell engraftment/expansion every 24 h. Significant cell engraftment/expansion was noted by greatly increased bioluminescence about 1 week posttransplant. Then PET was applied to acquire three-dimensional images of the whole-body in vivo biodistribution of the transplanted cells. To localize cells in the skeleton, PET was followed by computed tomography (CT). Co-registration of PET and CT mapped the sites of BM engraftment. Multiple, discrete BM cell engraftment sites were observed. Taken together, this multimodality approach may be useful for further in vivo characterization of various therapeutic cell types.

Animals↗

A multimodal, multidimensional atlas of the C57BL/6J mouse brain.

Strains of mice, through breeding or the disruption of normal genetic pathways, are widely used to model human diseases. Atlases are an invaluable aid in understanding the impact of such manipulations by providing a standard for comparison. We have developed a digital atlas of the adult C57BL/6J mouse brain as a comprehensive framework for storing and accessing the myriad types of information about the mouse brain. Our implementation was constructed using several different imaging techniques: magnetic resonance microscopy, blockface imaging, classical histology and immunohistochemistry. Along with raw and annotated images, it contains database management systems and a set of tools for comparing information from different techniques. The framework allows facile correlation of results from different animals, investigators or laboratories by establishing a canonical representation of the mouse brain and providing the tools for the insertion of independent data into the same space as the atlas. This tool will aid in managing the increasingly complex and voluminous amounts of information about the mammalian brain. It provides a framework that encompasses genetic information in the context of anatomical imaging and holds tremendous promise for producing new insights into the relationship between genotype and phenotype. We describe a suite of tools that enables the independent entry of other types of data, facile retrieval of information and straightforward display of images. Thus, the atlas becomes a framework for managing complex genetic and epigenetic information about the mouse brain. The atlas and associated tools may be accessed at http://www.loni.ucla.edu/MAP.

Anatomy, Artistic↗