Exploring evolutionary trajectories in ovarian cancer patients by longitudinal analysis of ctDNA.

OBJECTIVES: We analysed whether temporal heterogeneity of ctDNA encodes evolutionary patterns in ovarian cancer. METHODS: Targeted sequencing of 275 cancer-associated genes was performed in a primary tumor biopsy and in ctDNA of six longitudinal plasma samples from 15 patients, using the Illumina platform. RESULTS: While there was low overall concordance between the mutational spectrum of the primary tumor biopsies vs. ctDNA, TP53 variants were the most commonly shared somatic alterations. Up to three variant clusters were detected in each tumor biopsy, likely representing predominant clones of the primary tumor, most of them harbouring a TP53 variant. By tracing these clusters in ctDNA, we propose that liquid biopsy may allow to assess the contribution of ancestral clones of the tumor to relapsed abdominal masses, revealing two evolutionary patterns. In pattern#1, clusters detected in the primary tumor biopsy were likely relapse seeding clones, as they contributed a major share to ctDNA at relapse. In pattern#2, similar clusters were present in tumors and ctDNA; however, they were entirely cleared from liquid biopsy after chemotherapy and were undetectable at relapse. ctDNA private variants were present among both patterns, with some of them mirroring subclonal expansions after chemotherapy. CONCLUSIONS: We demonstrate that tracing the temporal heterogeneity of ctDNA, even below exome scale resolution, deciphers evolutionary trajectories in ovarian cancer. Furthermore, we describe two evolutionary patterns that may help to identify relapse seeding clones for targeted therapy.

Rapid Antimicrobial Susceptibility Testing Using the MicroScan System: Performance Evaluation of a 4-Hour Bacterial Cultivation From Positive Blood Cultures.

A reliable and above all, rapid antimicrobial susceptibility test (AST) is required for the diganostics of blood stream infections (BSI). In this study, resistance testing using DxM MicroScan WalkAway (MicroScan) from a 4-h subculture is compared with the standard overnight culture (18-24 h). Randomly selected positive blood cultures (PBC, n = 102) with gram-negative bacteria were included in the study. PBC were sub-cultured onto appropriate agar plates and AST by MicroScan was performed after 4 h of incubation and repeated after incubation for 18-24 h as standard. In a total of 1909 drug-strain pairs, the 4-h subculture approach showed a very high essential agreement (EA) (98.6%) and categorical agreement (CA) (97.1%) compared with the standard. The incidence of minor error (mE), major error (ME), very major error (VME), and adjusted very major error (aVME) was 1.1%, 0.4%, 12.9%, and 5.3%, respectively. In summary, the use of 4-h subcultures for resistance testing with the MicroScan offers a very reliable and easy to realize time saving when testing positive blood cultures with gram-negative bacteria.

The time course of salience: not entirely caused by salience.

Visual salience is a key component of attentional selection, the process that guards the scarce resources needed for conscious recognition and perception. In previous works, we proposed a measure of visual salience based on a formal theory of visual selection. However, the strength of visual salience depends on the time course as well as local physical contrasts. Evidence from multiple experimental designs in the literature suggests that the strength of salience rises initially and declines after approximately 150 ms. The present article amends the theory-based salience measure beyond local physical contrasts to the time course of salience. It does so through a first experiment which reveals that-contrary to expectations-salience is not reduced during the first 150 ms after onset. Instead, the overall visual processing capacity is severely reduced, which corresponds to a reduced processing speed of all stimuli in the visual field. A second experiment confirms this conclusion by replicating the result. We argue that the slower stimulus processing may have been overlooked previously because the attentional selection mechanism had not yet been modeled in studies on the time course of salience.

The effect of the triazene compound CT913 on ovarian cancer cells in vitro and its synergistic interaction with the PARP-inhibitor olaparib.

OBJECTIVES: Extending the therapeutic spectrum of PARP-inhibitors (PARPi) beyond BRCA1-deficiency and/or overcoming PARPi-resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a possible strategy for defining new therapeutic standards. In this study, we analyzed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with the PARPi olaparib. METHODS: In vitro assays for drug characterization including RNA-Seq were applied in a selected panel of ovarian cancer cell lines. RESULTS: CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the higher micromolar range (553-1083 µM), whereas its metabolite CT913-M1 was up to 69-fold more potent, especially among long-term treatment (IC50 range: 8-138 µM). Neither of the drugs sensitized for cisplatin. CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that its effect is augmented by a deficiency in homologous recombination repair (HR). Furthermore, CT913 showed a synergistic interaction with olaparib, independently of BRCA1 mutational status. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It moreover downregulated a variety of transcripts involved in DNA-repair pathways. CONCLUSIONS: This is the first study, suggesting the novel triazene drug CT913 as enhancer drug for extending the therapeutic spectrum of PARPi.

Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples.

BACKGROUND: With the introduction of Olaparib treatment for BRCA-deficient recurrent ovarian cancer, testing for somatic and/or germline mutations in BRCA1/2 genes in tumor tissues became essential for treatment decisions. In most cases only formalin-fixed paraffin-embedded (FFPE) samples, containing fragmented and chemically modified DNA of minor quality, are available. Thus, multiplex PCR-based sequencing is most commonly applied in routine molecular testing, which is predominantly focused on the identification of known hot spot mutations in oncogenes. METHODS: We compared the overall performance of an adjusted targeted capture-based enrichment protocol and a multiplex PCR-based approach for calling of pathogenic SNVs and InDels using DNA extracted from 13 FFPE tissue samples. We further applied both strategies to seven blood samples and five matched FFPE tumor tissues of patients with known germline exon-spanning deletions and gene-wide duplications in BRCA1/2 to evaluate CNV detection based solely on panel NGS data. Finally, we analyzed DNA from FFPE tissues of 11 index patients from families suspected of having hereditary breast and ovarian cancer, of whom no blood samples were available for testing, in order to identify underlying pathogenic germline BRCA1/2 mutations. RESULTS: The multiplex PCR-based protocol produced inhomogeneous coverage among targets of each sample and between samples as well as sporadic amplicon drop out, leading to insufficiently or non-covered nucleotides, which subsequently hindered variant detection. This protocol further led to detection of PCR-artifacts that could easily have been misinterpreted as pathogenic mutations. No such limitations were observed by application of an adjusted targeted capture-based protocol, which allowed for CNV calling with 86% sensitivity and 100% specificity. All pathogenic CNVs were confirmed in the five matched FFPE tumor samples from patients carrying known pathogenic germline mutations and we additionally identified somatic loss of the second allele in BRCA1/2. Furthermore we detected pathogenic BRCA1/2 variants in four the eleven FFPE samples from patients of whom no blood was available for analysis. CONCLUSIONS: We demonstrate that an adjusted targeted capture-based enrichment protocol is superior to commonly applied multiplex PCR-based protocols for reliable BRCA1/2 variant detection, including CNV-detection, using FFPE tumor samples.

Prostate cancer patients' quality of life assessments across the primary treatment trajectory: 'True' change or response shift?

Background Self-report questionnaires are widely used to assess changes in quality of life (QoL) during the course of cancer treatment. However, comparing baseline scores to follow-up scores is only justified if patients' internal measurement standards have not changed over time, that is, no response shift occurred. We aimed to examine response shift in terms of reconceptualization, reprioritization and recalibration among prostate cancer patients. Material and methods We included 402 newly diagnosed patients (mean age 65 years) and assessed QoL at the beginning of cancer treatment and three months later. QoL was measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). We employed structural equation modeling testing measurement invariance between occasions to disentangle 'true' change and change in the measurement model (response shift). Results We found reprioritization effects for both the Physical Functioning and Role Functioning subscales of the EORTC QLQ-C30, indicating that both had gained importance for representing the latent construct of QoL at follow-up. These effects added to the worsening effect evident in the latent construct, thus rendering observed changes even more pronounced. In addition, we found recalibration effects for both the Emotional Functioning and Cognitive Functioning subscales indicating judgments becoming more lenient over time. These effects counteracted 'true' negative changes thus obscuring any substantial changes on the observed level. Conclusion Our results suggest that changes observed in some subscales of the EORTC QLQ-C30 should not be taken at face value as they may be affected by patients' changed measurement standards.

Non-invasive in vivo imaging by confocal laser scanning microscopy of gingival tissues following natural plaque deposition.

AIM: Imaging with Confocal Laser Scanning Microscopy (CLSM) generates high-resolution images and may be well suited for basic research in Periodontology and Implant Dentistry. The present study was aimed to explore the in vivo application of CLSM in experimentally induced gingivitis. MATERIALS AND METHODS: Ten subjects were recruited and were advised to stop any oral hygiene of the upper front teeth for 7 days. The gingival tissues were observed using a Heidelberg Retina Tomograph combined with a Rostock Cornea Module at baseline and day 7. The system used a laser of 670 nm and the contrast was given by backscattering from different tissues. Each examination created 800-1200 images that were descriptively analysed. RESULTS: After 7 days of abandoned oral hygiene, plaque scores and bleeding frequencies increased. By using CLSM images tooth hard substances, cells and plaque deposits were distinguishable. Increased epithelial cell irregularities, the apical migration of the sulcular epithelium, cellular infiltrates within the sulcus and plaque deposits were observed at day 7. CONCLUSIONS: The present study showed for the first time that CLSM is suitable for in vivo imaging of the gingival sulcus and adjacent tissues.

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC with high rates of metastasis. Targeted therapies such as tyrosine kinase and checkpoint inhibitors have improved treatment success, but therapy-related side effects and tumor recurrence remain a challenge. As a result, ccRCC still have a high mortality rate. Early detection before metastasis has great potential to improve outcomes, but no suitable biomarker specific for ccRCC is available so far. Therefore, molecular biomarkers derived from body fluids have been investigated over the past decade. Among them, RNAs from urine-derived extracellular vesicles (EVs) are very promising. METHODS: RNA was extracted from urine-derived EVs from a cohort of 78 subjects (54 ccRCC patients, 24 urolithiasis controls). RNA-seq was performed on the discovery cohort, a subset of the whole cohort (47 ccRCC, 16 urolithiasis). Reads were then mapped to the genome, and expression was quantified based on 100 nt long contiguous genomic regions. Cluster analysis and differential region expression analysis were performed with adjustment for age and gender. The candidate biomarkers were validated by qPCR in the entire cohort. Receiver operating characteristic, area under the curve and odds ratios were used to evaluate the diagnostic potential of the models. RESULTS: An initial cluster analysis of RNA-seq expression data showed separation by the subjects' gender, but not by tumor status. Therefore, the following analyses were done, adjusting for gender and age. The regions differentially expressed between ccRCC and urolithiasis patients mainly overlapped with small nucleolar RNAs (snoRNAs). The differential expression of four snoRNAs (SNORD99, SNORD22, SNORD26, SNORA50C) was validated by quantitative PCR. Confounder-adjusted regression models were then used to classify the validation cohort into ccRCC and tumor-free subjects. Corresponding accuracies ranged from 0.654 to 0.744. Models combining multiple genes and the risk factors obesity and hypertension showed improved diagnostic performance with an accuracy of up to 0.811 for SNORD99 and SNORA50C (p = 0.0091). CONCLUSIONS: Our study uncovered four previously unrecognized snoRNA biomarkers from urine-derived EVs, advancing the search for a robust, easy-to-use ccRCC screening method.

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer.

Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a BRCA1-proficient or BRCA1-deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the BRCA1-proficient vs. BRCA1-deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers.

Ultrasound Elastography in Neurosurgery: Current Applications and Future Perspectives.

BACKGROUND: Similar to clinical palpation, Ultrasound elastography (USE) helps distinguish between tissues by providing information on their elasticity. While it has been widely explored and has been applied to many body organs, USE has not been studied as extensively for application in neurosurgery. The current systematic review was performed to identify articles related to the use of interoperative USE in neurosurgery. METHODS: Search included MEDLINE(R) database. Only original peer-reviewed full-text articles were included. No language or publication year restrictions were imposed. Two independent reviewers assessed the search results for relevance. The identified articles were screened by title, abstract, and full-text review. RESULTS: Seventeen articles were included in the qualitative analysis and 13 articles were related to oncology, epilepsy (n = 3), and spine (n = 1). In oncology, USE was found useful in defining tumor stiffness, aiding surgical planning, detecting residual tumors, discriminating between tumor and brain tissue, and differentiating between different tumors. In epilepsy, USE could improve the detection of epileptogenic foci, thereby enhancing the prospect of complete and safe resection. The application in spinal surgery was limited to demonstrating that a compressed spinal cord is stiffer than the decompressed one. CONCLUSIONS: USE was found to be a safe, quick, portable, and economic tool that was a useful intraoperative adjunct to provide information corresponding to a variety of neurosurgical diseases, at different stages of surgery. This review describes the current intraoperative neurosurgical applications of USE, the concept of elasticity, and different USE modalities as well as the technical challenges, limitations, and possible future implications.

Plasma extracellular vesicle messenger RNA profiling identifies prognostic EV signature for non-invasive risk stratification for survival prediction of patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6-8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery. METHODS: Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan-Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR. RESULTS: Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis. CONCLUSION: This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.

Signaling-induced systematic repression of miRNAs uncovers cancer vulnerabilities and targeted therapy sensitivity.

Targeted therapies are effective in treating cancer, but success depends on identifying cancer vulnerabilities. In our study, we utilize small RNA sequencing to examine the impact of pathway activation on microRNA (miRNA) expression patterns. Interestingly, we discover that miRNAs capable of inhibiting key members of activated pathways are frequently diminished. Building on this observation, we develop an approach that integrates a low-miRNA-expression signature to identify druggable target genes in cancer. We train and validate our approach in colorectal cancer cells and extend it to diverse cancer models using patient-derived in vitro and in vivo systems. Finally, we demonstrate its additional value to support genomic and transcriptomic-based drug prediction strategies in a pan-cancer patient cohort from the National Center for Tumor Diseases (NCT)/German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication (MASTER) precision oncology trial. In conclusion, our strategy can predict cancer vulnerabilities with high sensitivity and accuracy and might be suitable for future therapy recommendations in a variety of cancer subtypes.

The Impact of Anxiety and Depression on Surgical and Functional Outcomes in Patients Who Underwent Radical Prostatectomy.

BACKGROUND: Depression and anxiety are associated with worse surgical outcomes and higher complication rates among various types of general or orthopedic surgeries. OBJECTIVE: To assess the impact of depression and anxiety on surgical, oncological, and functional outcomes in radical prostatectomy (RP) patients. DATA, SETTING, AND PARTICIPANTS: Retrospective analysis of 5862 RP patients (2014-2016). INTERVENTION: RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline depression and anxiety were assessed using the Patient Health Questionnaire-4 (PHQ-4) and categorized into 0-2 (normal), 3-5 (mild), and ≥6 (moderate to severe) points. Surgical outcomes included length of hospital stay (LOS), blood loss, and complications (Clavien-Dindo grading). Functional outcomes included urinary incontinence (UI) and erectile dysfunction (ED). Oncological outcomes focused on biochemical recurrence (BCR). Kaplan-Meier plots, multivariable logistic analyses, and Cox regression analyses were used. RESULTS AND LIMITATIONS: Overall, 28% patients had abnormal PHQ-4 scores and 8% a score ≥6 points. Higher PHQ-4 was significantly associated with worse surgical outcomes (longer LOS and higher complication rates) and higher risk for UI. No statistically significant difference was found for ED. However, we observed a higher use of phosphodiesterase type 5 inhibitors and intracavernous injection therapies among men with PHQ-4 score of ≥3. BCR was not affected by PHQ-4. The main limitations are the retrospective design as well as the lack of information on concomitant medications or follow-up PHQ-4 scores. CONCLUSIONS: Higher PHQ-4 scores are significantly associated with worse surgical outcomes and higher risk for UI. Our study highlights the importance of preoperative depression and anxiety assessment to optimize quality of life and to reduce health-related costs. PATIENT SUMMARY: Patients with preoperative depression or anxiety are at higher risk for postoperative complications and urinary incontinence after radical prostatectomy.

[Course of psychosocial distress and health-related quality of life in patients at different age groups during cancer rehabilitation]. / Verlauf der psychosozialen Belastung und gesundheitsbezogenen Lebensqualitat bei Patienten verschiedener Altersgruppen in der onkologischen Rehabilitation.

OBJECTIVES: This study investigates psychosocial distress and health-related quality of life in younger (up to 40 years), middle-aged (up to 50 years), and elderly cancer patients (up to 60 years). METHODS: 637 patients (94%women, 75% breast-cancer patients) completed validated questionnaires measuring distress, anxiety, depression, fear of progression, and quality of life at the beginning (T0) and the end (T1) of a cancer rehabilitation program (T0/T1 response rate: 72 %) as well as at 1-year follow-up (T2) (n = 485, T2 response rate: 76 %). RESULTS: Patients in the different age groups did not differ significantly in psychosocial distress at T0 except for fear of progression, which is lower among the younger age group. Elderly patients have a significantly lower physical quality of life. At the beginning of the rehabilitation program, patients in all age groups were significantly more anxious compared to population-based normative values, whereas higher depression was found only in younger and middle-aged patients. Patients in all age groups have a significantly lower quality of life compared to population-based normative values. In particular, large effect sizes were found for physical functioning domains. Patients in all age groups improve significantly in psychosocial distress and quality of life over time; however, significant interaction effects between age group and time were not observed in psychosocial distress and quality of life. CONCLUSIONS: Age differences are predominantly observed in physical quality-of-life dimensions rather than in psychosocial distress. This finding should be considered for the development of rehabilitation services.

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin.

IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.

Measuring Attention and Visual Processing Speed by Model-based Analysis of Temporal-order Judgments.

This protocol describes how to conduct temporal-order experiments to measure visual processing speed and the attentional resource distribution. The proposed method is based on a new and synergistic combination of three components: the temporal-order judgments (TOJ) paradigm, Bundesen's Theory of Visual Attention (TVA), and a hierarchical Bayesian estimation framework. The method provides readily interpretable parameters, which are supported by the theoretical and neurophysiological underpinnings of TVA. Using TOJs, TVA-based estimates can be obtained for a broad range of stimuli, whereas traditional paradigms used with TVA are mainly limited to letters and digits. Finally, the meaningful parameters of the proposed model allow for the establishment of a hierarchical Bayesian model. Such a statistical model allows assessing results in one coherent analysis both on the subject and the group level. To demonstrate the feasibility and versatility of this new approach, three experiments are reported with attention manipulations in synthetic pop-out displays, natural images, and a cued letter-report paradigm.

Measuring and modeling salience with the theory of visual attention.

For almost three decades, the theory of visual attention (TVA) has been successful in mathematically describing and explaining a wide variety of phenomena in visual selection and recognition with high quantitative precision. Interestingly, the influence of feature contrast on attention has been included in TVA only recently, although it has been extensively studied outside the TVA framework. The present approach further develops this extension of TVA's scope by measuring and modeling salience. An empirical measure of salience is achieved by linking different (orientation and luminance) contrasts to a TVA parameter. In the modeling part, the function relating feature contrasts to salience is described mathematically and tested against alternatives by Bayesian model comparison. This model comparison reveals that the power function is an appropriate model of salience growth in the dimensions of orientation and luminance contrast. Furthermore, if contrasts from the two dimensions are combined, salience adds up additively.

Fast and Conspicuous? Quantifying Salience With the Theory of Visual Attention.

Particular differences between an object and its surrounding cause salience, guide attention, and improve performance in various tasks. While much research has been dedicated to identifying which feature dimensions contribute to salience, much less regard has been paid to the quantitative strength of the salience caused by feature differences. Only a few studies systematically related salience effects to a common salience measure, and they are partly outdated in the light of new findings on the time course of salience effects. We propose Bundesen's Theory of Visual Attention (TVA) as a theoretical basis for measuring salience and introduce an empirical and modeling approach to link this theory to data retrieved from temporal-order judgments. With this procedure, TVA becomes applicable to a broad range of salience-related stimulus material. Three experiments with orientation pop-out displays demonstrate the feasibility of the method. A 4th experiment substantiates its applicability to the luminance dimension.

Adaptive optics assisted and optical coherence tomography guided fs-laser system for ophthalmic surgery in the posterior eye.

While fs-lasers are clinically established for surgery in the anterior eye, their use in the posterior eye is impeded by aberrations and focus position errors. We implemented a laboratory system to investigate whether fs-laser surgery in the posterior eye is made more feasible by aberration correction and tomographic image guidance. Aberration correction is obtained by adaptive optics (AO) and the image guidance is accomplished by optical coherence tomography (OCT). System characteristic measurements and cutting experiments were performed inside an eye model. By aberration correction, wavefront errors were reduced from 270 nm root-mean-square (rms) to 64 nm rms, ignoring Zernike terms for tilts and focus. The Strehl ratio of the assigned point spread function is improved from 0.11 to 0.78. The threshold pulse energy of laser-induced optical breakdown in water is lowered from about 3.0 to about 1.3???J measured at the eye model entrance. After laser cutting of a synthetic foil placed 300???m in front of porcine retinal tissue with the corrected system, postoperative three-dimensional OCT imaging showed no lesions in the tissue. Our results corroborate that AO and OCT will be two essential assistive components for possible clinical systems for fs-laser­based surgery in the posterior eye.

Measurement of Ex Vivo Porcine Lens Shape During Simulated Accommodation, Before and After fs-Laser Treatment.

PURPOSE: According to Helmholtz, accommodation is based on the flexibility of the crystalline lens, which decreases with age, causing presbyopia. With femtosecond (fs)-lentotomy treatment, it is possible to restore the flexibility of presbyopic lenses. The efficiency of the treatment can be systematically evaluated using the finite element method based on experimental data. The purpose of this study was to quantify the shape change of ex vivo lenses in different accommodation states according to the fs-lentotomy treatment. METHODS: Five lenses with ciliary body excised from ex vivo porcine eyes (age: approximately 6 months, exact age unknown) were stretched in an accommodation device before and after laser treatment. Depending on the accommodation state, the lens shape, reconstructed from lens thickness, diameter, and anterior and posterior curvature, was measured using optical coherence tomography (OCT). The complete lens shape was parameterized and each measured parameter was compared to the results of a control group (n = 5, age: approximately 6 months, exact age unknown) without treatment. RESULTS: The amplitudes of the parameters thickness (+140%), diameter (+54%), and anterior radius of curvature (+57%) significantly increased after treatment (P < 0.05), and showed no significant change for the control group. By contrast, the amplitude of the posterior radius of curvature showed no change after treatment (P > 0.05). CONCLUSIONS: Measurement of the lens shape in different accommodation states was successful and showed significant changes after the treatment. The resulting data will be utilized as input for a finite element model to systematically evaluate the effect of fs-lentotomy treatment in future work.