Comparison of Framingham risk score and chest-CT identified coronary artery calcification in breast cancer patients to predict cardiovascular events.

BACKGROUND: In breast cancer patients, coincidental detection of CAC at chest CT may be important in determining cardiovascular (CV) outcomes and facilitate CV disease primary prevention strategies. METHODS: 408 consecutive breast cancer patients referred to cardiac oncology clinic were included in the study. 256 patients without a prior history of coronary artery disease had undergone a chest CT. CT images were reviewed to detect CAC. Framingham risk score (FRS) was calculated and patient electronic medical records were interrogated to document the incidence of a composite clinical end point of all-cause mortality and cardiac events (coronary revascularization, heart failure hospitalization and de novo atrial fibrillation). Prevalence of statin prescribing was also collected. RESULTS: Patients were followed for a median of 6.5 years. 112 clinical events occurred. Clinical follow up was 98%. CAC was found in 26% of patients. On multivariable analysis, CAC and advance cancer stage, but not FRS predicted the composite clinical end point (OR for CAC 2.59, p < 0.01). CAC but not FRS also predicted the incidence of cardiac events (OR for CAC 4.90, p < 0.01). CAC was present in 7.3% of patients with low FRS; none had been prescribed a statin. In patients with CAC and FRS ≥ 10%, 45% were not on a statin. CONCLUSION: CAC is a common coincidental finding at CT chest in breast cancer patients referred to cardiac oncology. CAC but not FRS was predictive of composite clinical events and cardiac events. Detection of CAC at chest CT could alter the prescribing of primary prevention strategies to help prevent future cardiac events in breast cancer patients.

Reporting of coronary artery calcification on chest CT studies in breast cancer patients at high risk of cancer therapy related cardiac events.

BACKGROUND: The identification of coronary artery calcification (CAC) detected coincidentally on chest CT exams could assist in cardiovascular risk assessment but may not be reported consistently on clinical studies. Cardiovascular risk factor stratification is important to predict short term cardiac events during cancer therapy and long term cardiac event free survival in cancer patients. We sought to determine the prevalence of CAC and clinical reporting rates in a cohort of cancer patients at high risk of cancer therapy related cardiac events. METHODS: 408 Breast cancer patients who were referred to a cardiac oncology clinic were screened. Inclusion criteria included having had a CT chest and the absence of known coronary disease. Among those screened 263 patients were included in the study. RESULTS: CAC was identified in 70 patients (26%). CAC was reported in 18% of studies. The reporting rates of CAC increased with the extent of coronary calcification (p < 0.01) and increased during the period of the study (p < 0.05). CONCLUSIONS: CAC was commonly detected on chest CT studies in this observational study of breast cancer patients at high risk of cardiac oncology events. The presence of CAC was often not reported clinically but reporting rates have increased over time. Recent SCCT/STR guidelines recommend reporting the presence of CAC on routine chest CT scans in recognition of the importance of CAC as a predictor of cardiovascular events. Reporting of CAC on chest CTs may help to further risk stratify breast cancer patients and improve cardiovascular outcomes in this vulnerable population.

Multifluorophore localization as a percolation problem: limits to density and precision.

We show that the maximum desirable density of activated fluorophores in a superresolution experiment can be determined by treating the overlapping point spread functions as a problem in percolation theory. We derive a bound on the density of activated fluorophores, taking into account the desired localization accuracy and precision, as well as the number of photons emitted. Our bound on density is close to that reported in experimental work, suggesting that further increases in the density of imaged fluorophores will come at the expense of localization accuracy and precision.

Lengthening strategies for Peyronie's disease.

Loss of penile length is a common complaint of men with Peyronie's disease (PD), both before and after corrective intervention, which has a significant negative effect on patient quality of life. We sought to identify and describe the methods by which penile length can be preserved or increased. We conducted an extensive, systematic literature review, based on a search of the PUBMED database for articles published between 1990 and 2015. Articles with the key words "Peyronie's disease", "penile length" and/or "penile lengthening" were reviewed if they contained subjective or objective penile length outcomes. Only English-language articles that were related to PD and penile size were included. We found no evidence in the literature that medical therapy alone increases penile length. Classic inflatable penile prosthesis (IPP) placement, plication procedures, and the Nesbit procedure appear likely to maintain or decrease penile length. Plaque incision (PI) and grafting appears likely to maintain or increase penile length, but is complicated by risk of post-operative erectile dysfunction (ED). There are several surgical procedures performed concomitantly with IPP placement that may be suitable treatment options for men with comorbid ED, and consistently increase penile length with otherwise good outcomes concerning sexual function. These include the subcoronal penile prosthesis (scIPP), Egydio circumferential technique, the sliding technique, the modified sliding technique (MoST), and the multiple slice technique (MuST). In addition, adjuvant therapies such as penile traction therapy (PTT), post-operative inflation protocols, suspensory ligament relaxation, lipectomy, and adjuvant medical therapy for glans engorgement appear to increase subjective and/or objective penile length for men at high risk of decreased penile length after PD surgery. Considering the psychological burden of length loss in men with PD, providers with adequate volume and expertise should attempt, if possible, to maintain or increase penile length for men undergoing surgical intervention. There are several evidence-based, safe, and effective ways to increase penile length for these men and multiple emerging adjuvant therapies that may help ensure adequate length.

Fluorophore localization algorithms for super-resolution microscopy.

Super-resolution localization microscopy methods provide powerful new capabilities for probing biology at the nanometer scale via fluorescence. These methods rely on two key innovations: switchable fluorophores (which blink on and off and can be sequentially imaged) and powerful localization algorithms (which estimate the positions of the fluorophores in the images). These techniques have spurred a flurry of innovation in algorithm development over the last several years. In this Review, we survey the fundamental issues for single-fluorophore fitting routines, localization algorithms based on principles other than fitting, three-dimensional imaging, dipole imaging and techniques for estimating fluorophore positions from images of multiple activated fluorophores. We offer practical advice for users and adopters of algorithms, and we identify areas for further development.

Generalization of the optical theorem for light scattering from a particle at a planar interface.

The optical theorem provides a powerful tool for calculating the extinction cross section of a particle from a solution to Maxwell's equations, relating the cross section to the scattering amplitude in the forward direction. The theorem has been generalized by a number of other workers to consider a particle near an interface between media with different refractive indices. Here we present a derivation of the generalized optical theorem that is valid for a particle embedded in the interface, as well as an incident beam undergoing total internal reflection. We also obtain an additional useful physical result: we show that the far-field scattered field must be zero in the direction parallel to the interface. Our results enable the verification of computations of scattering by particles embedded in interfaces and may be relevant to experiments on colloidal particles at fluid interfaces.

Comparison of 3 upper tract anticarcinogenic agent delivery techniques in an ex vivo porcine model.

OBJECTIVE: To evaluate the degree of urothelial exposure using 3 upper tract delivery techniques in an ex vivo porcine model, to determine the optimal modality to locally deliver topical anticarcinogenic agents in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS: An indigo carmine solution was infused into en bloc porcine urinary tracts to test the 3 techniques: antegrade infusion via nephrostomy tube, reflux via indwelling double-pigtail stent, and retrograde administration via a 5F open-ended ureteral catheter. Nine renal units (3 per delivery method) were used. After a 1-hour dwell time, the urinary tracts were bivalved and photographed. Each renal unit was evaluated by 3 blinded reviewers who estimated the total percentage of stained urothelial surface area using a computer-based area approximation system. In addition, as a surrogate for exposure adequacy, a validated equation was used to calculate the staining intensity at 6 predetermined locations in the upper tract, with lower values representing more efficient staining. RESULTS: Mean percent of surface area stained for the nephrostomy tube, double-pigtail stent, and open-ended ureteral catheter groups was 65.2%, 66.2%, and 83.6%, respectively (P = .002). Mean staining intensities were 40.9, 33.4, and 20.4, respectively (P = .023). CONCLUSION: Our results suggest that retrograde infusion via open-ended ureteral catheter is the most efficient method of upper tract therapy delivery. Larger studies using in vivo models should be performed to further validate these findings and potentially confirm this method as optimal for delivery of topical anticarcinogenic agents in upper tract urothelial carcinoma.

Fast maximum likelihood algorithm for localization of fluorescent molecules.

A common task in microscopy is to fit an image of a fluorescent probe to a point spread function (PSF) in order to estimate the position of the probe. The PSF is often approximated as a Gaussian for mathematical simplicity. We show that the separable property of the Gaussian PSF enables a reduction of computational time from O(L2) to O(L), where L is the width (in pixels) of the image. When tested on realistic simulated data, our algorithm is able to localize the probes with precision close to the Cramér-Rao lower bound.

Model of bleaching and acquisition for superresolution microscopy controlled by a single wavelength.

We consider acquisition schemes that maximize the fraction of images that contain only a single activated molecule (as opposed to multiple activated molecules) in superresolution localization microscopy of fluorescent probes. During a superresolution localization microscopy experiment, irreversible photobleaching destroys fluorescent molecules, limiting the ability to monitor the dynamics of long-lived processes. Here we consider experiments controlled by a single wavelength, so that the bleaching and activation rates are coupled variables. We use variational techniques and kinetic models to demonstrate that this coupling of bleaching and activation leads to very different optimal control schemes, depending on the detailed kinetics of fluorophore activation and bleaching. Likewise, we show that the robustness of the acquisition scheme is strongly dependent on the detailed kinetics of activation and bleaching.

Optimal acquisition scheme for subwavelength localization microscopy of bleachable fluorophores.

We consider the problem of optimizing superresolution microscopy with photoswitchable molecules that irreversibly photobleach. Using variational methods, we show that the number of single-molecule images is maximized in a simple scheme with a constant number of activated fluorophores per cycle. For high-speed acquisition, deviations from the optimal scheme do reduce the information collected but fortuitously also reduce certain types of errors, making the scheme very robust. Finally, we calculate the amount of information lost due to bleaching and noise.

Topology of the heterogeneous nature of the extracellular matrix on stochastic modeling of tumor-induced angiogenesis.

We have modeled tumor-induced angiogenesis; our model includes the phenomena of the migratory response of endothelial cells (ECs) to tumor angiogenic factors, and the interaction of ECs with the extracellular matrix (ECM). ECs switch between growth, differentiation, motility, or apoptotic behavior in response to the local topology and composition of the ECM. Assuming the ECM medium as a statistically inhomogeneous medium (some area support sprout growth, some not), we show that the ECM can be a natural barrier to angiogenesis. We study vascular network formation for several ECM distributions and topologies, and we find an analogy with percolation. A threshold exists, under which sprouts cannot reach the tumor. During the growth of the vascular network, a competition exists between the attraction exerted by tumor and the preferred path created by the ECM. We also examined the influence of branching on the tumor vascularization. Branching is a natural phenomenon which helps the tumor become vascularized. By increasing the number of sprouts, the vascular network increases the probability of reaching the tumor, as it can explore more pathways. Our simulations show after two branching events, the vascular network is very likely to reach the tumor.

Thin films of oriented collagen fibrils for cell motility studies.

Collagen films with oriented fibrils mimic tissues that have been remodeled by fibroblasts, which naturally tend to orient collagen fibrils in vivo. We have prepared thin films of ordered fibrils of collagen I, a major component of the extracellular matrix. The films were prepared by modifying a technique previously used to produce collagen I films for studies of cell morphology and intracellular signaling. By modifying the drying step, we were able to produce thin monolayers of collagen fibrils with consistent orientations over macroscopic (>100 microm) distances. We quantified the degree of orientation of the collagen fibrils using Fourier analysis of optical microscopy images. We also conducted experiments with vascular endothelial cells, and found that cell orientation and migration are well-correlated with fibril orientation. Using polarized cells, we showed oriented thin collagen film induces natural migration along the fibrils without using any sort of attractor. Taken together, these results demonstrate additional functionality and physiological relevance for a class of films being successfully applied in a variety of cell biology experiments.

Delocalization of classical waves in highly anisotropic random media.

We discuss localization phenomena in multilayer films doped with scattering particles. If the films exhibit a particular type of transmission resonance then above a critical frequency waves in the sample can decay as a power law rather than exponentially. This phenomenon is independent of the scattering strength of the particles, in stark contrast to previous work. We find that this phenomenon has many similarities to a second order phase transition. This work points to interesting avenues in the study of waves in anisotropic disordered media.

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.

Stochastic modeling of tumor induced angiogenesis in a heterogeneous medium, the extracellular matrix.

Angiogenesis, the formation of blood vessels, is a process whereby capillary sprout are formed in response to external stimuli. We model the tumor induced angiogenesis on keys events such of migratory response of endothelial cells to tumor angiogenic factors and the local cell interaction with the extracellular matrix (ECM). We consider the ECM medium as a statistically inhomogeneous two-phase random medium. Numerical simulations of the model are presented. Using this model, we will compare the influence of ECM distribution on vascular network formation. By developing mathematical models of angiogenesis, we hope to provide a deeper insight into the mechanisms underlying angiogenesis.

Enhancing diffraction-limited images using properties of the point spread function.

We propose an algorithm to enhance diffraction-limited images based on pixel-to-pixel correlations introduced by the finite width of the Point Spread Function (PSF). We simulate diffraction-limited images of point sources by convolving the PSF of a diffraction-limited lens with simulated images, and enhance the blurred images with our algorithm. Our algorithm reduces the PSF width, increases the contrast, and reveals structure on a length scale half of that resolvable in the unenhanced image. Our enhanced images compare favorably with images enhanced by conventional Tikhonov regularization.