Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

Rural versus urban commuting patients with stage III colon cancer: is there a difference in treatment and outcome?

BACKGROUND: To evaluate if there are differences in outcomes for patients with stage III colon cancer in those from urban vs. rural commuting areas. METHODS: Data were evaluated on patients diagnosed with stage III colon cancer between 2012 and2018 from the Louisiana Tumor Registry. Patients were classified into rural and urban groups. Data on overall survival, time from diagnosis to surgery and time from surgery to chemotherapy, and sociodemographic factors (including race, age, and poverty level) were recorded. RESULTS: Of 2652 patients identified, 2159 were urban (81.4%) and 493 rural (18.6%). No age difference between rural and urban patients (p = 0.56). Stage IIIB accounted for 66.7%, followed by IIIC (21.6%) and IIIA (11%), with a significant difference between rural and urban patients based on stage (p = 0.02). There was no difference in the extent of surgery (p = 0.34) or tumor size (p = 0.72) between urban and rural settings. No difference in undergoing chemotherapy (p = 0.12). There was a statistically significant difference in receiving timely treatment for hospital volume (p < 0.0001) and poverty level (p < 0.0001), but no difference in time from diagnosis to surgery (p = 0.48), and time from surgery to chemotherapy (p = 0.27). Non-Hispanic Blacks were less likely to receive timely treatment when compared with non-Hispanic Whites for both surgery and adjuvant chemotherapy, (aHR 0.91, 95% CI 0.83-0.99) and (aHR 0.86, 95% CI 0.77-0.97), respectively. There was no difference in Kaplan-Meier overall survival curves comparing rural vs. urban patients (p = 0.77). CONCLUSIONS: There was no statistical difference in overall survival, time to surgery, and time to adjuvant chemotherapy between rural and urban patients with Stage III colon cancer.

Positive impact of the Patient Protection and Affordable Care Act Medicaid expansion on Louisiana women with breast cancer.

BACKGROUND: Louisiana is one of the few Southern states that enacted the Medicaid expansion of the Patient Protection and Affordable Care Act (ACA). To the authors' knowledge, the issue of how this has affected the breast cancer landscape in Louisiana is unknown. The authors have postulated that ACA expansion had a positive impact for Louisiana women diagnosed with breast cancer. METHODS: Data from the Louisiana Tumor Registry regarding 14,640 women aged 20 to 64 years who resided in Louisiana and were diagnosed with American Joint Committee on Cancer stage 0 to stage IV breast cancer between 2012 and 2018 were analyzed. The study period was divided into 2 groups: 1) before ACA expansion (January 1, 2012-May 31, 2016); and 2) after ACA expansion (June 1, 2016-December 31, 2018). The chi-square test and multivariable logistic regression models were used to assess the impact of ACA expansion. A P value <.05 was considered statistically significant. RESULTS: After ACA expansion, the rate of uninsured patients decreased from 5.4% to 3.0% (P < .0001), and the rate of Medicaid recipients increased from 11.6% to 17.7% (P < .0001). The diagnosis of stage I breast cancer increased from 36.8% to 44.7% (P < .0001), whereas the diagnosis of stage III breast cancer decreased from 10.7% to 8.5% (P < .0001). The receipt of radiotherapy after breast-conserving surgery increased from 81.2% to 84.0% (P = .0035), and the receipt of radiotherapy within 90 days increased from 57.2% to 61.7% (P = .0012). After adjustment for sociodemographic and clinical variables, the models demonstrated that ACA expansion decreased the uninsured rate by 48% (odds ratio [OR], 0.52; 95% CI, 0.43-0.63), increased the diagnosis of early-stage disease (stage0 to stage II) by 27% (OR, 1.27; 95% CI, 1.15-1.41), increased receipt of radiotherapy after breast-conserving surgery by 19% (OR, 1.19; 95% CI, 1.03-1.37), and reduced the delay of receipt of radiotherapy by 16% (OR, 0.84; 95% CI, 0.74-0.95). CONCLUSIONS: ACA expansion in Louisiana reduced the uninsured rate, increased the diagnosis of early-stage disease, and increased access to treatment.

Controlling the Speed of Light-Activated Colloids with a Constant, Uniform Magnetic Field.

It is demonstrated how the strength of activation for photocatalytic, self-propelled colloids can be enhanced with a constant, uniform magnetic field. When exposed to ultraviolet light and hydrogen peroxide, the titanium dioxide-based colloids become actively propelled. Due to the iron oxide core, a uniform field oriented perpendicular to the surface where motion takes place causes the asymmetrically shaped particles to rotate, which consequently leads to an increase in activity. The field-dependent dynamics of self-propulsion is quantified, and a qualitative description of how this effect arises is proposed. Since the application of the field is easily reversible, modulating the field on-and-off serves as a de facto "switch" that controls particle behavior.

Shape- and Material-Dependent Self-Propulsion of Photocatalytic Active Colloids, Interfacial Effects, and Dynamic Interparticle Interactions.

Active colloids powered by self-generated, local chemical concentration gradients exhibit dynamics that are a function of the particles' morphology and material properties. These characteristics also govern how the active colloids interact with surfaces, including other particles and nearby walls. Thus, by targeted design, the dynamic behavior, on average, can be engineered, despite a lack of "external" control such as an applied magnetic field. This allows for the development of new applications and the investigation of novel effects that arise when self-propelled active colloids have complex shapes and material composition. Here, we explore some of our recent work on this topic including the dynamics and interactions of photoactivated, self-propelled colloids with such multifaceted properties. We also delve into some special cases, such as a new variety of active particle-particle interaction that we recently developed, in which direct contact between the active colloids is forbidden, and the direction of propulsion for pairs of particles is correlated. The unifying theme of the work highlighted herein is the relationship between the physical, chemical, and material properties of active colloids and their motive behavior, the understanding of which opens up a wide range of new possibilities as we move toward the ultimate goal of realizing functional, man-made micro- and nanomachinery.

Shape-Dependent, Chiro-optical Response of UV-Active, Nanohelix Metamaterials.

We harness a synergy between morphology and the electromagnetic response of semiconducting material to engineer the chiro-optical properties of metamaterials that are active at ultraviolet (UV) wavelengths. Chiral metamaterials have recently ushered in new research directions in fundamental light-matter interactions, while simultaneously opening a range of promising photonics-based applications from polarization control to improved biosensing methods. Despite these recent advances, to date, very little attention has been focused upon engineered large UV-chiro-optical activity, where naturally occurring molecular optical activity bands are most typically encountered. Here, we systematically alter the morphology of titanium dioxide nanohelices, which make up the elements of the chiral metamaterials, to investigate how the nanoparticle shape affects chiro-optical activity across the UV spectrum. When the nanoscale critical dimensions fall within a particular size range, giant chiro-optical activity is observed, which is on the order of the strongest demonstrated in the UV to date and can be tuned by slight alterations of the nanohelices' morphology.

Defend, Stand By, or Join In?: The Relative Influence of Moral Identity, Moral Judgment, and Social Self-Efficacy on Adolescents' Bystander Behaviors in Bullying Situations.

In bullying situations, adolescent bystanders may help bullied others, just stand by, or join in the antisocial behavior. Current studies have yet to fully examine the moral and social factors motivating these varied responses to bullying encounters. Extending from pertinent developmental theories, the present study investigated the relative contributions of moral identity (i.e., viewing moral qualities as central to the self), moral judgment, and social self-efficacy to adolescents' bystander behaviors vis-à-vis bullies. Also investigated were the interactions among these variables. Three hundred and thirty-seven adolescents (M age = 13 years, 56.1% female) who self-identified as Caucasian (90.2%), Hispanic-American (2.1%), Asian-American (0.9%), African-American (3.9%), or Other/Unknown (2.9%) participated in the study. Students completed questionnaires assessing moral identity, moral judgment, social self-efficacy, and how they would respond if they observed a peer being bullied. Moral identity predicted more prosocial action, particularly for adolescents high in social self-efficacy. Moral identity related positively to moral judgment, and both predicted less antisocial (joining in) behavior. Interestingly, moral judgment maturity primarily diminished antisocial behavior when moral identity was relatively low. Social self-efficacy predicted less passive bystanding. Overall, moral identity strongly relates to defending behavior, and-as does moral judgment maturity-predicts less antisocial behavior among bystanders.

Light-Activated, Multi-Semiconductor Hybrid Microswimmers.

Using a dynamic fabrication process, hybrid, photoactivated microswimmers made from two different semiconductors, titanium dioxide (TiO2 ) and cuprous oxide (Cu2 O) are developed, where each material occupies a distinct portion of the multiconstituent particles. Structured light-activated microswimmers made from only TiO2 or Cu2 O are observed to be driven in hydrogen peroxide and water most vigorously under UV or blue light, respectively, whereas hybrid structures made from both of these materials exhibit wavelength-dependent modes of motion due to the disparate responses of each photocatalyst. It is also found that the hybrid particles are activated in water alone, a behavior which is not observed in those made from a single semiconductor, and thus, the system may open up a new class of fuel-free photoactive colloids that take advantage of semiconductor heterojunctions. The TiO2 /Cu2 O hybrid microswimmer presented here is but an example of a broader method for inducing different modes of motion in a single light-activated particle, which is not limited to the specific geometries and materials presented in this study.

Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia.

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously. Evolocumab area under concentration-time curve from 8 to 12 weeks (AUCwk8-12) was simulated for individuals using the popPK model and was used to predict the LDL-C response in relation to AUCwk8-12. Evolocumab was eliminated through nonspecific (linear) and target-mediated (nonlinear) clearance. PopPK parameters and associated variabilities of evolocumab were similar to those of other monoclonal antibodies. The exposure-response model predicted a maximal 66% reduction in LDL-C from baseline to the mean of weeks 10 and 12 for doses of evolocumab 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. After inclusion of statistically significant covariates in an uncertainty-based simulation, LDL-C reduction from baseline at the mean of weeks 10 and 12 was predicted to be within 74% to 126% of the reference patient for all simulated patient groups. Evolocumab had nonlinear pharmacokinetics. The range of responses based on intrinsic and extrinsic factors was not predicted to be sufficiently different from the reference patient to warrant evolocumab dose adjustment.

Active Nanorheology with Plasmonics.

Nanoplasmonic systems are valued for their strong optical response and their small size. Most plasmonic sensors and systems to date have been rigid and passive. However, rendering these structures dynamic opens new possibilities for applications. Here we demonstrate that dynamic plasmonic nanoparticles can be used as mechanical sensors to selectively probe the rheological properties of a fluid in situ at the nanoscale and in microscopic volumes. We fabricate chiral magneto-plasmonic nanocolloids that can be actuated by an external magnetic field, which in turn allows for the direct and fast modulation of their distinct optical response. The method is robust and allows nanorheological measurements with a mechanical sensitivity of ∼0.1 cP, even in strongly absorbing fluids with an optical density of up to OD ∼ 3 (∼0.1% light transmittance) and in the presence of scatterers (e.g., 50% v/v red blood cells).

Compliance Disengagement in Research: Development and Validation of a New Measure.

In the world of research, compliance with research regulations is not the same as ethics, but it is closely related. One could say that compliance is how most societies with advanced research programs operationalize many ethical obligations. This paper reports on the development of the How I Think about Research (HIT-Res) questionnaire, which is an adaptation of the How I Think (HIT) questionnaire that examines the use of cognitive distortions to justify antisocial behaviors. Such an adaptation was justified based on a review of the literature on mechanisms of moral disengagement and self-serving biases, which are used by individuals with normal personalities in a variety of contexts, including research. The HIT-Res adapts all items to refer to matters of research compliance and integrity rather than antisocial behaviors. The HIT-Res was administered as part of a battery of tests to 300 researchers and trainees funded by the US National Institutes of Health. The HIT-Res demonstrated excellent reliability (Cronbach's alpha = .92). Construct validity was established by the correlation of the HIT-Res with measures of moral disengagement (r = .75), cynicism (r = .51), and professional decision-making in research (r = -.36). The HIT-Res will enrich the set of assessment tools available to instructors in the responsible conduct of research and to researchers who seek to understand the factors that influence research integrity.

Rotational Analysis of Spherical, Optically Anisotropic Janus Particles by Dynamic Microscopy.

We analyze the rotational dynamics of spherical colloidal Janus particles made from silica (SiO2) with a hemispherical gold/palladium (Au/Pd) cap. Since the refractive index difference between the surrounding fluid and a two-faced, optically anisotropic Janus microsphere is a function of the particle's orientation, it is possible to observe its rotational dynamics with bright-field optical microscopy. We investigate rotational diffusion and constant rotation of single Janus microspheres which are partially tethered to a solid surface so they are free to rotate but show little or no translational motion. Also, since the metal cap is a powerful catalyst in the breakdown of hydrogen peroxide, H2O2, the particles can be activated chemically. In this case, we analyze the motion of coupled Janus dimers which undergo a stable rotary motion about a mutual center. The analysis of both experimental and simulation data, which are microscopy and computer-generated videos, respectively, is based upon individual particle tracking and differential dynamic microscopy (DDM). DDM, which typically requires ensemble averages to extract meaningful information for colloidal dynamics, can be effective in certain situations for systems consisting of single entities. In particular, when translational motion is suppressed, both rotational diffusion and constant rotation can be probed.

Self-propelling nanomotors in the presence of strong Brownian forces.

Motility in living systems is due to an array of complex molecular nanomotors that are essential for the function and survival of cells. These protein nanomotors operate not only despite of but also because of stochastic forces. Artificial means of realizing motility rely on local concentration or temperature gradients that are established across a particle, resulting in slip velocities at the particle surface and thus motion of the particle relative to the fluid. However, it remains unclear if these artificial motors can function at the smallest of scales, where Brownian motion dominates and no actively propelled living organisms can be found. Recently, the first reports have appeared suggesting that the swimming mechanisms of artificial structures may also apply to enzymes that are catalytically active. Here we report a scheme to realize artificial Janus nanoparticles (JNPs) with an overall size that is comparable to that of some enzymes ∼30 nm. Our JNPs can catalyze the decomposition of hydrogen peroxide to water and oxygen and thus actively move by self-electrophoresis. Geometric anisotropy of the Pt-Au Janus nanoparticles permits the simultaneous observation of their translational and rotational motion by dynamic light scattering. While their dynamics is strongly influenced by Brownian rotation, the artificial Janus nanomotors show bursts of linear ballistic motion resulting in enhanced diffusion.

Hybrid nanocolloids with programmed three-dimensional shape and material composition.

Tuning the optical, electromagnetic and mechanical properties of a material requires simultaneous control over its composition and shape. This is particularly challenging for complex structures at the nanoscale because surface-energy minimization generally causes small structures to be highly symmetric. Here we combine low-temperature shadow deposition with nanoscale patterning to realize nanocolloids with anisotropic three-dimensional shapes, feature sizes down to 20 nm and a wide choice of materials. We demonstrate the versatility of the fabrication scheme by growing three-dimensional hybrid nanostructures that contain several functional materials with the lowest possible symmetry, and by fabricating hundreds of billions of plasmonic nanohelices, which we use as chiral metafluids with record circular dichroism and tunable chiroptical properties.

Integrated approach to the data processing of four-dimensional datasets from phase-contrast x-ray tomography.

Phase contrast X-ray tomography (PCT) enables the study of systems consisting of elements with similar atomic numbers. Processing datasets acquired using PCT is nontrivial because of the low-pass characteristics of the commonly used single-image phase retrieval algorithm. In this study, we introduce an image processing methodology that simultaneously utilizes both phase and attenuation components of an image obtained at a single detector distance. This novel method, combined with regularized Perona-Malik filter and bias-corrected fuzzy C-means algorithm, allows for automated segmentation of data acquired through four-dimensional PCT. Using this integrated approach, the three-dimensional coarsening morphology of an Aluminum-29.9 wt% Silicon alloy can be analyzed.

Shape control in wafer-based aperiodic 3D nanostructures.

Controlled local fabrication of three-dimensional (3D) nanostructures is important to explore and enhance the function of single nanodevices, but is experimentally challenging. We present a scheme based on e-beam lithography (EBL) written seeds, and glancing angle deposition (GLAD) grown structures to create nanoscale objects with defined shapes but in aperiodic arrangements. By using a continuous sacrificial corral surrounding the features of interest we grow isolated 3D nanostructures that have complex cross-sections and sidewall morphology that are surrounded by zones of clean substrate.

Chiral colloidal molecules and observation of the propeller effect.

Chiral molecules play an important role in biological and chemical processes, but physical effects due to their symmetry-breaking are generally weak. Several physical chiral separation schemes which could potentially be useful, including the propeller effect, have therefore not yet been demonstrated at the molecular scale. However, it has been proposed that complex nonspherical colloidal particles could act as "colloidal molecules" in mesoscopic model systems to permit the visualization of molecular phenomena that are otherwise difficult to observe. Unfortunately, it is difficult to synthesize such colloids because surface minimization generally favors the growth of symmetric particles. Here we demonstrate the production of large numbers of complex colloids with glancing angle physical vapor deposition. We use chiral colloids to demonstrate the Baranova and Zel'dovich (Baranova, N. B.; and Zel'dovich, B. Y. Chem. Phys. Lett. 1978, 57, 435) propeller effect: the separation of a racemic mixture by application of a rotating field that couples to the dipole moment of the enantiomers and screw propels them in opposite directions. The handedness of the colloidal suspensions is monitored with circular differential light scattering. An exact solution for the colloid's propulsion is derived, and comparisons between the colloidal system and the corresponding effect at the molecular scale are made.

Early percutaneous valve failure within bioprosthetic tricuspid tissue valve replacements.

OBJECTIVE: To describe the cases of percutaneous valve failure following implantation of the Medtronic Melody™ and the Edwards Sapien™ valve in the tricuspid position. BACKGROUND: There have been recent reports of the use of percutaneously delivered valves to manage failing bioprosthetic tricuspid valves. Total patient numbers remain small and follow-up times are limited. METHODS: We describe four procedures in three patients from two centers where implantation of percutaneous valves within the scaffold of a bioprosthetic tricuspid valve was technically successful but there was early valve failure. RESULTS: In all cases, immediate results suggested excellent valve function; however, valve failure occurred early in three and later in one. Two patients elected for valve explantation and surgical placement of a further tricuspid valve. The third patient underwent a second percutaneous valve-in-valve procedure though this valve is also showing early signs of failure. CONCLUSIONS: Transcatheter placement of percutaneous valves in the tricuspid position is technically a relatively straightforward procedure but early valve failure raises some concerns about the viability of the valve in this position, at least in some patients.

MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models.

To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma.

Use of diagnostic information submitted to the United Kingdom Central Cardiac Audit Database: development of categorisation and allocation algorithms.

OBJECTIVE: To categorise records according to primary cardiac diagnosis in the United Kingdom Central Cardiac Audit Database in order to add this information to a risk adjustment model for paediatric cardiac surgery. DESIGN: Codes from the International Paediatric Congenital Cardiac Code were mapped to recognisable primary cardiac diagnosis groupings, allocated using a hierarchy and less refined diagnosis groups, based on the number of functional ventricles and presence of aortic obstruction. SETTING: A National Clinical Audit Database. Patients Children undergoing cardiac interventions: the proportions for each diagnosis scheme are presented for 13,551 first patient surgical episodes since 2004. RESULTS: In Scheme 1, the most prevalent diagnoses nationally were ventricular septal defect (13%), patent ductus arteriosus (10.4%), and tetralogy of Fallot (9.5%). In Scheme 2, the prevalence of a biventricular heart without aortic obstruction was 64.2% and with aortic obstruction was 14.1%; the prevalence of a functionally univentricular heart without aortic obstruction was 4.3% and with aortic obstruction was 4.7%; the prevalence of unknown (ambiguous) number of ventricles was 8.4%; and the prevalence of acquired heart disease only was 2.2%. Diagnostic groups added to procedural information: of the 17% of all operations classed as "not a specific procedure", 97.1% had a diagnosis identified in Scheme 1 and 97.2% in Scheme 2. CONCLUSIONS: Diagnostic information adds to surgical procedural data when the complexity of case mix is analysed in a national database. These diagnostic categorisation schemes may be used for future investigation of the frequency of conditions and evaluation of long-term outcome over a series of procedures.