Search

Aim: The aim of this review is to document pain assessment tools used primarily for older adults in long-term care facilities and compare self-report and observer-rated tools. Methods: A literature search was conducted in Ovid MEDLINE®, Embase, Cochrane and PsycINFO. Keywords included ‘dementia’, ‘pain management’ and ‘managing pain’. Results: Of 1033 references, 23 articles were selected for inclusion. Six tools were self-rated and 18 tools were administered by an observer. 13 studies evaluated the reliability/validity of their scales; four studies compared different scales against each other. Conclusion: Self-report should be the first-line approach when possible, with observational assessment used as a supplementary tool. Reliable observational tools have been shortened, and shown to maintain high reliability/validity, and positive psychometric properties.

Introduction A nipple shield is a breastfeeding aid with a nipple-shaped shield that is positioned over the nipple and areola prior to nursing. Nipple shields are usually recommended to mothers with flat nipples or in cases in which there is a failure of the baby to effectively latch onto the breast within the first 2 days postpartum. The use of nipple shields is a controversial topic in the field of lactation. Its use has been an issue in the clinical literature since some older studies discovered reduced breast milk transfer when using nipple shields, while more recent studies reported successful breastfeeding outcomes. The purpose of this review was to examine the evidence and outcomes associated with nipple shield use. Methods A literature search was conducted in Ovid MEDLINE, OLDMEDLINE, EMBASE Classic, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. The primary endpoint was any breastfeeding outcome following nipple shield use. Secondary endpoints included the reasons for nipple shield use and the average/median length of use. For the analysis, we examined the effect of nipple shield use on physiological responses, premature infants, mothers’ experiences, and health professionals’ experiences. Results The literature search yielded 261 articles, 14 of which were included in this review. Of these 14 articles, three reported on physiological responses, two reported on premature infants, eight reported on mothers’ experiences, and one reported on health professionals’ experiences. Conclusion Through examining the use of nipple shields, further insight is provided on the advantages and disadvantages of this practice, thus allowing clinicians and researchers to address improvements on areas that will benefit mothers and infants the most.

Background: Single fraction radiotherapy (SFRT) and multiple fraction radiotherapy (MFRT) are effective for painful uncomplicated bone metastases and have been shown to be of similar efficacy. The optimal conventional external beam SFRT dose for maximum pain relief remains uncertain. The aim of this systematic review was to comprehensively review and synthesize overall pain response rates by dose. Methods: A literature search was conducted in Ovid MEDLINE(R) (1946 to June 2016 week 3), Embase Classic & Embase (1947 to 2016 week 26) and Cochrane Central Register of Controlled Trials (May 2016) using keywords such as bone metastases, radiotherapy and single fraction (SF). Results: The 635 results from the search were screened, and ultimately 27 were included for quantitative synthesis. The review indicated that 10 and 6 Gy may produce superior overall response (OR) and complete response (CR) rates compared to 8 Gy, and 6 Gy may result in better partial response (PR) than 8 Gy. However, only a few studies documented doses other than 8 Gy. In trials that directly compared 8 Gy to 4 Gy or 6 Gy, 8 Gy was deemed statistically superior. Conclusions: 8 Gy SFRT was the most commonly administered dose for palliation of bone metastases supporting its efficacy and safety. Future studies should explore the efficacy of 10 Gy while minimizing its side effects.

Pain is one of the most prominent symptoms faced by cancer patients. It is known that patient and caregiver-targeted educational interventions addressing the proper use of pain management may provide significant clinical value. This review examines the literature surrounding the use of multimedia interventions for patient and caregiver education (PCE) on pain management compared to traditional educational interventions. A literature search was conducted in Ovid MEDLINE (1946-July Week 2, 2016), Ovid Embase (1947-2016 Week 29), and Ovid Cochrane Central Register of Controlled Trials (up to June 2016). Paired reviewers conducted title and abstract screening and full-text screening to identify experimental, quasi-experimental and cohort studies evaluating one or more multimedia-based PCE interventions focused on cancer pain and pain management and targeting patients and/or caregivers. Findings were extracted by paired reviewers and synthesized qualitatively. Of the 68 full-text papers assessed, 7 were deemed relevant, of which 5 were RCTs and 2 were observational studies. We found limited but convincing quantitative data to suggest that the use of multimedia use in pain management education for patients/caregivers has greater value-added benefit compared to standard education. While there is evidence suggesting a positive effect on pain-related outcomes with the use of multimedia-based patient and caregiver-targeted interventions, it is limited to a small number of lower-quality studies. More robust and large-scale studies are needed to supplement existing evidence and provide more insight regarding the usability and user-friendliness of these tools in practice.

A progressive stepping program (PSP) comprising of 28 sessions each of 75 minutes were offered to two groups of community dwelling older adults with different levels of mobility at a frequency of 3 times a week so as to assess the program's effect on lower limb function as reflected in the Timed Up-and-Go test (TUG) and the Timed Open-eyed Single Leg Stand test (TOLS). Significant differences were found among the different groups in the TUG score (F = 11.05, p

This case history describes a rare complaint - Calciphylaxis, seen in a New Zealand Maori patient undergoing renal dialysis. This condition causes non-healing tissue ulceration, typically with sepsis and is associated with a very high mortality rate. The need for vigilance among health professionals is highlighted, including the risk factors that may faciliate an early diagnosis; together with the value associated with a multi-disciplinary team approach to management.

Aircraft tracking via satellite uses four dimensional aircraft position information to enhance flight safety by recording, scrutinizing and visualizing the information generated by an Airborne Tracking Unit (ATU) fitted onboard of aircraft flying from one point to another. It is an important device for aircraft operator to ensure its operational safety. Starfish Tracker SF3100-1 aircraft tracking unit can be used in aircraft satellite tracking applications. Research collaboration between Worldgate Technologies (WGT), Universiti Pertahanan Nasional Malaysia (UPNM) and Universiti Putra Malaysia (UPM) has developed the ATU originally from land base to airborne vehicles tracking, hence it provides multitudes of civil and military applications. The ATU is a unique device that enables multi-tasking application such as Air Combat Manoeuvring Instrumentation (ACMI), Network Centric Warfare and Flight Data Monitoring systems. In this paper, system characteristics and its applications are presented with the potential applications for Flight Data Monitoring system.

3533Background: Utilization of ctDNA has been rapidly adopted as a predictive diagnostic in advanced Non-Small Cell Lung Cancer and indications in GI cancers may be emerging. We aimed to evaluate c...

3595Background: AT-rich interactive domain 1A (ARID1A) is a component of the SWI/SNF chromatin remodeling complex that regulates gene expression. Inactivating mutations of ARID1A have been reported...

e15600Background: The CMS provide a representation of CRC heterogeneity. Upregulated immune pathways are suggested in CMS1 through lymphocyte (lymph) reactivity and CMS4 with an inflammatory respon...

640 Background: In advanced gastrointestinal (GI) malignancies, genetic profiling is often performed with the goal of facilitating enrollment of patients into clinical trials. While multigene genetic profiling has become the standard of care in many practices, the data on success rate of identifying actionable genomic alterations remain limited. In this study, we aimed to characterize the rate of actionable mutations using larger ( > 150 genes) and smaller ( < 150 genes) panels across different GI malignancies. Methods: We reviewed all reports of formalin-fixed paraffin-embedded clinical specimens sent for next-generation sequencing (NGS-using assays of at least 45 genes) for patients with advanced GI malignancies between 2012-2017 at MD Anderson Cancer Center. Actionable mutations were defined as those matching or informing the use of targeted therapies available in clinical trials, or FDA-approved. These were determined by a precision oncology support team (pct.mdanderson.org), using available literature and functional genomic screens. Novel actionable mutations were defined as those not used in current testing guidelines for GI malignancies. Results: Out of 11968 detected mutations, 3832(32.0%) were deemed to be actionable mutations and the remainder were either in non-actionable genes, deemed benign, or variants of unknown significance. Therefore, 1987 (65.1%) of assays had actionable mutations. When limited to novel actionable mutations, the rate fell to 21.5% (659/3052). Compared to CRC, other GI malignancies were 1.65 times more likely to have a novel actionable mutation (95% CI 1.35-2.00, p< .001). The use of larger and smaller panels did not differ in detecting novel actionable mutations, but larger panels resulted in a 3.5-fold higher number of mutations not deemed clinically actionable. Conclusions: Despite incorporation of NGS in oncology practice for GI malignancies, the success rate of detecting novel actionable mutations beyond those in the current guidelines remains low. Using assays with larger gene numbers does not seem to improve this detection rate. Future studies are required to evaluate the success rate of clinical interventions when actionable alterations are present.

641 Background: Circulating tumor DNA (ctDNA) represents an ideal platform to obtain the most current genomic profile of a patient’s tumor. We aimed to investigate how stable these profiles remain during serial ctDNA assays in metastatic colorectal cancer (mCRC). Methods: In 77 patients (pts) with mCRC and serial Guardant360 assays with a detectable mutation (mt), we compared mt stability by assessing whether variants were gained/lost between serial assays and changes in relative mutant allele frequency (rMAF). rMAF of a mt was defined as (mt allele frequency / mt present at the maximum allele frequency in that assay). rMAF results were normalized to detected ctDNA concentration changes between assays to ensure changes in rMAF were not due to changes in ctDNA concentration. MAPK pathway mutations were defined as RAS, BRAF, EGFR, KIT, or MET mutations. Results: Of 77 pts, 64 (83%) had 2 serial assays and 13 (16.9%) had 3 or 4 assays performed. Serial assays occurred an average of 138 days apart (+/- SD of 111 days). Only 13/77 (17%) pts had no change in the number of mts detected between assays. A new mt was detected in 42/77 (55%) pts, while 43/77 (56%) lost a previously detected mt. Of 52 mts detected in patients with > 2 assays, 16 (31%) were gained and subsequently lost. After controlling for ctDNA concentration, mts were equally likely to have an increasing (129/308 – 42%) or decreasing (150/308 – 49%) allele frequency. Potentially clinically relevant MAPK variants were gained/lost in 29% of patients; though MAPK mts developed in a large number of pts (16/77 – 21%), many pts also lost MAPK mts (9/77 – 12%), showing ongoing subclonal dynamics. Median time between assays did not differ between pts with gain/lost mts or stable mt profiles (P = 0.73), however mt rMAF shift of > 25% was more common if assays were > 90 days apart (OR 4.3, P < 0.0001). Conclusions: Serial ctDNA assays demonstrate ongoing mutational changes in mCRC, with emergence/disappearance of MAPK variants being more common than expansion of a pre-existing clone. Our results suggest repeated sampling may be important to optimize selection of targeted therapies at each regimen alteration.

619 Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.

634 Background: Utilization of ctDNA has been rapidly adopted as a predictive diagnostic in advanced NSCLC and indications in GI cancers may be emerging. While tissue-based assays have yields above 90%, there is less known about factors that influence the sensitivity of ctDNA for detecting mutations. Methods: We retrospectively evaluated mCRC patients (pts) who had plasma-derived NGS utilizing a highly-sensitive 68-73-gene assay. Tissue from prior resections or biopsies underwent concurrent 46-gene sequencing. In a case-control design, pts with a known mutation on tissue and radiologic evidence of metastatic disease but no detectable ctDNA mutation were matched 1:3 with randomly selected pts with detectable mutations and compared according to clinical, laboratory, and radiologic characteristics. A binary logistic regression was performed and Kaplan-Meier and Cox-proportional hazards models were used to compare overall (OS) and progression-free (PFS) survivals. Results: Of 427 mCRC pts who underwent ctDNA testing, 416 pts met inclusion criteria. Plasma-derived NGS did not find tumor mutations in 66 cases (15.9%); 198 pts with detectable alterations were selected as controls. After multivariate analysis, the lack of detection of ctDNA was associated with decreasing age (OR 0.94; 95%CI 0.91-0.98; p = 0.004), absence of liver (OR 0.19; 95%CI 0.08-0.45; p < 0.001) and lymph node metastases (OR 0.28; 95%CI 0.12-0.70; p = 0.006). A key determinant was timing of collection relative to disease status: plasma collected after evidence of progression was substantially more likely to have detectable alterations (OR 10.95; 95%CI 4.23-28.33; p < .001); in these pts, the modeled rate of detection was 98%, which increased to > 99% if the pts also had either liver or nodal disease. Pts with no detectable ctDNA had better OS (HR 0.38; 95%CI 0.21-0.69, p = 0.002) and PFS (HR 0.52; 95%CI 0.32-0.85; p = 0.009). Conclusions: When limited to ctDNA collected in newly diagnosed or recently progressing pts, the yield of ctDNA is 98%, which equals or exceeds the yield of tissue based testing. Our findings support the notion that ctDNA testing, when appropriately utilized, can replace tissue based testing and may provide prognostic information.

689 Background: Recent reports suggest colorectal cancer incidence is steadily increasing in adults < 50 years old. This population has a number of unique pre-disposing conditions, such as inflammatory bowel disease (IBD), that may alter the disease biology within these patients. Methods: Using a cohort of 1876 patients with metastatic CRC (mCRC), we identified 622 patients aged < 50 years and reviewed their medical records for a diagnosis of IBD. Clinical, pathologic and overall survival (OS) were compared between patients with and without IBD in this age group. Results: Twenty of 622 (3.2%) early-onset mCRC patients had IBD. These patients were more likely to have mucinous or signet ring histologic features (50.0% vs 15.6%, OR 5.43, 95% CI 2.20-13.41, P < 0.0001) and less likely to have APC mutations (15.0% vs 42.7%, P = 0.019). A trend toward an increased prevalence of right-sided location (40.0% vs 24.1%, P = 0.053) and TP53 mutations (85.0% vs 65.1%, P = 0.091) and decreased prevalence of PIK3CA mutations (0.0% vs 15.5%, P = 0.057) and KRAS mutations (35.0% vs 50.0%, P = 0.11) were noted. There were no differences in prevalence of BRAF V600 (P = 0.99), CTNNB1 (P = 0.99), NRAS (P = 0.99), PTEN (P = 0.43), or SMAD4 (P = 0.75) mutations between patients with IBD and other early-onset mCRC. The presence of IBD in early-onset mCRC patients was associated with a worse OS compared to patients without IBD but who had mCRC (HR 1.82, 95% CI 0.90-3.69, P = 0.026). Conclusions: Early-onset mCRC patients with IBD are significantly more likely to have mucinous or signet ring histologic features and have fewer mutations in canonical CRC genes such as KRAS, PIK3CA, and APC. This suggests that this population likely develops through a unique molecular pathogenesis and they may respond differently to therapy. Further molecular characterization of this population is required.

616 Background: For mCRC, the contribution of clinical and pathologic factors to concordance between formalin-fixed, paraffin-embedded (FFPE) tissue-based and ctDNA-based mutation profiling remains unclear. MSI is hypothesized to confer a higher rate of somatic alteration resulting in clonal evolution over time compared to microsatellite stable (MSS) patients, but this has not been previously confirmed. Methods: All mCRC patients were consented for a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]) using CLIA-certified platforms. Archived tumor DNA from primary or metastatic tissue was sequenced on a 46- or 50-gene panel (Ion Torrent). Paired ctDNA samples were isolated from blood and sequenced with an ultra high-sensitivity assay (Guardant360). Mutation data were normalized by excluding genomic regions not covered on both platforms and were filtered to remove germline or synonymous variants. Results: An initial cohort of 139 patients was included in our analyses, with a median of two lines of intervening chemotherapy between FFPE and plasma DNA collection; 6 (4.3%) of the patients had MSI (MSI-H) mCRC. We detected 472 total mutations in either tissue or ctDNA, with a global concordance rate of 34.5%. Global concordance was not associated with tissue source, nor treatment with specific standard cytotoxic and/or biologic agents. Mutations detected in MSI-H CRC showed significantly greater discordance compared to MSS CRC (OR = 2.5, p = 0.025). This finding was validated using an independent cohort of 17 MSI-H mCRC patients (OR = 2.78, p = 0.00015). Among recurrently altered genes, we found that MSI-H cases were significantly more likely to have gained new TP53 mutations (OR = 8.17, p = 0.001) and to have lost PIK3CA mutations (OR = 8.04, p = 0.036) in ctDNA compared to MSS cases. Conclusions: MSI correlates with discordance between tissue DNA and ctDNA-based mutation profiling, which suggests that MSI-H CRC undergoes distinct patterns of clonal evolution including acquisition of new TP53 mutations. This may have implications for targeted and immunologic therapies in this unique population, and suggests a utility for repeated molecular testing.

Controlled navigation promotes full utilization of capsule endoscopy for reliable real-time diagnosis in the gastrointestinal (GI) tract, but intermittent natural peristalsis can disturb the navigational control, destabilize the capsule and take it out of levitation. The focus of the present work was to develop an economical and effective real-time magnetic capsule-guiding system that can operate in the presence of naturally existing peristalsis while retaining navigational control. A real-size magnetic navigation system that can handle peristaltic forces of up to 1.5 N was designed utilizing the computer-aided design (CAD) system Maxwell 3D (Ansoft, Pittsburg, PA) and was verified using a small-size physical experimental setup. The proposed system contains a pair of 50 cm diameter, 10,000-turn copper electromagnets with a 10 cm x 10 cm ferrous core driven by currents of up to 300 A and can successfully maintain position control over the levitating capsule during peristalsis. The addition of bismuth diamagnetic casing for stabilizing the levitating capsule was also studied. A modeled magnetic field around the diamagnetically cased permanent magnet was shown to be redistributed aligning its interaction with the external electromagnets, thus stabilizing the levitating capsule. In summary, a custom-designed diamagnetically facilitated capsule navigation system can successfully steer an intraluminal magnet-carrying capsule.

The hybrid Hopkins-Abbe method is presented and shown to resolve the problem of the traditional Hopkins theory, namely the requirement for constant mask diffraction efficiencies. Simulation of electromagnetic scattering from the mask that takes into account the oblique angles of incidence from the illumination is performed by application of the domain decomposition method that is extended for offaxis illumination. Examples of 45nm and 32nm lines and spaces through pitch and through focus are presented to demonstrate the validity and accuracy of the hybrid Hopkins-Abbe method. The results obtained are in excellent agreement with a rigorous and independent (third party) simulator.

Acute appendicitis is the most common surgical abdominal emergency. Although the clinical diagnosis can be made accurately in typical cases, imaging plays an important role in improving diagnostic accuracy of this condition, especially when the clinical diagnosis is uncertain. Magnetic resonance imaging is an emerging promising technique for the diagnosis of acute appendicitis, especially in patients with nondiagnostic ultrasound and in patients where radiation is a clinical concern. In the following review, the role of magnetic resonance in the diagnosis of appendicitis will be discussed.

Newborn babies in need of critical medical attention are normally admitted to the neonatal intensive care unit (NICU). These infants tend to be preterm, have low birth weight, and/or have serious medical conditions. Neonatal survival varies, but progress in perinatal and neonatal care has notably diminished mortality rates. In this selected review, we examine and compare the NICU mortality rates and etiologies of death in different countries. Methods: A literature search was conducted in Ovid MEDLINE, OLDMEDLINE, EMBASE Classic and EMBASE. The primary endpoint was the mortality rates in NICUs. Secondary endpoints included the reasons for death and the correlation between infant age and mortality outcome. For the main analysis, we examined all infants admitted to NICUs. Subgroup analyses included extremely low birth weight infants (based on the authors’ own definition), very low birth weight infants, very preterm infants, preterm infants, preterm infants with a birth weight of ≤1500g, and by developed and developing countries. Results: The literature search yielded 1,865 articles, of which 20 were included. The total mortality rates greatly varied among countries. Infants in developed and developing countries had similar ages at death, ranging from 4 – 20 days and 1 – 28.9 days, respectively. The mortality rates ranged from 4% – 46% in developed countries and 0.2% – 64.4% in developing countries. Conclusion: The mortality rates of neonatal intensive care units vary between nations but remain high in both developing and developed countries.

The process of formulating an accurate survival prediction is often difficult but important, as it influences the decisions of clinicians, patients, and their families. The current article aims to review the accuracy of clinicians' predictions of survival (CPS) in advanced cancer patients. A literature search of Cochrane CENTRAL, EMBASE, and MEDLINE was conducted to identify studies that reported clinicians' prediction of survival in advanced cancer patients. Studies were included if the subjects consisted of advanced cancer patients and the data reported on the ability of clinicians to predict survival, with both estimated and observed survival data present. Studies reporting on the ability of biological and molecular markers to predict survival were excluded. Fifteen studies that met the inclusion and exclusion criteria were identified. Clinicians in five studies underestimated patients' survival (estimated to observed survival ratio between 0.5 and 0.92). In contrast, 12 studies reported clinicians' overestimation of survival (ratio between 1.06 and 6). CPS in advanced cancer patients is often inaccurate and overestimated. Given these findings, clinicians should be aware of their tendency to be overoptimistic. Further investigation of predictive patient and clinician characteristics is warranted to improve clinicians' ability to predict survival.

Our centre introduced peritoneoscopic insertion of peritoneal dialysis (PD) catheter by nephrologists as a new method in August 2009 for its potential benefits.The aim of this study was to compare perioperative complications and catheter survival of three techniques: peritoneoscopic, surgical and radiological techniques within a single dialysis centre.This study used retrospective analysis of all PD catheter inserted from 1 August 2009 to 31 July 2013 within Counties Manukau DHB, Auckland, New Zealand.During the study period, 293 PD catheters were inserted, 84 (29%) peritoneoscopic (P), 140 (48%) surgical (S) and 69 (23%) radiological (R). Total duration of follow-up was 5848 catheter-months, with median follow-up of 17 months. There was no difference in perioperative exit-site infections and overall early infections. There was however increased overall perioperative complications in P compared with R (HR 2.08; P 0.05), predominantly from catheter removal within 60 days. Although there was no difference observed in first catheter 1-year and overall survival between insertion techniques, there was poorer complication-free survival comparing P to S (HR 1.82, P = 0.001) but not to R. Analyses of the latter cohort of P confirmed improvement in catheter survival compared with an earlier cohort and to other insertion techniques.Peritoneoscopic PD catheter insertion is demonstrated to be a suitable alternative technique. As with any new procedure, 'learning curve' effects and development of operator expertise need to be taken into consideration.

The mainstream approach to structured prediction problems in computer vision is to learn an energy function such that the solution minimizes that function. At prediction time, this approach must solve an often-challenging optimization problem. Search-based methods provide an alternative that has the potential to achieve higher performance. These methods learn to control a search procedure that constructs and evaluates candidate solutions. The recently-developed ℋC-Search method has been shown to achieve state-of-the-art results in natural language processing, but mixed success when applied to vision problems. This paper studies whether ℋC-Search can achieve similarly competitive performance on basic vision tasks such as object detection, scene labeling, and monocular depth estimation, where the leading paradigm is energy minimization. To this end, we introduce a search operator suited to the vision domain that improves a candidate solution by probabilistically sampling likely object configurations in the scene from the hierarchical Berkeley segmentation. We complement this search operator by applying the DAgger algorithm to robustly train the search heuristic so it learns from its previous mistakes. Our evaluation shows that these improvements reduce the branching factor and search depth, and thus give a significant performance boost. Our state-of-the-art results on scene labeling and depth estimation suggest that ℋC-Search provides a suitable tool for learning and inference in vision.

The physical process of mask manufacturing produces absorber geometry with significantly less than 90 degree fidelity at corners. The non-Manhattan mask geometry is an essential contributor to the aerial image and resulting patterning performance through focus. Current state of the art models for corner rounding employ “chopping” a 90 degree mask corner, replacing the corner with a small 45 degree edge. In this paper, a methodology is presented to approximate the impact of 3D EMF effects introduced by corners with rounded edges. The approach is integrated into a full chip 3D mask simulation methodology based on the Domain Decomposition Method (DDM) with edge to edge crosstalk correction.

Inflammation is increasingly recognized as a major factor in cancer development and progression. While local inflammation, represented by higher density of tumor infiltrating immune cells, is associated with better outcomes, the presence of systemic inflammation is conversely associated with poorer outcomes. This has been studied extensively in colorectal cancer where surrogates of systemic inflammation, such as serum albumin, C-reactive peptide, neutrophils and lymphocytes, have been shown to have prognostic significance independent of traditional clinicopathological factors. Despite the strength of this clinical data, the biological mechanisms underlying the poor outcomes are not well understood. This review details the impact of systemic inflammation on outcomes in colorectal cancer and examines what is known about the underlying biology.

As extreme ultraviolet lithography becomes closer to reality for high volume production, its peculiar modeling challenges related to both inter and intrafield effects have necessitated building an optical proximity correction (OPC) infrastructure that operates with field position dependency. Previous state-of-the-art approaches to modeling field dependency used piecewise constant models where static input models are assigned to specific x/y-positions within the field. OPC and simulation could assign the proper static model based on simulation-level placement. However, in the realm of 7 and 5 nm feature sizes, small discontinuities in OPC from piecewise constant model changes can cause unacceptable levels of edge placement errors. The introduction of dynamic model generation (DMG) can be shown to effectively avoid these dislocations by providing unique mask and optical models per simulation region, allowing a near continuum of models through the field. DMG allows unique models for electromagnetic field, apodization, aberrations, etc. to vary through the entire field and provides a capability to precisely and accurately model systematic field signatures.

Background: Side of primary tumor has prognostic and predictive significance in metastatic colorectal cancer (mCRC). RAS/BRAF wild type (WT) left (L) sided tumors have improved outcomes with anti-EGFR therapy while right (R) sided tumors do worse. We aimed to identify mutations (MTS) in RAS/BRAF WT patients (pts) which may explain the differing response. Methods: Using a 46 gene panel, we compared MT frequencies by side in 1880 mCRC pts. Overall survival (OS) was summarized with Kaplan-Meier curves, the log rank test, and Cox models. Microsatellite unstable pts were excluded from univariate OS analysis. Results: RAS mutant (MT) pts were more likely to be APC MT (OR 1.64, P Given the association of tumor location and OS, we stratified pts by side and compared APC MT/WT pts. Improved OS with APC MTS was independent of side (L-HR 0.70, P=0.0011; R-HR 0.62, P=0.0012), but pts with R APC WT tumors stood out as an extreme risk group with the worst OS of all L/R and APC MT/WT combinations even in RAS/BRAF WT pts (P When stratifying APC MT by genomic location, only MTS in the mutation cluster region (n=686) that contains axin and β-catenin binding sites remained prognostic in multivariate models (HR 0.63, P Conclusion: APC WT R sided pts represents a group with poor prognosis regardless of RAS/BRAF MT status. Given the difference in CTNNB1 MT rate and importance of MTS in axin/ β-catenin binding sites, WNT signaling differences between L and R sided tumors may be important to explore further. Baseline Characteristics of Patients with APC/RAS/BRAF Wild Type Right Sided TumorsBaseline CharacteristicRight Sided APC/RAS/BRAF WT (N=88, 15.2%)Other Right Sided Tumors (N=492, 84.8%)P-ValueMedian Age (IQR)56 (47-61)56 (48-64)0.23GenderFemale46 (52.3%)241 (49.0%)0.56Male42 (47.7%)251 (51.0%)MSI-H8 (10.5%)25 (6.5%)0.22HistologyAdenocarcinoma50 (56.8%)366 (74.4%)0.0018Mucinous / Signet38 (43.2%)123 (25.0%)Other03 (0.6%)Average # of Mutations Per Patient (+/- SD)1.38+/- 2.013.10 +/- 1.79 Citation Format: Jonathan M. Loree, Krittiya K. Korphaisarn, Michael Lam, Van K. Morris, Kanwal P. Raghav, Michael J. Overman, Cathy Eng, Arvind Dasari, Bryan K. Kee, David Fogelman, Robert A. Wolff, Kenna Shaw, Russell Broaddus, Mark J. Routbort, Rajyalakshmi Luthra, Dipen M. Maru, David G. Menter, Funda Meric-Bernstam, Scott Kopetz. APCWT/RASWT/BRAFWT tumors represent an under recognized poor prognostic group of right sided colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4742. doi:10.1158/1538-7445.AM2017-4742

3589 Background: Mutations (mts) in RAS predict lack of response to anti-EGFR therapy in colorectal cancer. Outside the “typical RAS” mts ( KRAS/NRAS Codons 12, 13, 59, 61, 117, 146) cited in guidelines and anti-EGFR labeling, clinical impact of other “atypical RAS” mts is uncertain. Methods: Available literature and databases were surveyed to identify 80 KRAS/NRAS mts. We used the NovellusDx Functional Annotation for Cancer Treatment (FACT) to transfect these RAS mts (repeated a mean of 5.5 times/mt) in a cell-based assay that quantifies nuclear ERK localization as a measure of MAPK pathway activation, and normalized to wild type (WT) transfection. In 963 metastatic colorectal cancer patients (pts) with BRAF WT/ KRAS mutant tumors, overall survival (OS) was evaluated by level of RAS signaling activity. Results: Of the surveyed mutations,96% (45/47) of typical mts and 39% (13/33) of atypical mts increased MAPK pathway activation above WT (range: 107%-211% of WT activity). Within the typical RAS mts, mts in NRAS or exon 3, 4 of KRAS had higher activity than mts in exon 2 (codons 12/13) of KRAS, reaffirming the biologic relevance of expanded RAS testing (median activity of 130% vs 178%, P < 0.001). The median activity of atypical RAS mts was lower than typical RAS mts (110% vs 159%, P < 0.001). Several notable exceptions in atypical RAS mts with high activity levels were KRAS V14I, Q22K, D33E, N116S, and F156L (all > 165% of WT activity). Conversely, within the typical RAS mts in the guidelines, KRAS G13C and K117R were not shown to increase activity significantly above WT. Pts with any RAS mt with MAPK activity above the median of typical mts had a worse OS compared to pts below the median in univariate (HR 1.45, 95% CI 1.04-2.32, P = 0.033) and multivariate models (HR 1.96, 95% CI 1.13-3.42, P = 0.017) that controlled for age, gender, sidedness, and synchronous vs metachronous presentation. Conclusions: Functional characterization confirmed activity of RAS mts in the current guidelines, but also suggested that a subset of atypical RAS mutations have similar levels of activation of the MAPK pathway. Within the subset of pts with RAS mts, those mts resulting in high MAPK activity are associated with notably shorter OS.

e15143 Background: TP53 mutations (mut) are prevalent in colorectal cancer (CRC) patients (pts) and can result in oncogenic gain of function effect as well as loss of tumor suppressor function depending on the mut. Methods: The Cancer Genome Atlas (TCGA) data of 220 CRC pts with tumors sequenced and gene copy numbers (CN) annotated was obtained. Pts with CMS subtype data also available were included (n = 167). Chi square test was used to compare frequency of TP53 mut and CN change among CMS subtypes. TP53 mRNA and protein levels were compared by TP53 mut and CN change using independent sample t test. Results: 86 (51.5%) pts were TP53 mutant, with 35.3% missense and 16.2% loss of function (LOF) mut. LOF mut included 14 non-sense and 13 frameshift mut, and occurred mostly in codons 213 and 306. Missense mut mostly affected codons 175, 248 and 273 in 10, 9 and 8 pts respectively. TP53 mut were most frequent in CMS2 and CMS4 subtypes (62.7 and 62.5% respectively). TP53 mut in CMS2 were mostly missense and CMS 4 pts mostly had LOF mut. TP53 CN loss was seen in 74.7% CMS 2, 68.8% CMS 4, 43.5% CMS 3 and 6.9% CMS1 pts. 84.9% pts with TP53 mut had CN loss vs 28.4% of wild type pts (p < 0.001). Frequency of TP53 CN loss did not vary significantly by type of TP53 mut. Pts with TP53 missense mut had higher p53 mRNA and protein levels than those with LOF mut. Pts with TP53 CN loss had lower mRNA levels but no change in protein levels than those with normal CN. Conclusions: The higher TP53 mRNA and protein levels with missense mut suggest possible gain of function. Research on interactions of TP53 change with wnt, myc, and TGF beta pathway genes may reveal synthetic lethal treatment combinations. [Table: see text]

586 Background: The impact of intratumor heterogeneity on prognosis in metastatic colorectal cancer (mCRC) is unclear, however relative variant allele frequency (rVAF) of key mutations within a tumor may impact outcomes. Therefore, we sought to determine whether rVAF of RAS ( KRAS & NRAS) mutant (mt) clones impacts overall survival (OS) in mCRC patients (pts). Methods: Using a next generation sequencing panel of 201 cancer related genes, we tested 200 mCRC tumors / matched normals. Mutations, indels, and copy number variant (CNV) information were obtained. An rVAF of RAS clones was determined by dividing RAS mt VAF by the VAF of the mutated gene with the highest allele frequency. This truncal gene served as a marker of the total malignant population in a specimen. Pts were stratified at an rVAF of 50%. OS was compared with Kaplan-Meier curves, the log-rank test, and Cox regression. We assessed the impact of CNV on our findings by correcting the rVAF for CNVs in RASand truncal mutations. Results: Of 200 pts, 15% had RAS mt rVAF < 50%, 40.5% had rVAF ≥ 50%, and 44.5% were RAS wild type (WT). Age, gender, MSI status, histology, and stage at diagnosis were similar between groups. More RAS WT pts had BRAF mutations (19.1% vs 1.2% and 3.3%, P< 0.0001), left sided (78.7% vs 56.8% and 60%, P= 0.02), or poorly differentiated tumors (27.3% vs 8.6% and 13.3%, P= 0.003) compared to pts with rVAF ≥ 50% or rVAF < 50%, respectively. Mean coverage was 807x for RAS and 602x for truncal mutations. OS was better in pts with an rVAF < 50% compared to pts with rVAF ≥ 50% regardless of whether rVAF was corrected for CNV (HR 0.6; 95% CI 0.39-0.93, P =0.029) or not (HR 0.48; 95% CI 0.31-0.82, P= 0.010). mOS for pts with WT, rVAF < 50% and rVAF ≥ 50% tumors were 65.8, 55.7, and 38.6 months ( P= 0.0025). In multivariate models controlling for stage at diagnosis and BRAF mutation, pts with rVAF < 50% (HR 1.75; 95% CI 1.03-2.97, P = 0.04) and rVAF ≥ 50% (HR 2.46; 95% CI 1.66-3.65, P< 0.0001) had worse OS compared to WT pts. When rVAF was used as a continuous variable, every 1% increase in rVAF RAS mt resulted in a 1% increased hazard of death ( P

It has long been known that platelets facilitate metastasis formation (1). In cancer, platelets are known to contain tumor related microRNA and serve as a biomarker for cancer (2-4). Cancer related platelet profiles also associate with consensus molecular subtypes of colorectal cancer (5).

Purpose To describe the spectral-domain optical coherence tomography and fundus autofluorescence findings in a case of laser pointer-induced maculopathy. Methods Observational case report of a patient with bilateral decreased visual acuity after exposure to a handheld green laser pointer. Results A 15-year-old boy presented with decreased vision after exposure to a green laser pointer. Fundoscopy revealed gray and yellowish round spots in the foveal area of both eyes. Fundus autofluorescence imaging revealed subtle changes of the normal background macular autofluorescence of the right eye, with hyperautofluorescence dots in the fovea of the left eye. Spectral-domain optical coherence tomography showed a variety of changes of the outer retina and retinal pigment epithelium, with disruption of the external limiting membrane, the photoreceptor ellipsoid zone of the inner segments, and the interdigitation zone in the foveal region in both eyes. Six months after laser exposure, fundoscopic examination showed persistent alterations at the level of the retinal pigment epithelium in the fovea in both eyes. Fundus autofluorescence revealed mild but persistent changes of the normal autofluorescent macular background in both eyes. Spectral-domain optical coherence tomography showed partial resolution of the outer retinal disruption noted on his initial visit with persistent, small foveal photoreceptor defects in both eyes. Conclusion Laser pointer maculopathy may disturb the outer retinal architecture in a manner evident on spectral-domain optical coherence tomography and fundus autofluorescence, resulting in decreased visual acuity. Proper warnings should accompany these devices and access to them by minors should be limited.

This study quantifies the impact of systematic mask errors on OPC model accuracy and proposes a methodology to reconcile the largest errors via calibration to the mask error signature in wafer data. First, we examine through simulation, the impact of uncertainties in the representation of photomask properties including CD bias, corner rounding, refractive index, thickness, and sidewall angle. The factors that are most critical to be accurately represented in the model are cataloged. CD bias values are based on state of the art mask manufacturing data while other variable values are speculated, highlighting the need for improved metrology and communication between mask and OPC model experts. It is shown that the wafer simulations are highly dependent upon the 1D/2D representation of the mask, in addition to the mask sidewall for 3D mask models. In addition, this paper demonstrates substantial accuracy improvements in the 3D mask model using physical perturbations of the input mask geometry when using Domain Decomposition Method (DDM) techniques. Results from four test cases demonstrate that small, direct modifications in the input mask stack slope and edge location can result in model calibration and verification accuracy benefit of up to 30%. We highlight the benefits of a more accurate description of the 3D EMF near field with crosstalk in model calibration and impact as a function of mask dimensions. The result is a useful technique to align DDM mask model accuracy with physical mask dimensions and scattering via model calibration.

Myeloma cast nephropathy contributes to high morbidity and early mortality associated with the development of end-stage renal disease. Treatment with extended high cut-off haemodialysis coupled with novel anti-myeloma therapies enables significant reduction of serum-free light chains and has been shown to improve renal outcomes. In this case series, medical records of 6 patients who received high cut-off haemodialysis for biopsy-proven cast nephropathy were retrospectively reviewed. Patients received a total of 344 hours of high cut-off haemodialysis and concurrent chemotherapy. Only 50% became dialysis independent following treatment. One patient who achieved sustained remission remained dialysis dependent. The added benefit of high cut-off haemodialysis in the light of novel anti-myeloma therapies requires further evaluation.

This paper extends the state of the art by demonstrating performance improvements in the Domain Decomposition Method (DDM) from a physical perturbation of the input mask geometry. Results from four testcases demonstrate that small, direct modifications in the input mask stack slope and edge location can result in model calibration and verification accuracy benefit of up to 30%. All final mask optimization results from this approach are shown to be valid within measurement accuracy of the dimensions expected from manufacture. We highlight the benefits of a more accurate description of the 3D EMF near field with crosstalk in model calibration and impact as a function of mask dimensions. The result is a useful technique to align DDM mask model accuracy with physical mask dimensions and scattering via model calibration.

The most common type of intraocular tumor in adults is the metastatic variety, with the choroid as the typical site of involvement. The case of a patient with non-small cell lung cancer, who presented with choroidal metastasis, is described in the current report. In addition, the limitation of using a chest X-ray to identify a large primary lung lesion is highlighted. A 71-year-old female that presented with a choroidal mass lesion is described in the current report. A chest X-ray was conducted and was considered to be normal following detailed investigation, however, a computed tomography (CT) scan of the thorax revealed a large lobulated mass in the right upper lobe. On further histopathological analysis, the patient was diagnosed with a non-small cell lung carcinoma. Thus, when a large choroidal lesion and overlying exudative retinal detachment is observed, a diagnosis of choroidal metastasis should be considered. X-ray images may appear to be normal even in the presence of a large pulmonary lesion. Therefore, in cases where there may be a metastatic lesion, a CT scan is proposed as the optimal diagnostic imaging technique.

This paper presents a learning approach for detecting nematocysts in Scanning Electron Microscope (SEM) images. The image dataset was collected and made available to us by biologists for the purposes of morphological studies of corals, jellyfish, and other species in the phylum Cnidaria. Challenges for computer vision presented by this biological domain are rarely seen in general images of natural scenes. We formulate nematocyst detection as labeling of a regular grid of image patches. This structured prediction problem is specified within two frameworks: CRF and HC-Search. The CRF uses graph cuts for inference. The HC-Search approach is based on search in the space of outputs. It uses a learned heuristic function (H) to uncover high-quality candidate labelings of image patches, and then uses a learned cost function (C) to select the final prediction among the candidates. While locally optimal CRF inference may be sufficient for images of natural scenes, our results demonstrate that CRF with graph cuts performs poorly on the nematocyst images, and that HC-Search outperforms CRF with graph cuts. This suggests biological images of flexible objects present new challenges requiring further ad- vances of, or alternatives to existing methods.

Biologists collect and analyze phenomic (e.g., anatomical or non-genomic) data to discover relationships among species in the Tree of Life. The domain is seeking to modernize this very time-consuming and largely manual process. We have developed an approach to detect and localize object parts in standardized images of bat skulls. This approach has been further developed for unannotated images by leveraging knowledge learned from a few annotated images. The key challenge is that the unlabeled images show bat skulls of "unknown" species that may have types, total numbers, and layouts of the teeth that differ from the "known" species appearing in the labeled images. Our method begins by matching the unlabeled images to the labeled ones. This allows a transfer of tooth annotations to the unlabeled images. We then learn a tree parts model on the transferred annotations, and apply this model to detect and label teeth in the unlabeled images. Our evaluation demonstrates good performance, which is close to our upper bound performance by the fully supervised model.

The Domain Decomposition Method (DDM) for approximating the impact of 3DEMF effects was introduced nearly ten years ago as an approach to deliver good accuracy for rapid simulation of full-chip applications. This approximation, which treats mask edges as independent from one another, provided improved model accuracy over the traditional Kirchhoff thin mask model for the case of alternating aperture phase shift masks which featured severe mask topography. This aggressive PSM technology was not widely deployed in manufacturing, and with the advent of thinner absorbing layers, the impact of mask topography has been relatively well contained through the 32 nm technology node, where Kirchhoff mask models have proved effective. At 20 nm and below, however, the thin mask approximation leads to larger errors, and the DDM model is seen to be effective in providing a more accurate representation of the aerial image. The original DDM model assumes normal incidence, and a subsequent version incorporates signals from oblique angles. As mask dimensions become smaller, the assumption of non-interacting mask edges breaks down, and a further refinement of the model is required to account for edge to edge cross talk. In this study, we evaluate the progression of improvements in modeling mask 3DEMF effects by comparing to rigorous simulation results. It is shown that edge to edge interactions can be accurately accounted for in the modified DDM library. A methodology is presented for the generation of an accurate 3DEMF model library which can be used in full chip OPC correction.