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Purpose A significant number of survivors of hematopoietic stem-cell transplantation (HSCT) report enduring adverse effects of treatment, including illness-related post-traumatic stress disorder (PTSD) symptoms and general distress. We report results of a randomized clinical trial that tested the effects of a 10-session, telephone-administered cognitive-behavioral therapy (CBT) intervention on PTSD, depression, and distress symptoms. Methods Survivors who had undergone HSCT 1 to 3 years earlier (N = 408) were assessed for study eligibility. Those who met study eligibility criteria (n = 89) completed a baseline assessment that included a clinical interview and self-report measures of PTSD symptoms (the primary outcome) and depression and general distress (the secondary outcomes). Next, they were randomly assigned to CBT or an assessment-only condition. Survivors in the CBT group completed 10 individual telephone-based CBT sessions (T-CBT) that included strategies to reduce PTSD symptoms, depression, and general distress. Follow-up assessments occurred at 6, 9, and 12 months after the baseline assessment. Results Linear mixed-model analyses revealed that, compared with HSCT survivors in the assessment-only condition, survivors who completed T-CBT reported fewer illness-related PTSD symptoms, including less avoidance (P < .001) and fewer intrusive thoughts (P < .05) as well as less general distress and fewer depressive symptoms (P < .05) even after controlling for potential demographic and medical covariates. These results were consistent across the three follow-up assessments. Conclusion A brief, telephone-administered CBT intervention developed for HSCT survivors is an efficacious treatment for reducing illness-related PTSD symptoms and general distress.

As modulators of gene expression, microRNAs (miRNAs) are essential for normal development. Not surprisingly, aberrant expression of miRNAs is associated with many diseases, including cancer. Studies of various breast cancer subtypes have demonstrated that, like gene expression profiles and pathological differences, miRNA profiles can distinguish various tumor subtypes. Over the last few years, roles for miRNAs during many stages of breast cancer progression have been established. This includes potential breast cancer associated polymorphisms in miRNA target sites or miRNAs themselves, miRNAs that can act as tumor suppressors or oncogenes, and miRNAs that can modulate metastatic spread. Recent studies have also suggested key roles for miRNAs in regulating cancer stem cells. Thus, miRNAs have now become important therapeutic targets. This can be achieved by replacing miRNA expression where it has been lost or decreased, or conversely by inhibiting miRNA expression where it has been amplified or overexpressed in cancers. Ultimately, miRNAs should provide both important prognostic biomarkers as well as new targetable molecules for the treatment of breast cancer.

Transfer of the posterior tibialis tendon to the dorsum of the foot was compared with lengthening of this tendon in 15 patients with Duchenne's muscular dystrophy.Patients undergoing tendon transfer ( N = 9) had a longer operating time and two perioperative complications, but retained plantigrade posture of their feet even after walking ceased. By contrast, lengthening of the posterior tibialis tendon (A/ = 6) was associated with a recurrent equinovarus foot deformity that frequently interfered with shoe wear. Although transfer of the posterior tibialis is out of phase and technically more demanding, the unique prolongation of posterior tibialis strength in Duchenne's muscular dystrophy makes this operation a better option for these patients.

Fungal infections have only rarely been reported to occur in patients having undergone total knee arthroplasty. This case report documents the first known case of Aspergillus fumigatus as the offending organism. Its initial presentation as a popliteal cyst further reinforces the known association of popliteal cysts and intra-articular knee pathology.

SUMMARY A new cryo-jet freezing apparatus is described that is easy to use and gives good results using a propane-butene mixture (3: 1). Our use of the freezer in the study of mouse spinal cord explant cultures is discussed. At the tissue surface, the quality of tissue preservation from freezing, followed by freeze substitution, rivals that of conventional electron microscopic methods. Certain intracellular structures are better visualized using our methods. There is no evidence of the tissue being distorted by the cryogen jet when the freezer is operated correctly. A new freeze substitution device is also discussed.

We reviewed the cases of fifteen obese patients (twenty-one extremities) who had had adolescent tibia vara and had been followed for at least two years. Of the nine patients (eleven extremities) who had been initially managed with lateral tibial hemiepiphyseodesis, eight (ten extremities) were skeletally mature at the time of the review (mean duration of follow-up, five years). The mechanical alignment was judged to be excellent in three of these ten extremities, fair in three, and poor in four. Excellent mechanical alignment was defined as a value within the reported normal range of 5 degrees of varus to 2 degrees of valgus. A poor result was defined as alignment that was more than 5 degrees outside the normal range. After secondary operative procedures, three of the extremities for which the result had been poor and one for which it had been fair had excellent alignment. Five of the nine patients had bilateral involvement. Two of them were managed with bilateral tibial hemiepiphyseodesis; two, with contralateral proximal tibial osteotomy; and one had a mild deformity on the contralateral side that was not treated. Six extremities in six patients (two of whom had a contralateral hemiepiphyseodesis) were managed primarily with proximal tibial osteotomy and were evaluated an average of seven years postoperatively. Two additional patients were managed with proximal tibial osteotomy because of residual varus deformity after the hemiepiphyseodesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychological investigations of pronoun resolution have implicitly assumed that the processes involved automatically provide a unique referent for every pronoun. We challenge this assumption and propose a new framework for studying pronoun resolution. Drawing on advances in discourse representation and global memory modeling, this framework suggests that automatic processes may not always identify a unique referent for a pronoun. In 9 experiments, we demonstrate that, unlike noun anaphors, pronouns sometimes do not produce relative facilitation of their referents in comparison with nonreferents. We argue that research on pronoun resolution must consider the discourse contexts in which pronouns are likely to occur.

Background Little is known about how optimism/pessimism and health-related quality of life compare across cultures. Methods Three samples of pregnant women in their final trimester were recruited from China, Ghana, and the United States (U.S.). Participants completed a survey that included the Life Orientation Test - Revised (LOT-R, an optimism/pessimism measure), the Short Form 12 (SF-12, a quality of life measure), and questions addressing health and demographic factors. A three-country set was created for analysis by matching women on age, gestational age at enrollment, and number of previous pregnancies. Anovas with post-hoc pairwise comparisons were used to compare results across the cohorts. Multivariate regression analysis was used to create a model to identify those variables most strongly associated with optimism/pessimism. Results LOT-R scores varied significantly across cultures in these samples, with Ghanaian pregnant women being the most optimistic and least pessimistic and Chinese pregnant women being the least optimistic overall and the least pessimistic in subscale analysis. Four key variables predicted approximately 20% of the variance in overall optimism scores: country of origin (p = .006), working for money (p = .05); level of education (p = .002), and ever being treated for emotional issues with medication (p < .001). Quality of life scores also varied by country in these samples, with the most pronounced difference occurring in the vitality measure. U.S. pregnant women reported far lower vitality scores than both Chinese and Ghanaian pregnant women in our sample. Conclusion This research raises important questions regarding what it is about country of origin that so strongly influences optimism/pessimism among pregnant women. Further research is warranted exploring underlying conceptualization of optimism/pessimism and health related quality of life across countries.

Rapid progression of hip subluxation was noted in the year after selective dorsal rhizotomy in seven hips (six patients). The hips that subluxed progressed from a lateral extrusion index averaging 25% preoperatively as compared with 50% after rhizotomy. Although preexistent hip dysplasia was a predisposing factor, hips with an intermediate degree of preoperative lateral extrusion (12-25%) had variable results. Ongoing and more frequent evaluation of hip stability is necessary after dorsal rhizotomy.

The records of all thirteen patients for whom a diagnosis of cloacal exstrophy had been recorded in our hospitals were analyzed for evidence of musculoskeletal problems. All thirteen patients had spina bifida, four had congenital scoliosis, two had congenital kyphosis, and three had non-congenital scoliosis. All had a lipomeningocele, and eleven had paralysis of the lower extremities. Hydrocephalus and its associated problems were not found, but tethered-cord syndrome was diagnosed in eleven patients. Persistent diastasis of the symphysis pubis was found in all patients. Abduction and external rotation of the hips were more than normal. Mild dysplasia was seen in six of the twenty-six hips. Deformities of the foot were common, and twelve feet had been operated on for correction. Recurrent equinovarus deformity of the foot was associated with tethered-cord syndrome in two patients.

For the first time, embedded Si:C (eSi:C) was demonstrated to be a superior nMOSFET stressor compared to SMT or tensile liner (TL) stressors. eSi:C nMOSFET showed higher channel mobility and drive current over our best poly-gate 45 nm-node nMOSFET with SMT and tensile liner stressors. In addition, eSi:C showed better scalability than SMT plus tensile liner stressors from 380 nm to 190 nm poly-pitches.

To define the scope of bone disease among men referred for parathyroidectomy and to document bone density screening trends in this high-risk population.Clinical data were analyzed from a prospectively maintained database of 1000 patients undergoing parathyroidectomy for sporadic primary hyperparathyroidism at the Cleveland Clinic between 2000 and 2006. Information collected included demographics, reason for referral, body mass index, intraoperative findings, preoperative and postoperative laboratory values (serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D, and 24-hour urinary calcium excretion), and preoperative and postoperative dual-energy x-ray absorptiometry (DXA) findings.Of the 1000 patients, 243 (24%) were men. As with women, bone health-related issues were the most common reason for referral (32%). In 2000, only 12% of men had preoperative DXA scans; this rose to 42% by 2005. The frequency of prereferral DXA screening increased throughout the study, but even by 2006, referring physicians did not screen most of their male patients. In 2000, the prevalence of bone disease (osteoporosis or osteopenia) in men was 8%, but with improved screening, this increased to 26%, approaching the 34% rate in women. Preoperative and postoperative levels of calcium, parathyroid hormone, phosphorus, 24-hour urinary calcium, and 25-hydroxyvitamin D were the same among men with and without bone disease. Analysis of postoperative DXA scans revealed that gains in postparathyroidectomy bone density were significantly greater in men than in women at all anatomic testing sites. In men, lowest T scores improved by a mean +/- SEM of +0.35 +/- 0.09 compared with +0.098 +/- 0.035 in women (P = .009). Men were 4 times less likely than women to have continued bone loss after parathyroidectomy.Clinical and laboratory parameters cannot identify men with hyperparathyroidism who have bone loss, illustrating the need for routine DXA screening. Despite this, DXA remains underused. Improved screening practices will favorably effect men's health.

BACKGROUND Despite the prevalence of evidence-based interventions to improve quality in health care systems, there is a paucity of documented evidence of a financial return on investment (ROI) for these interventions from the perspective of the investing entity. PURPOSES To report on a demonstration project designed to measure the business case for selected quality interventions in high-risk high-cost patient populations in 10 Medicaid managed care organizations across the United States. METHODOLOGY/APPROACH Using claims and enrollment data gathered over a 3-year period and data on the costs of designing, implementing, and operating the interventions, ROIs were computed for 11 discrete evidence-based quality-enhancing interventions. FINDINGS A complex case management program to treat adults with multiple comorbidities achieved the largest ROI of 12.21:1. This was followed by an ROI of 6.35:1 for a program which treated children with asthma with a history of high emergency room (ER) use and/or inpatient admissions for their disease. An intervention for high-risk pregnant mothers produced a 1.26:1 ROI, and a program for adult patients with diabetes resulted in a 1.16:1 return. The remaining seven interventions failed to show positive returns, although four sites came close to realizing sufficient savings to offset investment costs. PRACTICE IMPLICATIONS Evidence-based interventions designed to improve the quality of patient care may have the best opportunity to yield a positive financial return if it is focused on high-risk high-cost populations and conditions associated with avoidable emergency and inpatient utilization. Developing the necessary tracking systems for the claims and financial investments is critical to perform accurate financial ROI analyses.

163 Background: AR directed Tx, including Abiraterone (A) and Enzalutamide (E), prolong survival in patients with mCRPC and are FDA approved. After primary Tx with either A or E, the response to E or A is decreased as is the duration of response. NGS tissue sequencing of mCRPC shows a range of disease phenotypes and genotypes which are associated with increased tumor heterogeneity. Single site biopsy, may not represent the diversity of disease. Our objective is to develop biomarkers of heterogeneity from the analysis of single cells from patients with mCRPC. Methods: 221 blood samples from 179 unique patients (pts) were collected from pts about to begin AR Tx (n = 150) or Taxanes (n = 71). Samples were analyzed with the Epic Sciences platform. Analysis included digital pathology of 20 discrete phenotypic cell features inclusive of AR, CK, size and shape measures. 9225 single CTCs were characterized, data standardized, features clustered and categorized into 15 phenotypically distinct CTC subtypes. Individual pt samples were then analyzed for the frequency and heterogeneity (Shannon Index) of CTC subtypes and monitored for clinical endpoints. A subset of CTCs (n = 350) were individually sequenced and analyzed for clonality and CNV to assess genomic heterogeneity. Results: A diversity of CTC phenotypes were observed at each line of therapy. In AR Tx pts, high heterogeneity predicts 6mo PFS (OR = 2.57, p = 0.01) and shorter OS (HR = 4.5, p < 0.001). Separately, specific CTC phenotypes also predict 6mo PFS (OR = 5, p < 0.001) and shorter OS (HR = 5.8, p < 0.001). Heterogeneity scores were not associated with taxane resistance. NGS analysis identified subclonal drivers of disease progression including multiple private and/or clustered genomic drivers. Conclusions: Single CTC characterization of phenotype and genotype supports the concept of tumor heterogeneity as a driver of disease resistance. The heterogeneity observed supports the potential value of single cell characterization to identify rare somatic sub-clonal alterations and can aid in the development of rational therapeutic trials.

307 Background: AR targeted therapies in combination with PARP inhibitors have recently shown efficacy in mCRPC patients with specific DNA repair gene mutations in metastatic tissue biopsies. Homologous recombination DNA repair deficiencies (HRD), associated with response to PARP inhibitors, can also be assessed by genomic instability/scarring. Accurate genomic scarring measurement in tumors can be confounded by intra-tumor heterogeneity and/or non-tumor genome contamination. To better identify PARPi sensitivity in mCRPC patients, we developed a genomic instability and scarring assay starting from single CTCs. Methods: VCaP, LnCaP or PC3 cell lines were spiked into healthy donor blood. Individual spiked cells were identified and recovered for genomic analysis using the standard Epic CTC assay. Post recovery, cells were lysed, whole genome amplified, constructed into shotgun libraries and sequenced to ~2M 2x150bp PE reads. Following alignment, whole genome copy number and instability analysis was performed to identify large scale transitions (LST, n of chromosomal breaks between adjacent regions of at least 10 Mb), % of genome altered (percentage of 1Mbp bins with copy number alterations), as well as specific tumor suppressor/oncogene copy number alterations. The association of PTEN loss with increases in genomic instability and scaring was performed. Results: Loss of PTEN function was previously shown to be associated with genomic instability. Our assessment of PTEN deletion was confirmed in PC3, while at least one genomic copy was observed in LnCaP and VCaP. The number of LSTs and % of genome altered was higher in PC3 (n = 19 +/- 3; 9.3% +/- 2.6%) than both VCaP and LnCap (n = 8 +/- 2; 6.1% +/- 0.4%). Conclusions: The association of higher genomic instability in a PTEN null cell line (PC3) vs. those with either heterozygous (LnCaP) or wild type (VCaP) PTEN status, matches published reports associating PTEN loss with increased genomic instability. Although, PC3 only demonstrates mild PARPi sensitivity in vitro, the detection of increased genomic scarring vs. cells with at least 1 functional PTEN allele confirms the assays ability to quantify genome instability at the single cell level from CTCs in a liquid biopsy.

The tibial metaphyseal-diaphyseal (MD) and tibial-femoral (TF) angles were measured on the radiographs of 33 knees in young children (aged 12-36 months) with bowleg deformity. Four observers of differing experience measured the films in a blinded fashion to determine the intraobserver and interobserver variability of these measurements. The clinical implications of these variabilities are described. Very little instruction and experience is necessary to make these measurements correctly and precisely. Measurement of the MD angle was superior to measurement of the TF angle. Contrary to published opinion, rotation can have a small but potentially significant effect on the measured MD angle.

Twenty-two patients (24 hips) with Legg-Perthes disease received 49 magnetic resonance (MRI) scans. The scans and corresponding radiographs were independently evaluated in a blinded fashion to assess the capabilities of, and indications for, MRI in Legg-Perthes disease. Early in the disease process, MRI often more clearly delineated the extent and location of areas of involvement than did plain radiographs. In one patient, MRI failed to indicate necrosis early in the course of the disease, but it was detected on plain radiographs. MRI can also be used to give a rough estimate of sphericity, which in some phases of the disease process is better than plain radiographs. For serially following the disease process through the natural healing course, plain radiographs were as good or better than MRI and considerably less costly.

Thirty patients who had hemophilia and were seropositive for the human immunodeficiency virus were evaluated. The preoperative CD4 lymphocyte count was decreased to an average of 336 x 10(9) per liter (range, 27 to 708 x 10(9) per liter). After twenty-six orthopaedic operations in patients who had no previous bacterial infection, a nosocomial infection (cellulitis in the forearm, at the site of an intravenous catheter) developed in only one patient, but five patients had an abnormal postoperative fever that was not accompanied by the expected increase in the white blood-cell count. The preoperative CD4 lymphocyte count was significantly reduced in the patients who had an abnormal elevation in body temperature (p less than 0.004). The functional result or outcome after operation was similar to that in hemophilic patients treated before 1982. Subsequent progression of infection with the human immunodeficiency virus, as determined by the CD4 lymphocyte count and the Walter Reed classification system, occurred in most patients. Acquired immunodeficiency syndrome was diagnosed in six patients. A more rapid progression to acquired immunodeficiency syndrome was seen in the patients who had a lower CD4 lymphocyte count preoperatively. Preoperative evaluation of the CD4 lymphocyte count and the response to intradermal skin-test antigens in patients who are at risk for infection postoperatively provides additional information concerning immunological competence. With these data, the possible risk of infection in patients who are seropositive for the human immunodeficiency virus can be estimated more accurately.

While traumatic brain injury is a major public health issue, schizophrenia-like psychosis following traumatic brain injury is relatively rare and poorly studied. Yet the risk of developing schizophrenia-like psychosis after traumatic brain injury is 3 times more important than in the general population.Risk factors associated with onset of psychosis after traumatic brain injury include: left hemispheric lesions, closed head injury and coma of duration superior to 24 hours. Most patients develop symptoms of psychosis after a moderate to severe traumatic brain injury and often have lesions of the frontal and temporal lobes. CHOLINERGIC HYPOTHESIS:Neuropathologic, electrophysiological and pharmacologic evidence show that cognitive impairment including attention, memory and executive functioning impairment may be related with cholinergic dysfunction in patients with traumatic brain injury. The cholinergic hypothesis is also incriminated in the genesis of schizophrenia. The same biochemical disorders found in schizophrenia which imply many neurotransmitters are often present immediately after traumatic brain injury. However in chronic cognitive disorders secondary to traumatic brain injury, the cholinergic system alone seems to be specifically implied. This is due to the fragility of the cholinergic fibres and a chronic yet reversible reduction of the cholinergic reserves after traumatic brain injury. Cholinergic function can be studied by the P50 evoked response to paired auditory stimuli.While this is disturbed in patients presenting with cognitive impairment after traumatic brain injury its normalisation can be obtained after administration of an acetylcholine esterase inhibitor. In schizophrenic patients there is also an abnormal P50 evoked response due in part to a low number of alpha 7 nicotinic receptors which are implicated in sensory filtering in the frontal lobe. Moreover in schizophrenia, post-mortem studies show a negative correlation between the activity of acetylcholine transferase in the parietal cortex and the severity of the cognitive deficits, as well as a lesser density of the muscarinic M1 and M4 receptors in the frontal lobe. The lower concentration of M1 receptors in the frontal cortex is correlated with the severity of the positive symptoms. THERAPEUTICAL PERSPECTIVES: Antipsychotics have emerged as the first line treatment of psychotic disorders. In research, their ability for enhancing cognitive function could result in the increase of acetylcholine in the medial prefrontal cortex. Acetylcholinesterase inhibitors have been widely used for treatment of cognitive impairment in Alzheimer's disease. Galantamine could be interesting in schizophrenia and psychosis following traumatic brain injury because it has a dual mechanism of action: selective competitive inhibition of acetylcholinesterase and allosteric potentialisation of nicotinic receptor response. Therefore Galantamine remains active in nicotine addicted schizophrenic patients who may smoke as an auto treatment. Galantamine has shown efficacy in adjunction to Risperidone in one patient presenting with psychosis following traumatic brain injury and in 3 case reports of schizophrenic patients.Further systematic studies are needed to confirm this hypothesis.

Background: Mostly asymptomatic until late stage, colorectal cancer is driven by the successive accumulation of genetic alterations resulting in genomic instability within subclonal tumor populations. mCRC often progresses as a subclonally diverse multifocal disease due to selective therapeutic pressure, the surrounding tumor microenvironment, and underlying genomic heterogeneity. Targeted therapies against EGFR, VEGF or BRAF have shown increased response in a subset of patients; however, patient stratification using standard population analysis of DNA markers from tumor biopsy, (i.e. chromosomal instability, microsatellite instability, promoter methylation, resistance mutations), is problematic due to tumor heterogeneity. CTCs reflect the active metastatic subclonal populations at any given time, making single cell analysis of DNA markers a more accurate, real-time picture of cumulative metastatic diversity. Using Epic's enrichment-free CTC analysis platform, we characterized individual CTCs from a mCRC patient to understand the extent of intra-patient genomic heterogeneity, including the presence genomic instability and point mutations. We compared the prevalence of clinically relevant subclonal alterations within patient CTCs to CRC TCGA data, offering insights into identification of therapeutic opportunities and potential mechanisms of resistance. Methods: Blood was collected from a heavily pretreated mCRC patient and was processed for CTC analysis using the Epic Platform. 34 CTCs were individually recovered, lysed, whole genome amplified, constructed into shotgun libraries and target enriched for all coding regions of 500 pan-cancer genes. Enriched libraries were sequenced to an average depth of 697X coverage by 2×150 PE sequencing. Sequences were aligned and somatic mutations were determined using VarScan with the patient's WBC as germline reference. Variants were filtered for functional gain- or loss-of-function mutations by SIFT/PolyPhen2 and selected based on low frequency in 1000g database. Genomic instability and loss of heterozygosity (LOH) was also assessed. Somatic variants deriving from the patient CTC cohort and TCGA CRC cohort of 302 patients were annotated, analyzed, and compared using GenePool™ software (Station X). Results: MLL3 alterations, frequently observed in primary CRC biopsies (14%), were identified in 70% of all CTCs sequenced. Previously cited somatic variants were detected in minor subclonal populations of CTCs, including APC (12%), BRCA1/2 (8%), KRAS (6%), PI3KCA (6%) and TP53 (6%). A wide range of genomic instabilities and LOH was also observed across CTCs. Conclusions: The Epic CTC platform is suited to identify subclonal population of CTCs harboring clinically relevant genomic alterations on a single cell level, which can inform clonal drift, identify rare clonal populations, and enable patient stratification at higher resolution. Citation Format: Stephanie Greene, Jerry Lee, Mark Landers, Sandeep Sanga, Adam Jendrisak, Ryon Graf, Jessica Louw, Shannon Werner, Yipeng Wang, Ryan Dittamore, Dena Marrinucci. Single cell genomic profiling of circulating tumor cells (CTCs) from metastatic colorectal cancer (mCRC) identify tumor heterogeneity and rare somatic driver alterations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A35.

Introduction: CTCs hold promise as prognostic and predictive biomarkers for cancer management. Many CTC technologies enrich CTCs based on cell surface markers or physical parameters such as cell size. However, genomic and phenotypic intra-tumor heterogeneity is well documented and similarly observed in CTCs. We sought to validate the Epic Platform, an enrichment-free approach, for CTC identification and biomarker characterization. In addition, we sought to enumerate and molecularly characterize CTCs in Metastatic Castrate Resistant Prostate Cancer (mCRPC) patients. Experimental Procedures: To assess intra/inter-assay and -operator reproducibility, cell line cells (CLCs) were spiked into healthy donor (HD) blood and processed onto slides (∼0.5mL/slide) in dilutions ranging from 6-300 CLCs/slide and assessed by%CV of CLC counts in replicate samples. Accuracy and linearity were assessed via linear regression and slope of all dilutions. CLCs were also molecularly characterized by immunofluorescence (IF), FISH, and NGS. To test clinical sensitivity, ∼1mL of blood from 28 mCRPC patients was processed. CTCs (CK+, CD45-, DAPI+) and CTC subtypes including apoptotic (CK+, CD45-, fragmented DAPI), and CK- (CK-, CD45-, DAPI+) were enumerated. Androgen receptor (AR) expression was quantitated on each CTC. A subset of samples were further analyzed for ERG rearrangements via FISH and whole genome copy number variation (CNV) by NGS. In addition, 18 HDs were tested to assess clinical specificity. Results: Intra/inter-assay and operator reproducibility across 3 runs each produced ≤ 20% CV at 300 CLC/slide and ≤ 30% CV at 25 CLC/slide. The CTC enumeration assay demonstrated accuracy, linearity and sensitivity throughout all dilutions tested, 6-300 CLC/mL, (x = 1.15, r2 = 0.9987,%CV ≤ 30%). CLCs exhibited expected biomarker expression (IF) and genetic aberrations (FISH and NGS). No CTCs or CTC subtypes were detected in HD samples. At least 1 CTC/mL was detected in 82% of mCRPC patient samples. Including CK- and apoptotic CTCs, 100% of mCRPC patients had at least 1 CTC/mL. Analysis of AR expression/localization, ERG rearrangements by FISH, and whole genome CNV analyses were consistent with malignant origin. Conclusions: We established the reproducibility, linearity, accuracy, and sensitivity of the Epic Platform. CTCs and CTC subtypes were absent in HDs and present in all mCRPC samples tested. We also demonstrated integrated IF, FISH, and NGS characterization of single CTCs, which has powerful implications for improved patient selection for targeted therapy and could enable a better understanding of intra-patient heterogeneity, clonal evolution, and drug resistance and response over time. Citation Format: Ryon P. Graf, David T. Valenta, Mark Landers, Bryan Taggart, Stephanie Greene, Shannon L. Werner, Ryan Dittamore, Dena Marrinucci. Analytical and clinical validation of the Epic Circulating Tumor Cell (CTC) Platform: enrichment-free CTC detection and biomarker characterization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1584. doi:10.1158/1538-7445.AM2015-1584

Objective . To describe the steps in developing a business case for quality-enhancing interventions (QEIs) in health care. Analysis . The development of a business case for QEIs in health care involves 11 steps. These steps include (1) describing the intervention, (2) determining perspective, (3) identifying the effects of the intervention on quality, (4) designing the study, (5) identifying and measuring cash flows, (6) considering the effects of capacity constraints, (7) selecting a measure of return on investment, (8) determining the time horizon for the analysis, (9) determining the discount rate, (10) adjusting costs and savings for inflation, and (11) determining organizational readiness for business case development. A checklist offers guidance on assessing readiness for the business case. Conclusion . The absence of a ‘business case’ for quality is frequently cited as the reason health care organizations do not implement QEIs, despite decades of careful research demonstrating their effectiveness. Our continuing commitment to advancing the discipline of business case analysis is based on a belief that delineating the cost and economic implications of investments in QEIs is a critical threshold issue to widespread adoption of evidence-based quality improvements. We believe it is appropriate and timely to consider how best to standardize approaches and move the field of business case analysis forward.

The authors compare the effects of small intestinal submucosa (SIS) treatment to suture repair with respect to histologic and functional outcomes for complete muscle lacerations in a rabbit model. The authors hypothesized that SIS treatment of full-thickness muscle belly lacerations would significantly improve muscle function, strength, and regeneration compared to the current standard-of-care treatment. Muscle belly lacerations were created in the extensor digitorum longus (EDL) of both hind limbs of each rabbit. After randomization, lacerations were left unrepaired (n = 48) or repaired using a 4-0 Prolene modified Kessler stitch (n = 48). A flap of SIS graft was sutured into half (n = 24 each) of the repaired and unrepaired muscles forming four study groups. Suture repair with SIS augmentation of complete muscle lacerations resulted in healed tissue that most closely resembled normal muscle in terms of morphology and function when compared to current standard-of-care treatments. Active force production in this group reached 79% of uninjured controls 12 weeks after surgery. SIS may have important clinical advantages over suture repair alone and warrants further clinical study.

Irvine-Gass syndrome, which describes visual loss after cataract surgery as a result of cystoid macular oedema (CMO), typically produces petalloid leakage around the fovea on fluorescein angiography (FA) often associated with late hyperfluorescence of the optic disc.1 Recently, optical coherence tomography (OCT) has confirmed the presence of perifoveal cystic spaces in vivo, consistent with histological specimens with CMO. OCT is increasingly used as a first test, before FA, for diagnosing unexplained visual loss after cataract surgery. Here we report a case of Irvine-Gass syndrome that demonstrated perifoveal leakage and late optic disc staining on FA, whose predominant OCT finding was a localised foveolar detachment. Isolated foveal detachment has been described in diabetic …

Septic arthritis is a commonly reported complication of rheumatoid arthritis (RA). Tumor necrosis factor alpha (TNF-alpha) plays an important role in host defense against infection. Inhibition of its activity could therefore be anticipated to augment the risk of infection. Both opportunistic and bacterial infections have been described in patients with RA treated with anti-TNF-alpha therapy. We describe a patient who experienced 2 episodes of septic arthritis. Both occurred while the patient was on etanercept. Recurrence developed despite prolonged parenteral antibiotic. To our knowledge, this is the first report of relapsing oligoarticular methicillin-sensitive Staphylococcus aureus septic arthritis despite prolonged antibiotic treatment in a patient receiving etanercept therapy. Our case underscores the advisability of discontinuing TNF-alpha blockade in patients with septic arthritis during prolonged antimicrobial therapy.