Routine Clinical Care Of Patients Research Articles

Automatic classification of dopamine transporter SPECT: deep convolutional neural networks can be trained to be robust with respect to variable image characteristics.

This study investigated the potential of deep convolutional neural networks (CNN) for automatic classification of FP-CIT SPECT in multi-site or multi-camera settings with variable image characteristics. The study included FP-CIT SPECT of 645 subjects from the Parkinson's Progression Marker Initiative (PPMI), 207 healthy controls, and 438 Parkinson's disease patients. SPECT images were smoothed with an isotropic 18-mm Gaussian kernel resulting in 3 different PPMI settings: (i) original (unsmoothed), (ii) smoothed, and (iii) mixed setting comprising all original and all smoothed images. A deep CNN with 2,872,642 parameters was trained, validated, and tested separately for each setting using 10 random splits with 60/20/20% allocation to training/validation/test sample. The putaminal specific binding ratio (SBR) was computed using a standard anatomical ROI predefined in MNI space (AAL atlas) or using the hottest voxels (HV) analysis. Both SBR measures were trained (ROC analysis, Youden criterion) using the same random splits as for the CNN. CNN and SBR trained in the mixed PPMI setting were also tested in an independent sample from clinical routine patient care (149 with non-neurodegenerative and 149 with neurodegenerative parkinsonian syndrome). Both SBR measures performed worse in the mixed PPMI setting compared to the pure PPMI settings (e.g., AAL-SBR accuracy = 0.900 ± 0.029 in the mixed setting versus 0.957 ± 0.017 and 0.952 ± 0.015 in original and smoothed setting, both p < 0.01). In contrast, the CNN showed similar accuracy in all PPMI settings (0.967 ± 0.018, 0.972 ± 0.014, and 0.955 ± 0.009 in mixed, original, and smoothed setting). Similar results were obtained in the clinical sample. After training in the mixed PPMI setting, only the CNN provided acceptable performance in the clinical sample. These findings provide proof of concept that a deep CNN can be trained to be robust with respect to variable site-, camera-, or scan-specific image characteristics without a large loss of diagnostic accuracy compared with mono-site/mono-camera settings. We hypothesize that a single CNN can be used to support the interpretation of FP-CIT SPECT at many different sites using different acquisition hardware and/or reconstruction software with only minor harmonization of acquisition and reconstruction protocols.

Suboptimal Immunization Coverage among Canadian Rheumatology Patients in Routine Clinical Care.

To assess vaccination coverage and predictors of vaccination among a Canadian population of rheumatology patients in routine clinical care. In this cross-sectional study, consecutive adult patients presenting to a tertiary rheumatology clinic at the McGill University Health Center between May and September 2015 were asked to fill a survey on vaccination. Patients self-identified as having rheumatoid arthritis (RA), systemic autoimmune rheumatic diseases (SARD), spondyloarthropathies (SpA), or other diseases (OD). Multivariate logistical regression analyses were performed to evaluate patient and physician factors associated with various vaccinations [for influenza, pneumococcus, and hepatitis B virus (HBV)]. Published Quebec general population influenza and pneumococcal vaccination rates in those aged ≥ 65 years were used as comparative baseline rates. Three hundred fifty-two patients were included in the analysis (RA: 136, SARD: 113, SpA: 47, OD: 56). Vaccination rates were reported as follows: (1) influenza: RA 48.5%, SARD 42.0%, SpA 31.9%, OD 88.9%, Quebec general population 58.5%; (2) pneumococcal: RA 42.0%, SARD 37.8%, SpA 29.7%, OD 33.3%, Quebec general population 53.2%; (3) HBV: RA 33.6%, SARD 55.6%, SpA 73.5%, OD 36.8%; and (4) herpes zoster: RA 5.6%, SARD 28.6%, SpA 25.0%, OD 16.7%. Physician recommendation was the strongest independent predictor of vaccination across all vaccine types (influenza: OR 8.56, 95% CI 2.80-26.2, p < 0.001; pneumococcal: OR 314, 95% CI 73.0-1353, p < 0.001; HBV: OR 12.8, 95% CI 5.27-31.1, p < 0.001). Disease group, disease duration, comorbidities, treatment type, and being followed by a primary care physician were not significantly associated with vaccination. There is suboptimal immunization coverage among ambulatory rheumatology patients. An important role for patient and physician education is highlighted in our study, especially because physician recommendation of vaccination was strongly predictive of vaccine uptake.

From Hypertrophy to Heart Failure: What Is New in Genetic Cardiomyopathies.

The purpose of this review is to provide an update on the recent advances in the research and clinical care of patients with the major phenotypes of inherited cardiomyopathies-hypertrophic, dilated, and arrhythmogenic. Developments in genetics, risk stratification, therapies, and disease modeling will be discussed. Diagnostic, prognostic, and therapeutic tools which incorporate genetic and genomic data are being steadily incorporated into the routine clinical care of patients with genetic cardiomyopathies. Human pluripotent stem cells are a breakthrough model system for the study of genetic variation associated with inherited cardiovascular disease. Next-generation sequencing technology and molecular-based diagnostics and therapeutics have emerged as valuable tools to improve the recognition and care of patients with hypertrophic, dilated, and arrhythmogenic cardiomyopathies. Improved adjudication of variant pathogenicity and management of genotype-positive/phenotype-negative individuals are imminent challenges in this realm of precision medicine.

Human prion diseases.

Prion diseases are rapidly progressive neurodegenerative conditions that can be difficult to diagnose and are transmissible under specific circumstances. The authors will provide background regarding prion disease and focus on diagnostic tools. Prion disease is caused by misfolded prion protein. The three possible causes of prion disease include sporadic (85%), genetic (10-15%), and acquired (<1%). Acquired prion diseases include kuru, iatrogenic, and variant Creutzfeldt-Jakob disease. Prion diseases differ in their clinical manifestation, neuropathology, and diagnostic test results. A variety of recent diagnostic tools have evolved that allow more reliable antemortem diagnosis of prion disease such as brain MRI and cerebrospinal fluid real-time quaking-induced conversion. Special infectivity guidelines must be followed when dealing with central nervous system tissue, but only standard precautions are needed for routine clinical care of patients with prion disease. The only way to definitely diagnose prion disease and determine its type is via neuropathologic examination. However, brain MRI and cerebrospinal fluid real-time quaking-induced conversion have drastically increased diagnostic accuracy and are important tests to use when evaluating patients with suspected prion disease.

1050-P: Development and Validation of the Continuous Subcutaneous Insulin Infusion-Related Quality of Life (CSII-QoL) Scale

Continuous subcutaneous insulin infusion (CSII) is associated with improved glycemic control, reduced incidence of hypoglycemia and improved quality of life (QoL). To date, however, there is no QoL scale specific to CSII. The objective of this study was to develop and validate a scale to measure CSII-QoL for patients with type 1 diabetes (T1D).A total of 50 T1D patients aged ≥15 years who used CSII (28% males; age 47.6±17.0 years, mean±SD; duration of diabetes 14.7±9.7 years; duration of CSII use 6.1±3.3 years; HbA1c 7.4±0.8%) took part in the CSII-QoL study. Twenty-eight potential CSII-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. The resulting CSII-QoL was tested for factor analysis, validity, reliability and influence factors. The final 25-item questionnaire was found to have a three-domain structure (“convenience,” “social restriction,” and “psychological problems”), high internal consistency (Cronbach’s alpha = 0.851), and substantial test-retest reliability (intraclass correlation coefficient = 0.69). The CSII-QoL score correlated positively with basal insulin ratio, but not with age, sex, HbA1c, or total daily insulin dose. The CSII-QoL score correlated negatively with the Problem Areas in Diabetes (PAID) score. The CSII-QoL is the first CSII-related QoL scale for patients with T1D. This short, validated and reliable instrument can potentially be useful in future clinical studies and in routine clinical patient care. (UMIN-CTR: UMIN000031595). Disclosure M. Toyoda: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. A. Tone: Speaker's Bureau; Self; Lilly Diabetes, Medtronic Japan Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. K. Kato: None. M. Kimura: None. S. Kawashima: Speaker's Bureau; Self; Novo Nordisk Inc., Sumitomo Dainippon Pharma Co., Ltd. H. Sawaki: None. Y. Hirota: Speaker's Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. A. Okada: None. A. Kuroda: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi. M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. T. Watanabe: None. A. Suganuma: None. T. Murata: Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Kowa Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K.K. N. Sakane: Board Member; Spouse/Partner; Kao Corporation.

Diagnostic performance of the specific uptake size index for semi-quantitative analysis of I-123-FP-CIT SPECT: harmonized multi-center research setting versus typical clinical single-camera setting

IntroductionThe specific uptake size index (SUSI) of striatal FP-CIT uptake is independent of spatial resolution in the SPECT image, in contrast to the specific binding ratio (SBR). This suggests that the SUSI is particularly appropriate for multi-site/multi-camera settings in which camera-specific effects increase inter-subject variability of spatial resolution. However, the SUSI is sensitive to inter-subject variability of striatum size. Furthermore, it might be more sensitive to errors of the estimate of non-displaceable FP-CIT binding. This study compared SUSI and SBR in the multi-site/multi-camera (MULTI) setting of a prospective multi-center study and in a mono-site/mono-camera (MONO) setting representative of clinical routine.MethodsThe MULTI setting included patients with Parkinson’s disease (PD, n = 438) and healthy controls (n = 207) from the Parkinson Progression Marker Initiative. The MONO setting included 122 patients from routine clinical patient care in whom FP-CIT SPECT had been performed with the same double-head SPECT system according to the same acquisition and reconstruction protocol. Patients were categorized as “neurodegenerative” (n = 84) or “non-neurodegenerative” (n = 38) based on follow-up data. FP-CIT SPECTs were stereotactically normalized to MNI space. SUSI and SBR were computed for caudate, putamen, and whole striatum using unilateral ROIs predefined in MNI space. SUSI analysis was repeated in native patient space in the MONO setting. The area (AUC) under the ROC curve for identification of PD/“neurodegenerative” cases was used as performance measure.ResultsIn both settings, the highest AUC was achieved by the putamen (minimum over both hemispheres), independent of the semi-quantitative method (SUSI or SBR). The putaminal SUSI provided slightly better performance with ROI analysis in MNI space compared to patient space (AUC = 0.969 vs. 0.961, p = 0.129). The SUSI (computed in MNI space) performed slightly better than the SBR in the MULTI setting (AUC = 0.993 vs. 0.991, p = 0.207) and slightly worse in the MONO setting (AUC = 0.969 vs. AUC = 0.976, p = 0.259). There was a trend toward larger AUC difference between SUSI and SBR in the MULTI setting compared to the MONO setting (p = 0.073). Variability of voxel intensity in the reference region was larger in misclassified cases compared to correctly classified cases for both SUSI and SBR (MULTI setting: p = 0.007 and p = 0.012, respectively).ConclusionsThe SUSI is particularly useful in MULTI settings. SPECT images should be stereotactically normalized prior to SUSI analysis. The putaminal SUSI provides better diagnostic performance than the SUSI of the whole striatum. Errors of the estimate of non-displaceable count density in the reference region can cause misclassification by both SUSI and SBR, particularly in borderline cases. These cases might be identified by visual checking FP-CIT uptake in the reference region for particularly high variability.

Radioligand Therapy With 177Lu-PSMA for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE. Several clinical studies have shown the efficacy of 177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC). The purpose of this article is to present results of a systematic review and meta-analysis aimed at compiling and outlining efficacy and safety data on 177Lu-PSMA RLT for mCRPC across all studies published to date. CONCLUSION. The results of the systematic review and meta-analysis suggest that 177Lu-PSMA RLT is an effective treatment of advanced-stage mCRPC that is refractory to standard therapeutic options and that it has a low toxicity profile. High-level evidence from randomized control trials is crucial for confirming the effectiveness of 177Lu-PSMA RLT and for instituting this therapy in the routine clinical care of patients with mCRPC.

Exploring Patient Decision Making Regarding Discontinuation of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Multiple clinical trials have demonstrated that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now offered to select patients in routine clinical care. In order to better support patient decision making, we explored patients' views on TKI discontinuation and the factors patients consider when making this decision. Patients were recruited from three U.S. academic cancer centers. Qualitative interviews were recorded, transcribed, and content analyzed. We interviewed 22 patients, half of whom wanted to try TKI discontinuation. Eleven factors relevant to the decision emerged, and patients weighed these factors differently. Commonly mentioned factors included perceived risk of relapse, TKI side effects, financial considerations, polypharmacy, and willingness to change something that was working (status quo). There were notable differences in patients' understanding of the likelihood of achieving a treatment-free remission, with patients who did not want to stop TKIs more accurately reporting the risk of relapse than patients who wanted to stop. This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for patient education and decision support so that patients and providers can make shared decisions that are informed and values based. The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Clinical trials have shown that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now being offered to patients outside of clinical trials. This study explored factors that patients who are eligible to try TKI discontinuation considered when making this decision. Factors relevant to the decision included risk of relapse, side effects, financial considerations, polypharmacy, and willingness to change something that was working. This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for decision support and outline the factors that should be included so that patients and providers can make shared decisions that are informed and values based.

Validity of a multi-domain computerized cognitive assessment battery for patients with multiple sclerosis

BackgroundComputerized cognitive batteries may facilitate the integration of neuropsychological assessments into routine clinical care of patients with multiple sclerosis (PwMS). ObjectiveTo assess the construct and criterion validity of a computerized, multi-domain cognitive assessment battery (CAB, NeuroTrax) in MS. Methods81 PwMS and 15 healthy controls (HC) completed the CAB and a set of traditional neuropsychological tests recommended for MS on the same day. Principal component factor analysis was used to assess construct validity. For criterion validity, the gold standard definition of cognitive impairment was a score of ≥1.5SD below average on at least one cognitive domain, based upon traditional test normative data. Receiver operating characteristic (ROC) analysis was used to examine the ability of the CAB to discriminate cognitively impaired PwMS. ResultsTraditional and computerized tests of memory, processing speed, visuospatial and executive function converged by factor analysis. Computerized tests detected cognitive impairment with 85% sensitivity and 70% specificity. PwMS classified as impaired on only the computerized battery had significantly prolonged response times and a higher rate of unemployment compared with PwMS classified as unimpaired on both batteries. Poor executive function was more likely to be revealed by the CAB. ConclusionThe specific computerized assessment battery evaluated is valid for cognitive screening of people with MS and may be more likely to detect prolonged response times and impaired executive function.

Association of quality of life with disease characteristics and treatment outcomes in patients with advanced gastric cancer: Exploratory analysis of RAINBOW and REGARD phase III trials

BackgroundInadequate understanding of interpretation of quality of life (QoL) instruments leads to unsatisfactory data reporting and clinical decision-making, including in gastric cancer care. Materials and methodsPooled QoL data from two phase III studies of ramucirumab with or without paclitaxel in previously treated patients with gastric or gastroesophageal junction cancer were used to explore associations with clinical attributes, including tumour response, disease measurability and performance status (PS). The European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ)-C30 was used in both studies. Changes in QLQ-C30 scores from baseline to week 6 as a predictor of clinical outcomes and impacts of changes in clinical status on QoL were estimated by multivariate logistic regression and analyses of variance, respectively. ResultsBaseline QoL data were available for 989 patients. Fatigue, pain and appetite loss were prominent baseline symptoms. Disease progression resulted in worse QoL in all functional scales (p < 0.0001 to p = 0.0306), global QoL (p = 0.0011) and symptom scales (fatigue, p < 0.0001; nausea/vomiting, p = 0.0007; pain, p = 0.0052; appetite loss, p = 0.0061). Similar trends were seen with deterioration of PS on QoL. A 15- to 20-point change in global QoL and functional scale scores predicted change in tumour status as did change in fatigue, pain and appetite loss scores. Smaller QoL changes (5–15 points) predicted PS change. Results were similar in patients regardless of baseline disease measurability. ConclusionsOur study underscores the importance of disease control for maintaining or improving QoL. These data could improve future trial design and routine clinical care for patients receiving therapy for previously treated gastric cancer. NCT00917384, NCT01170663.

Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice

Background: A low estimated glomerular filtration rate (eGFR) and an increased urinary albumin-to-creatinine ratio (ACR) are well-recognised prognostic markers of cardiovascular (CV) risk, but their individual and combined relationship with CV disease and total mortality among insulin-treated type 2 diabetes (T2D) patients in routine clinical care is unclear. Methods: We analysed data for insulin users with T2D from UK general practices between 2007 and 2014 and examined the association between mortality rates and chronic kidney disease [categorised by low eGFR (< 60 mL/min/1.73 m²), high eGFR (≥60 mL/min/1.73 m²), low ACR (< 300 mg/g); and high ACR (≥300 mg/g) at insulin initiation] after a 5-year follow-up period using Cox proportional hazard models. Results: A total of 18,227 patients were identified (mean age: 61.5 ± 13.8 years, mean HbA1c: 8.6 ± 1.8%). After adjusting for confounders, when compared to adults on insulin therapy with an eGFR < 60 and an ACR ≥300 (low eGFR + high ACR) after a follow-up period of 5 years, patients with an eGFR < 60 and an ACR < 300 (low eGFR + low ACR) had a 6% lower mortality rate (aHR: 0.94; 95% CI 0.79–1.12); those with an eGFR > 60 and an ACR ≥300 (high eGFR + high ACR) had a 20% lower mortality rate (aHR: 0.80; 95% CI 0.68–0.96); and those with an eGFR > 60 and an ACR < 300 (high eGFR + low ACR) had the lowest death rate (28% less; aHR: 0.72; 95% CI 0.59–0.87). Conclusion: This study shows that among a large cohort of insulin-treated T2D patients in routine practice, the combination of reduced eGFR with increased ACR was associated with the greatest risk of premature death, followed closely by those with reduced eGFR and normal ACR levels. Adoption of aggressive CV risk management strategies to reduce mortality in patients with a low eGFR and albuminuria is essential in high-risk patients with T2D.

Prevalence and treatment of hip and knee osteoarthritis in people aged 60 years or older in Germany: an analysis based on health insurance claims data.

ObjectiveOsteoarthritis (OA) is highly prevalent throughout the world, especially in the elderly population, and is strongly associated with patients’ frailty. However, little is known about the prevalence and treatment of OA in elderly patients in routine clinical care in Germany.Materials and methodsAs a part of Linking Patient-Reported Outcomes with CLAIms Data for Health Services Research in Rheumatology (PROCLAIR), a cross-sectional study using claims data from a large Germany statutory health insurance (BARMER) was conducted. We included people aged 60 years or older and assessed the prevalence of OA of the hip or knee, defined as having outpatient diagnoses (ICD: M16 or M17) in at least two quarters of 2014. The use of conservative treatment, including analgesics and physical therapy, and total joint replacement was studied. Analyses were stratified by age, sex, comorbidities, and level of care dependency defined by social law.ResultsA total of 595,754 patients (mean age: 74.9 years; 69.8% female) were diagnosed with OA (21.8%), with the highest prevalence in those between 80 and 89 years (31.0%) and in females compared to males (23.9% vs 18.3%). Prevalence decreased with increasing level of care dependency from 30.5% in patients with a low level (0/1) to 18.7% in the highest level of care dependency. A total of 63.4% of the patients with OA received analgesics, with higher use with increasing age. Physical therapy was prescribed to 43.1% of the patients, but use decreased with age. In all, 5.3% of the patients received total joint replacement in 2014.ConclusionThe lower frequency of coded OA with increasing level of care dependency may reflect underdiagnosis, and patients with many other medical problems seem to be at risk for inadequate recognition and treatment of their OA.

Using patient-reported outcome measures (PROMs) to promote quality of care in the management of patients with established kidney disease requiring treatment with haemodialysis in the UK (PROM-HD): a qualitative study protocol

IntroductionPatients undergoing haemodialysis (HD) for end-stage kidney disease often report a poor quality of life (QoL) and identify that improving QoL has a higher priority for them than improvements in...

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.

Tropism, replication competence, and innate immune responses of influenza virus: an analysis of human airway organoids and ex-vivo bronchus cultures

Human airway organoids are three-dimensional cultures derived from stem cells, which self-organise in ex-vivo conditions to form so-called mini-airways. The cellular morphology of these cultures is physiologically similar to the human airway, with cilia, goblet cells, and club cells facing the inner lumen and basal cells situated at the outer layer. The aim of this study was to compare replication competence, tissue tropism, and host responses elicited by human and avian strains of influenza A virus in ex-vivo human bronchus and human airway organoids. Between Sept 29, 2016, and Jan 4, 2017, we obtained ex-vivo cultures of the human bronchus and cultured human airway organoids from lung stem cells obtained from human lung tissues removed as part of the routine clinical care of patients undergoing surgical resection at the Department of Cardiothoracic Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong. We compared viral replication competence, tissue tropism, and cytokine and chemokine induction of avian influenza A viruses isolated from humans (Sh2/H7N9, H5N1/483, H5N6/39715), and human H1N1pdm/415742 in airway organoids and ex-vivo bronchus explant cultures. Virus tropism and replication kinetics of human and avian influenza A viruses in human airway organoids mimicked those found in ex-vivo cultures of human bronchus explants. In both airway organoids and bronchus explants, influenza A H1N1 subtype (H1N1) and avian influenza A H7N9 viruses replicated to significantly higher titres than did the highly pathogenic avian influenza (HPAI) H5N1, whereas HPAI H5N6 replication was moderate. H1N1, H7N9, and H5N6 viruses infected ciliated cells and goblet cells, but not basal cells in both airway organoids and bronchus explants. The expression of cytokines, interleukin 6, and interferon β, and the chemokine regulated-on-activation, normal T-cell expressed and secreted, was significantly higher in human airway organoids infected with HPAI H5N1 virus than H1N1pdm/415742, Sh2/H7N9, and H5N6/39715 viruses, and the expression of monocyte chemoattractant protein-1 was significantly higher in human organoids infected with HPAI H5N1 virus than H1N1pdm/415742 and Sh2/H7N9 viruses. Human airway organoid cultures provided results that were comparable to those observed in human ex-vivo bronchus cultures, and thus provide an alternative physiologically relevant experimental model for investigating virus tropism and replication competence that could be used to assess the pandemic threat of animal influenza viruses. US National Institute of Allergy and Infectious Diseases, Research Grants Council of the Hong Kong Special Administrative Region.

Survival prediction based on qualitative MRI diffusion signature in patients with recurrent high grade glioma treated with bevacizumab.

Bevacizumab was approved by the FDA for the treatment of recurrent or progressive glioblastoma (GBM). Imaging responses are typically assessed by gadolinium-enhanced MRI. We sought to determine the significance of qualitative diffusion signature (manifest as variable degree of dark signal) on ADC maps in recurrent gliomas after treatment with bevacizumab. We performed an institutional review board (IRB) approved retrospective study on patients who underwent MRI of the brain after 8 weeks of receiving bevacizumab for recurrent glioma. Patients were divided into three groups based on qualitative diffusion signature: (I) lesion not bright on diffusion weighted imaging (DWI) suggestive of no restricted diffusion (FDR0); (II) lesion bright on DWI with corresponding homogenous dark signal on apparent diffusion coefficient (ADC) maps suggestive of focal restricted diffusion likely due to bevacizumab induced necrosis (FDRn); and (III) lesion bright on DWI with corresponding homogenous faint dark signal on ADC maps suggestive of focal restricted diffusion likely due to viable tumor or heterogeneous spectrum of dark and faint dark signals on ADC maps suggestive of focal restricted diffusion likely due to viable tumor surrounding the bevacizumab induced necrosis (FDRt). Based on the qualitative signal on diffusion weighted sequences after bevacizumab therapy, total number of patients in group (I) were 14 (36%), in group (II) were 17 (44%); and in group (III) were 8 (20%). The median overall survival (OS) from the time of recurrence in patients belonging to group (II) was 364 days vs. 183 days for those with group (I) vs. 298 days for group (III). On simultaneous comparison of survival differences in all three groups by Kaplan-Meier analysis, group (II) was significant in predicting survival with P values for the log-rank tests <0.033. In patients with recurrent glioma treated with bevacizumab, the presence of homogenous dark signal (FDRn) on ADC maps at 8 weeks follow-up MRI correlated with a longer survival. Thus, use of this qualitative diffusion signature in adjunct to contrast enhanced MRI may have the widest potential impact on routine clinical care for patients with recurrent high-grade gliomas. However, prospective studies analysing its predictive value are warranted.

Tenofovir and emtricitabine resistance among antiretroviral-naive patients in the Canadian Observational Cohort Collaboration: implications for PrEP.

The real-world effectiveness of pre-exposure prophylaxis (PrEP) may be influenced by circulating HIV strains resistant to either tenofovir or emtricitabine. Yet, few studies have examined rates of resistance to these drugs in clinical settings. We conducted a retrospective cohort study of antiretroviral-naive participants in the Canadian Observational Cohort collaboration who initiated antiretroviral therapy between 2006 and 2014. In separate analyses, we determined the prevalence of pretherapy resistance and cumulative incidence of follow-up resistance to tenofovir and emtricitabine. We used multivariable proportional hazards models to examine associations between baseline variables and the development of resistance. We studied 6,622 antiretroviral-naive participants initiating therapy, of whom 5,428 (82.0%) had a baseline resistance test. Baseline resistance to tenofovir and emtricitabine was observed in 83 (1.5%) and 21 (0.4%) patients, respectively. Among patients without baseline resistance, the cumulative incidence of resistance to tenofovir and emtricitabine 5 years following treatment initiation was 0.0070 (95% CI 0.0046, 0.0095) and 0.033 (95% CI 0.028, 0.038), respectively. Following multivariable analysis, a baseline viral load ≥100,000 copies/ml was associated with emergence of tenofovir (hazard ratio [HR] 2.88; 95% CI 1.35, 6.15) and emtricitabine (HR 2.27; 95% CI 1.64, 3.15) resistance. Initiating an integrase inhibitor-based regimen and CD4+ T-cell count below 200 cells/mm3 were also associated with resistance to each drug. We observed a low prevalence of baseline resistance and a low incidence of emergence of resistance to tenofovir and emtricitabine among antiretroviral-naive patients in routine clinical care.

Safe removal of gloves from contact precautions: The role of hand hygiene

Routine hand hygiene effectively removes methicillin-resistant Staphylococcus aureus (MRSA) and/or vancomycin resistant Enterococcus (VRE) from the ungloved hands of healthcare workers (HCWs) who are caring for patients under contact precautions, when exposure to bodily fluids is not expected. HCWs' ungloved hands were cultured after hand hygiene with alcohol-based hand rub (ABHR) or soap-and-water wash after routine clinical care of patients known to be colonized or infected with MRSA or VRE. Two hundred forty samples from 40 HCWs were tested and found to be culture negative for either MRSA or VRE after contact with patients when 3 pumps of ABHR (0/80) or plain soap-and-water wash (0/80) were used. No VRE was observed in any of the 120 samples collected. Two plates (2/40) grew 1 colony-forming unit of MRSA after 2 pumps of ABHR. Two HCWs with positive plates were cultured negative on retesting. We showed that appropriate hand hygiene was effective in removing MRSA and VRE even when gloves were not used for routine clinical care, despite contact with patients known to be colonized with MRSA or VRE. A modified approach to glove use for dry contact with patients on contact precautions might improve patient safety within healthcare settings.

Fluid therapy and outcome: a prospective observational study in 65 German intensive care units between 2010 and 2011

BackgroundOutcome data on fluid therapy in critically ill patients from randomised controlled trials may be different from data obtained by observational studies under “real-life” conditions. We conducted this prospective, observational study to investigate current practice of fluid therapy (crystalloids and colloids) and associated outcomes in 65 German intensive care units (ICUs). In total, 4545 adult patients who underwent intravenous fluid therapy were included. The main outcome measures were 90-day mortality, ICU mortality and acute kidney injury (AKI). Data were analysed using logistic and Cox regression models, as appropriate.ResultsIn the predominantly post-operative overall cohort, unadjusted 90-day mortality was 20.1%. Patients who also received colloids (54.6%) had a higher median Simplified Acute Physiology Score II [25 (interquartile range 11; 41) vs. 17 (7; 31)] and incidence of severe sepsis (10.2 vs. 7.4%) on admission compared to patients who received exclusively crystalloids (45.4%). 6% hydroxyethyl starch (HES 130/0.4) was the most common colloid (57.0%). Crude rates of 90-day mortality were higher for patients who received colloids (OR 1.845 [1.560; 2.181]). After adjustment for baseline variables, the HR was 1.666 [1.405; 1.976] and further decreased to indicate no associated risk (HR 1.003 [0.980; 1.027]) when it was adjusted for vasopressor use, severity of disease and transfusions. Similarly, the crude risk of AKI was higher in the colloid group (crude OR 3.056 [2.528; 3.694]), after adjustment for baseline variables OR 1.941 [1.573; 2.397], and after full adjustment OR 0.696 [0.629; 0.770]), the risk of AKI turned out to be reduced. The same was true for the subgroup of patients treated with 6% HES 130/0.4 (crude OR 1.931 [1.541; 2.419], adjusted for baseline variables OR 2.260 [1.730; 2.953] and fully adjusted OR 0.800 [0.704; 0.910]) as compared to crystalloids only.ConclusionsThe present analysis of mostly post-operative patients in routine clinical care did not reveal an independent negative effect of colloids (mostly 6% HES 130/0.4) on renal function or survival after multivariable adjustment. Signals towards a reduced risk in subgroup analyses deserve further study.Trial registration ClinicalTrials.gov Identifier: NCT01122277, registered May 11th, 2010

Abstract P5-21-20: Integrating comprehensive genomic profiling with treatment decisions – Experience gained while treating 139 advanced breast carcinomas

Abstract Background: Comprehensive Genomic Profiling (CGP) using next-generation sequencing (NGS) technology can provide insight into potentially clinically relevant genomic alterations (CRGA) within a patient's breast cancer. For example, HER2 amplification status and targetable short variants (SV), acquired ESR1 or BRCA1/2 resistance mutations, and the presence of targetable alterations in the PI3K kinase. We retrospectively reviewed CGP results and subsequent outcomes at one cancer center to illustrate the experience of using molecular subtyping to inform treatment decisions. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for patients (n=139) with predominantly relapsed, refractory or metastatic breast cancer was analyzed by hybrid-capture, NGS for all classes of GA: 1. base substitutions, 2. insertion and deletions, 3. rearrangements, and 4. copy number changes. Treatment decisions based on comprehensive genomic profiles were captured retrospectively. Tumor mutational burden (TMB), scored as mutations (mut)/Mb, was calculated on 0.8-1.2 Mb of sequenced DNA. Alterations affecting the ERBB family included amplification of or oncogenic mutations in ERBB2 (HER2), ERBB3, and EGFR. Results: From Jan 2013 to May 2017, FFPE tissue samples for 136 patients with advanced breast cancer were analyzed by CGP and 3 additional patients had circulating tumor DNA analyzed for alterations; 11 patients received profiling on multiple biopsies. Tumors analyzed were carcinomas (Ca) NOS (n=84), invasive ductal Ca (n=46), invasive lobular Ca (n=7), a neuroendocrine Ca, and a phyllodes tumor. In total, 118/139 (84.9%) samples harbored CRGA in a targetable pathway: PI3K/MTOR (n=67; 48.2%), CDK cell-cycle (n=40; 28.8%), ERBB family (n=24; 17.3%), FGFR (n=24; 17.3%), ESR1 (n=16; 11.5%), homologous repair (HRD)( n=14; 10.1%), and RAS/RAF/MEK (n=11; 7.9%). Targetable alterations in other cancer-related kinases were found in 10 (7.2%) samples and 10 (7.2%) samples were TMB high (≥20 mut/Mb) or had CD274 (PD-L1) amplification. There were 3 patients (2.1%) with HER2 short variants detected in the absence of ERBB2 amplification; these patients may respond to HER2-targeted therapies but would be HER2-negative by IHC. Many samples had alterations in ≥1 pathway, and overlap is particularly high for the CDK and FGFR pathways (12 samples). Alterations in pathways targeted by MTOR inhibitors, HER2-targeted therapies, or the CDK inhibitors were found in 93/136 (66.9%) tumors. Evaluation of outcomes for these 139 patients is ongoing and will be presented. Conclusions: Genomic profiling of breast carcinomas, using either tissue or liquid biopsies, provides potentially actionable information to guide treatment decisions. Overall, 84.9% of patient samples harbored oncogenic alterations in a targetable pathway, with two-thirds of tumors having alterations in pathways targeted by therapies with FDA approval for breast cancer and 7.2% of patients having high levels of TMB or amplification of PD-L1, suggesting that checkpoint inhibitors may be relevant options. Citation Format: Mahtani R, Gay LM, Chung J, Hartmaier R, Sokol E, Elvin JA, Daniel S, Ramkissoon S, Severson E, Suh J, Vergilio J-A, Stephens PJ, Ross JS. Integrating comprehensive genomic profiling with treatment decisions – Experience gained while treating 139 advanced breast carcinomas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-20.