Likelihood Of Disease Progression Research Articles

Comparing the effects of four common drug classes on the progression of mild cognitive impairment to dementia using electronic health records

The objective of this study was to investigate the potential association between the use of four frequently prescribed drug classes, namely antihypertensive drugs, statins, selective serotonin reuptake inhibitors, and proton-pump inhibitors, and the likelihood of disease progression from mild cognitive impairment (MCI) to dementia using electronic health records (EHRs). We conducted a retrospective cohort study using observational EHRs from a cohort of approximately 2 million patients seen at a large, multi-specialty urban academic medical center in New York City, USA between 2008 and 2020 to automatically emulate the randomized controlled trials. For each drug class, two exposure groups were identified based on the prescription orders documented in the EHRs following their MCI diagnosis. During follow-up, we measured drug efficacy based on the incidence of dementia and estimated the average treatment effect (ATE) of various drugs. To ensure the robustness of our findings, we confirmed the ATE estimates via bootstrapping and presented associated 95% confidence intervals (CIs). Our analysis identified 14,269 MCI patients, among whom 2501 (17.5%) progressed to dementia. Using average treatment estimation and bootstrapping confirmation, we observed that drugs including rosuvastatin (ATE = − 0.0140 [− 0.0191, − 0.0088], p value < 0.001), citalopram (ATE = − 0.1128 [− 0.125, − 0.1005], p value < 0.001), escitalopram (ATE = − 0.0560 [− 0.0615, − 0.0506], p value < 0.001), and omeprazole (ATE = − 0.0201 [− 0.0299, − 0.0103], p value < 0.001) have a statistically significant association in slowing the progression from MCI to dementia. The findings from this study support the commonly prescribed drugs in altering the progression from MCI to dementia and warrant further investigation.

Progression of symptomatic bilateral rotator cuff disease

Prior studies have demonstrated that conservatively treated rotator cuff tears and rotator cuff tendinopathy may continue to progress. It is unclear whether that rate of progression differs between sides in patients with bilateral disease. This study evaluated the likelihood of progression of rotator cuff disease as confirmed via magnetic resonance imaging (MRI) in individuals with symptomatic bilateral pathology, treated conservatively for a minimum of 1 year. We identified patients with bilateral rotator cuff disease confirmed via MRI within the Veteran's Health Administration electronic database. A retrospective chart review via the Veteran's Affairs electronic medical record was performed. Progression was determined using 2 separate MRIs with a minimum of 1 year apart. We defined progression as (1) a progression from tendinopathy to tearing, (2) an increase from partial-thickness to full-thickness tearing, or (3) an increase in tear retraction or tear width of at least 5 mm. Four hundred eighty MRI studies from 120 Veteran's Affair patients with bilateral, conservatively treated rotator cuff disease were evaluated. Overall, 42% (100/240) of rotator cuff disease had progressed. No significant difference was found between progression of right vs. left rotator cuff pathology, with right shoulder pathology progressing at a rate of 39% (47/120), while left shoulder disease progressed at a rate of 44% (53/120). The likelihood of disease progression was associated with less initial tendon retraction (P value=.016) and older age (P value=.025). Rotator cuff tears are no more likely to progress on the right, as compared to the left side. Older age and less initial tendon retraction were found to be predictors of disease progression. These suggest that higher activity level may not associate with greater progression of rotator cuff disease. Future prospective studies evaluating progression rates between dominant vs. nondominant shoulders are warranted.

The Differential Diagnosis and Treatment of Mild Cognitive Impairment and Alzheimer Disease

Identifying patients at risk for developing mild cognitive impairment (MCI) and Alzheimer disease (AD) remains challenging in clinical practice, even as scientific understanding of dementia advances generally. That said, successfully navigating the associated differential diagnosis in AD is essential, as various causes of cognitive impairment require different treatment strategies. In recent years, the armamentarium in AD has expanded with regulatory approval of a disease-modifying therapy-aducanumab-and may be shifting away from symptomatic treatments such as cholinesterase inhibitors and memantine. Concurrently, the role of biomarkers in AD is increasing, and these entities may soon play a greater role in determining patient eligibility for prophylactic interventions and the likelihood of disease progression. As the standard of care progresses, clinicians should educate patients and their care providers on the implications of these advances and reinforce lifestyle changes that can delay or prevent the onset of disease in those at risk of AD. In doing so, care providers can deliver the best care possible.

Data‐Driven Methods Highlight Early Signals of Tau in Patients Lacking Global Uptake: Facilitating Enrollment in Clinical Trials

AbstractBackgroundAlzheimer’s Disease (AD) patients showing neocortical Flortaucipir (FTP) tau levels above predetermined cutoffs based on the likelihood of disease progression are enrolled in Lilly trials. However, patients below the cutoffs can also exhibit disease progression, and clinical decline. These patients might be earlier in the course of disease progression and may benefit the most from therapy. The objective of this study is to apply data‐driven methods on regional tau measurements at baseline to identify a relatively homogeneous patient population showing earlier signals of tau.MethodA standardized uptake value ratio (SUVr) from a weighted composite region (MUBADA;Devous et al,JNM,2017) with respect to cerebral white matter reference signal intensity (Southekal et al,JNM,2018) was calculated using baseline FTP (n=1093) images from AVID FTP development studies (AV1451‐A05:NCT02016560) and Lilly clinical trials (EXPEDITION‐3:NCT01900665, NAVIGATE‐AD:NCT02791191, and AMARANTH:NCT02245737). Using the cutoff of 1.11, we identified a cohort of 431 subjects that were negative by MUBADA. Diagnostic breakdown included 67 cognitively‐normal, 135 mild‐cognitive‐impairment, and 229 AD subjects. Within this cohort, we calculated reference‐region independent, min‐max scaled regional tau measurements in 68 regions from FreeSurfer FsAverage template. An affinity propagation clustering analysis was applied to detect homogeneous subgroups showing patterns of similar tau uptake. Two distinct subgroups—FTPEarly (n=151), and FTPUndetected (n=280), names reflecting their tau uptake levels— emerged in the cohort. The groups were compared on clinical, cognitive, and genetic characteristics using Analysis‐Of‐Covariance.ResultFTPEarly group demonstrated relatively higher baseline plasma‐tau levels (p‐tau217) and pattern of elevated FTP uptake in inferior‐temporal, fusiform, entorhinal, and para‐hippocampal regions (P&lt;0.01 for all) compared to FTPUndetected group. In FTPEarly group, 98% were MCI or AD, 90% were amyloid+, and 69% were APOE4‐carriers, whereas in FTPUndetected group, the prevalence of MCI or AD, amyloid positivity, and APOE4‐carriers dropped to 76%, 43%, and 37%, respectively. When evaluated on longitudinal sub‐population, FTPEarly patients progressed faster than FTPUndetected patients on FTP SUVr (P&lt;0.01) and cognitive measures (ADAS; P&lt;0.01).ConclusionData‐driven methods identify visually difficult to recognize FTPEarly group characterized by distinct neuroimaging patterns and paralleled by relatively homogeneous clinical, genetic, and cognitive profile. These methods hold promise for targeting enrollment of FTPEarly patient populations into clinical trials.

Investigating Metabolic Response after CAR-T Therapy and Bridging Radiotherapy for Relapsed/Refractory B-Cell Lymphoma

Introduction: For patients with aggressive relapsed/refractory B-cell lymphoma (R/R BCL) undergoing CAR-T therapy, metabolic treatment response assessed at the 1-month interval following CAR-T infusion is associated with likelihood of disease progression (Kuhnl A, et al. Blood Adv 2022). In particular, SUV max on 1-month 18F-FDG positron emission tomography (PET) imaging is predictive of disease progression (Zaki A, et al. Blood Adv 2022). However, for patients who undergo bridging radiotherapy (RT) prior to CAR-T infusion, it remains unclear how to interpret metabolic activity for irradiated sites on surveillance PET imaging following CAR-T. We sought to characterize metabolic activity after CAR-T and bridging RT in a cohort of patients with R/R BCL. Methods: This IRB-approved retrospective cohort study included patients with R/R BCL who underwent bridging RT prior to CAR-T infusion at a single institution from January 1, 2019 to April 30, 2022. We measured baseline patient characteristics, treatment factors, and PET metrics prior to bridging RT. We then assessed tumor metabolic activity on surveillance PET imaging following CAR-T infusion until the time of disease progression (defined as Deauville 5 disease) or last follow up. Results: We identified 10 patients who completed bridging RT prior to CAR-T infusion with at least one post-CAR-T disease assessment with PET imaging. Median follow up was 152 days from CAR-T infusion (range: 31-1095). Most patients (90%) had bulky disease (≥7.5 cm) and all had elevated LDH at baseline. Bridging RT dosing ranged from 20-38.5 Gy (median: 20 Gy) over 5-14 fractions (median: 5 fractions). Bridging RT fields were directed at bulky disease sites for 8 of 9 patients with bulky disease. The median metabolic tumor volume (MTV) irradiated with bridging RT was 149 mL (range: 26-803) and the median proportion of total MTV irradiated was 97% (range: 8.7-100). The median time between pre-bridging RT PET imaging and CAR-T infusion was 49 days (range: 37-124) and the median time between the end of bridging RT and CAR-T infusion was 12 days (range: 5-106). On pre-bridging RT PET, the median SUV max in the irradiated field was 23.3 (range: 9.1-36.1) (Figure 1). On 1-month post-CAR-T PET, the median SUV max in the irradiated field decreased to 3.2 (range: 0-6.1) and median delta SUV max was -87% (range: -68% to -100%). At the 1-month post-CAR-T interval, 40% of patients had a complete metabolic response (Deauville 3 or below), 40% had Deauville 4 disease, and 20% had Deauville 5 disease. Among the 4 patients with Deauville 4 disease at 1-month post-CAR-T, 3 patients developed complete metabolic responses and 1 patient had persistent Deauville 4 disease on subsequent PET imaging. No patients in the cohort developed disease progression within the irradiated fields. At last follow up, 3 patients had developed Deauville 5 disease, and for 2 of the 3 patients, areas of disease progression included unirradiated sites of disease that were present on pre-bridging RT PET imaging. Conclusions: In this small retrospective cohort of patients undergoing bridging RT prior to CAR-T therapy for R/R BCL, patients with concern for refractory disease on initial imaging assessment demonstrated complete response or stable disease on subsequent follow up imaging. Caution may be warranted in interpreting metabolic activity levels on initial post-CAR-T surveillance PET imaging, and validation in larger cohorts is needed to better understand metabolic activity dynamics in disease sites treated with bridging RT prior to CAR-T therapy. Figure 1. SUV Max in Disease Sites Treated with Bridging RT* *Each line corresponds to one patient treated with bridging RT prior to CAR-T therapy. SUV max plotted on the vertical axis reflects metabolic activity within the irradiated fields. Time intervals indicated in months on the horizontal axis reflect the approximate time from CAR-T infusion with the exact range in days indicated in parentheses. The magnification box demonstrates metabolic activity at the 1-month post-CAR-T interval with corresponding Deauville score indicated by color. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The potential of erdosteine to reduce the rate of exacerbations of chronic obstructive pulmonary disease

Exacerbations of COPD worsen health status, increase the frequency of hospitalizations, the likelihood of disease progression, and the risk of adverse outcomes. One of the main goals of the treatment of stable COPD today is to reduce the frequency of exacerbations of the disease. Thus, the expansion of suitable therapeutic options is extremely relevant for clinical practice. Use of mucolytic drugs with antioxidant and anti-inflammatory effects in COPD is justified by the pathogenetic mechanisms. These drugs are able to reduce the frequency of exacerbations, among other positive effects.Aim. This article describes additional possibilities of pharmacotherapy using the mucoactive drug erdosteine as maintenance therapy for COPD aimed at preventing exacerbations of this disease.Conclusion. The use of erdosteine in patients with stable COPD helps reduce the frequency and duration of exacerbations of the disease, primarily in the patients with stage II according to GOLD.

Experiences of parents and patients hospitalised in a child psychiatric unit for anorexia nervosa after reorganisation of care imposed by the COVID-19 Pandemic in France: a qualitative study\u2014The QUALICOVID study

BackgroundAnorexia nervosa is a serious, albeit common mental illness that generally occurs during adolescence. Although outpatient care is recommended, hospitalisation is sometimes required. There is a dedicated hospitalisation unit caring for children and adolescents presenting with anorexia nervosa in Nancy, France. However, on 16 March 2020, a national lockdown was declared by the French government as the COVID-19 pandemic escalated in France. This resulted in the adjustment of hospital admissions accompanied by premature discharge and an intensive outpatient care programme. In the light of such changes, consideration should be given to the potential impact of changes in the care pattern for anorexic patients and their parents. The purpose of our study was to explore the experiences of anorexia nervosa patients hospitalised in the unit, and their parents, following changes in the care strategy.MethodsThe study was conducted between weeks four and eight after lockdown was announced. The study cohort included all the patients treated for anorexia nervosa and hospitalised in the treatment unit before 16 March 2020 and their parents. A qualitative method was used and every subject was offered a semi-structured interview. Data were analysed by means of inductive thematic analysis.ResultsSeven superordinate themes were identified: positive aspects, concerns, preparation, loss of landmarks and hospital security, gradual return to a “normal” life, relational aspects and the likelihood of disease progression. Moreover, all the parents and patients were satisfied with the intensive outpatient care offered on discharge.ConclusionDespite initial ambivalence, all patients and their parents viewed this unexpected hospital discharge positively in these exceptional conditions. This suggests that restructuring the care programme could prove beneficial with increasing use of outpatient management, thereby reducing the length of the hospital stay and adjusting the return to school.Trial registration: ID-RCB 2020-A01101-38—This project was approved by the Comité de Protection des Personnes (CPP) Sud Méditerranée IV [South Mediterranean IV Ethics Committee (EC)] on 5 May 2020.

So Shines a Good Deed in a Weary World.

So Shines a Good Deed in a Weary World.

Knockout of Calcyclin Binding Protein Impedes the Growth of Breast Cancer Cells by Regulating Cell Apoptosis and β-Catenin Signaling.

Breast invasive carcinoma (BRCA) is becoming the most common malignant disease worldwide, and there is intense interest in identifying diagnostic biomarkers that can be targeted for treatment of BRCA. Recent evidence has shown that calcyclin binding protein (CacyBP) can function as either a tumor promoter or suppressor during carcinogenesis. Data in The Cancer Genome Atlas (TCGA) database show that CacyBP is overexpressed in human BRCA tissues, and high levels of CacyBP are associated with shorter overall survival. Immunohistochemical staining has shown that CacyBP levels are high in cancer tissue samples and associated with a higher likelihood of disease progression. We, therefore, conducted a knockout assay to determine the role of CacyBP in the development of BRCA. Knockout of CacyBP significantly inhibited MCF7 cell proliferation and colony formation. Apoptosis was higher in CacyBP knockout cells compared with control cells. Microarray analysis showed that the CacyBP knockout caused dysregulation of numerous genes closely related to β-catenin signaling, whereas quantitative reverse-transcription PCR and immunoblotting showed that it to be inactivated. In summary, we conclude that when overexpressed, CacyBP acts as a potential oncogene for BRCA by regulating β-catenin signaling.

A natural language processing tool for automatic identification of new disease and disease progression: Parsing text in multi-institutional radiology reports to facilitate clinical trial eligibility screening.

1555 Background: Screening every patient for clinical trials is time-consuming, costly and inefficient. Developing an automated method for identifying patients who have potential disease progression, at the point where the practice first receives their radiology reports, but prior to the patient’s office visit, would greatly increase the efficiency of clinical trial operations and likely result in more patients being offered trial opportunities. Methods: Using Natural Language Processing (NLP) methodology, we developed a text parsing algorithm to automatically extract information about potential new disease or disease progression from multi-institutional, free-text radiology reports (CT, PET, bone scan, MRI or x-ray). We combined semantic dictionary mapping and machine learning techniques to normalize the linguistic and formatting variations in the text, training the XGBoost model particularly to achieve a high precision and accuracy to satisfy clinical trial screening requirements. In order to be comprehensive, we enhanced the model vocabulary using a multi-institutional dataset which includes reports from two academic institutions. Results: A dataset of 732 de-identified radiology reports were curated (two MDs agreed on potential new disease/dz progression vs stable) and the model was repeatedly re-trained for each fold where the folds were randomly selected. The final model achieved consistent precision (&gt;0.87 precision) and accuracy (&gt;0.87 accuracy). See the table for a summary of the results, by radiology report type. We are continuing work on the model to validate accuracy and precision using a new and unique set of reports. Conclusions: NLP systems can be used to identify patients who potentially have suffered new disease or disease progression and reduce the human effort in screening or clinical trials. Efforts are ongoing to integrate the NLP process into existing EHR reporting. New imaging reports sent via interface to the EHR will be extracted daily using a database query and will be provided via secure electronic transport to the NLP system. Patients with higher likelihood of disease progression will be automatically identified, and their reports routed to the clinical trials office for clinical trial screening parallel to physician EHR mailbox reporting. The over-arching goal of the project is to increase clinical trial enrollment. 5-fold cross-validation performance of the NLP model in terms of accuracy, precision and recall averaged across all the folds.[Table: see text]

NF-κB1 -94del/del ATTG polymorphic variant maintains CLL at an early, mildest stage.

NF-κB is an essential player in cancer biology, especially in tumor development, due to its constitutive activation, and because a four-base deletion (ATTG) in the NF-κB1 promoter region at site -94, alters mRNA stability and regulates translation efficiency. This polymorphism is a good candidate risk marker and modulator of clinical course in chronic lymphocytic leukemia (CLL). As the effect of this NF-κB1 gene polymorphism has not been studied in patients with CLL so far, the present study was undertaken to find out whether the NF-κB1 promoter -94 ins/del ATTG polymorphism might be an essential genetic risk factor and/or modulatory disease player associated with CLL. The NF-κB1 -94 ins/del ATTG (rs28362491) polymorphism was investigated as a potential CLL susceptibility and progression factor, along with demonstration of potential modulation of the stage of clinical disease based on Rai classification. The associations of NF-κB1 -94 ins/del ATTG polymorphism with CLL and its clinical manifestation in 282 Polish individuals, including 156 CLL patients, were analyzed using polymerase chain reaction (PCR) with primers including a labeled forward primer, followed by capillary electrophoresis. A higher occurrence of the del/del homozygosity was observed among patients when compared to controls, resulting in an increase in CLL risk of more than twofold in patients carrying this homozygous genotype (OR = 2.23, p = 0.02, 95% CI = 1.14-4.37). Moreover, the del/del-positive patients more frequently presented the less aggressive disease phenotype (Rai 0), suggesting a low probability of progression to more advanced disease. The NF-κB1 -94 del/del genetic variant, although associated with increased risk of CLL disease, may be associated with maintenance of disease severity in the early, mildest stage. The likelihood of disease progression may increase as the frequency of wild-type (insertion) alleles for this polymorphism increases.

ASSOCIATION OF NKT- AND ACTIVATED CD25&lt;sup&gt;+&lt;/sup&gt; PERIPHERAL BLOOD LYMPHOCYTES WITH DISEASE FREE AND OVERALL SURVIVAL OF TRIPLE NEGATIVE BREAST CANCER PATIENTS

Background. We previously found that a decrease in the number of NKT cells and activated CD 25+ peripheral blood lymphocytes (PBLs) before neoadjuvant chemotherapy was associated with an increased likelihood of disease progression in patients with locally advanced triple-negative breast cancer (TN BC).The purpose of this study was to determine the relationship between the initial number of NKT-and CD 25+ PBLs and relapsefree survival (RFS)/overall survival (OS ) in patients with TN BC who received neoadjuvant chemotherapy with cisplatin and paclitaxel followed by surgery.Material and Methods. The study included patients with stage II and III TN BC. The follow-up time was 36 and 66.9 months. Immediately before chemotherapy, the percentage of CD 3+CD 16+CD 56+ (NKT) -, CD 25+- and CD 8+ PBLs was determined by flow cytometry. Statistical analysis of the data was carried out using the Statistics 7 software package. The Kaplan-Meier method was used to determine the relationship between immunological parameters and RFS/ OS .Results. The decreased level of NKT cells before treatment was associated with a decrease in the 3-year RFS [Me: 20.1 (0.533 and 39.7) months] compared to that observed in patients with higher percentage of these cells than in the control (Me was not achieved). There were no statistically significant differences in the 3-year OS between the groups. The initially reduced number of CD 25+ lymphocytes in comparison with the control was associated with decreased rates of both RFS and OS . The difference in DFS and OS was more significant between the groups of patients who simultaneously had an increased initial number of both NKT and CD 25+ cells and patients in whom both cell populations were below normal levels.Conclusion. The initial (prior to chemotherapy) number of NKT and activated CD 25+ PBLs can apparently be a predictive factor in TN BC patients, who received neoadjuvant chemotherapy with cisplatin and paclitaxel.

Multidimensional Machine Learning Personalized Prognostic Model in an Early Invasive Breast Cancer Population-Based Cohort in China: Algorithm Validation Study.

BackgroundCurrent online prognostic prediction models for breast cancer, such as Adjuvant! Online and PREDICT, are based on specific populations. They have been well validated and widely used in the United States and Western Europe; however, several validation attempts in non-European countries have revealed suboptimal predictions.ObjectiveWe aimed to develop an advanced breast cancer prognosis model for disease progression, cancer-specific mortality, and all-cause mortality by integrating tumor, demographic, and treatment characteristics from a large breast cancer cohort in China.MethodsThis study was approved by the Clinical Test and Biomedical Ethics Committee of West China Hospital, Sichuan University on May 17, 2012. Data collection for this project was started in May 2017 and ended in March 2019. Data on 5293 women diagnosed with stage I to III invasive breast cancer between 2000 and 2013 were collected. Disease progression, cancer-specific mortality, all-cause mortality, and the likelihood of disease progression or death within a 5-year period were predicted. Extreme gradient boosting was used to develop the prediction model. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUROC), and the model was calibrated and compared with PREDICT.ResultsThe training, test, and validation sets comprised 3276 (499 progressions, 202 breast cancer-specific deaths, and 261 all-cause deaths within 5-year follow-up), 1405 (211 progressions, 94 breast cancer-specific deaths, and 129 all-cause deaths), and 612 (109 progressions, 33 breast cancer-specific deaths, and 37 all-cause deaths) women, respectively. The AUROC values for disease progression, cancer-specific mortality, and all-cause mortality were 0.76, 0.88, and 0.82 for training set; 0.79, 0.80, and 0.83 for the test set; and 0.79, 0.84, and 0.88 for the validation set, respectively. Calibration analysis demonstrated good agreement between predicted and observed events within 5 years. Comparable AUROC and calibration results were confirmed in different age, residence status, and receptor status subgroups. Compared with PREDICT, our model showed similar AUROC and improved calibration values.ConclusionsOur prognostic model exhibits high discrimination and good calibration. It may facilitate prognosis prediction and clinical decision making for patients with breast cancer in China.

Clinical significance of p27 Kip1 expression in advanced ovarian cancer

BackgroundOvarian cancer is the most common gynecological malignancy. In patients with advanced ovarian cancer, some biological parameters have prognostic implementations. P27kip1 is an inhibitor of a cycline-dependent kinase, its loss, can contribute to tumor progression.ObjectiveThis study aimed to examine the importance of P27KIP1 protein in predicting the prognosis and response to neoadjuvant chemotherapy in patients with advanced ovarian epithelial cancer and to compare the outcomes of immunohistochemistry with Quantitative Real-time PCR.Patients and methodsWe have studied P27KIP1expression by both immunohistochemistry and Quantitative Real-time PCR from 88 patients with advanced ovarian carcinomas undergone radical debulking surgery and received Paclitaxel followed by Cisplatin every 3 weeks for a total of 6 cycles. We also studied their association with both chemotherapy response and patient survival.ResultsNuclear expression of p27KIP1 protein was intense in 86 normal ovarian tissues and 42 of 88 carcinomas. The P27kip1mRNA expression level by qRT-PCR was very low in ovarian cancer tissues relative to its adjacent normal tissues. The results were statistically significant by both methods of determination. p27KIP1 expression was significantly related to good prognostic parameters as low stage tumors, differentiated tumors, absence of ascites, residual disease < 2 cm, and response to chemotherapy but not with histopathological type in case of determination by immunohistochemistry. Comparison of P27kip1 by both immunohistochemistry and qRT-PCR with different prognostic parameters revealed no significant difference between both methods in the assessment of these parameters. In 4 years of follow-up, 20.5% of patients were alive without evidence of disease. 6.8% were alive with disease. The disease-related four -year survival rate for the whole group was 28.2%. In multivariate analysis, residual disease, histological type, tumor differentiation, ascites was of independent prognostic significance.ConclusionIn ovarian cancer, patients with loss of p27KIP1 expression are at a greater likelihood of disease progression, p27KIP1 may be used as a molecular marker to predict response to chemotherapy and prognosis. Both immunohistochemistry and qRT-PCR have equal reliability in the determination of p27 KIP1.

256-OR: Costarting Sitagliptin with Metformin Is Associated with a Lower Likelihood of Disease Progression in Newly Treated Patients with Type 2 Diabetes

Aim: Sitagliptin can potentially preserve beta cell function by promoting local action of GLP-1 in the pancreas. This study examined if early addition of sitagliptin to metformin is associated with a delay in the progression of type 2 diabetes. Methods: Administrative health records from Alberta, Canada between April 1, 2008 and March 31, 2015 were used to conduct a retrospective cohort study. New metformin users were identified and included if they added sitagliptin during follow-up. Patients costarting therapy with sitagliptin and metformin were compared to those who added sitagliptin after initial metformin therapy. Potential confounding variables included age, sex, comorbidities, and cardiovascular medications at baseline. A multivariable logistic regression model was used to evaluate the association between sitagliptin addition (costart versus delayed) and insulin initiation. Change in A1c 1 year after adding sitagliptin was evaluated using a multivariable linear regression model. Results: Mean (SD) age of the 8,746 included patients was 52.1 (11.1) years, 5,655 (64.7%) were men, and 1,149 (13.1%) costarted treatment with metformin and sitagliptin. Insulin was added to the therapy of 192 (16.7%) costarters and 1,640 (21.6%) of delayed sitagliptin users (adjusted odds ratio 0.73; 95% CI: 0.62 to 0.86). The A1c change 1 year after starting sitagliptin was greater in the costarters (-2.1%; SD 2.8%) compared to delayed sitagliptin users (-1.0%; SD 1.9%). After adjusting for baseline A1c and other covariables, costarters had a greater reduction in A1c -0.56% (95% CI: -0.74% to -0.38%). Conclusions: Costarting sitagliptin with metformin is associated with a lower likelihood of disease progression in newly treated patients with type 2 diabetes compared with adding sitagliptin later in therapy. Disclosure S.A. Campbell: None. P.E. Light: None. S.H. Simpson: None. Funding Canadian Institutes of Health Research

Abstract 2503: Metabolomics identifies a caveolin-1-associated plasma glycosphingolipid and sphingomyelin signature that differentiates aggressive from indolent prostate cancer in an active surveillance cohort

Abstract Purpose: To identify a plasma signature that can distinguish aggressive from indolent prostate cancer in patients on active surveillance based on metabolomics profiling. Introduction: The slow growth rate and low likelihood of disease progression in low-risk prostate cancer patients have led to the widely implemented active surveillance (AS) strategy. Given tumor heterogeneity, a clinical challenge is how to expand the pool of patients eligible for AS safely. Consequently, additional markers able to identify patients at increased risk of disease progression are needed. We previously identified plasma caveolin-1 (CAV1) as predictive of aggressive prostate cancer in an AS cohort. Complementary in vitro and in vivo studies demonstrated that CAV1 mediates major reprogramming of lipid metabolism, collectively suggesting that dysregulated lipid biogenesis may be associated with aggressive prostate cancer. Experimental Procedures: An integrated approach was utilized which included multi-assay untargeted metabolomics to characterize alterations in the metabolome and lipidome of conditioned media from prostate cancer cell lines following overexpression of CAV1 (LNCaP) or CAV1 siRNA knockdown (PC3M). In parallel, sera from PBCre+PTENloxp/loxp;PBCav-1+ and PBCre+PTENloxp/loxp;PBCav-1- mice were collected for metabolomics analysis to further delineate signatures related to CAV1-associated aggressive prostate cancer. We further conducted untargeted metabolomic analysis on plasma samples (n=16 per group) prospectively collected from patients with early stage prostate cancer undergoing AS who exhibited early progression (defined as upgrading of Gleason score (GS) and/or increased tumor volume on surveillance biopsy within 18 months after start of AS) or indolent disease (did not progress for a minimum of 5 years after start of AS). Patients were matched with respect to age, clinical stage, prostate-specific antigen, and GS on baseline biopsy at start of AS. We evaluated plasma samples collected at baseline (start of AS) and after 12 months. Results: Analysis of conditioned media identified a metabolomics signature with major alterations in lipid composition highlighted by CAV1-mediated elevations in lipid-raft associated sphingomyelins and glycosphingolipids. This signature was observed in patients who had early progression but not in patients with indolent disease. Importantly, this signature was observed at baseline and at least 18 months prior to disease progression on surveillance biopsy. Conclusions: We have identified a plasma-derived lipid signature that differentiates aggressive versus indolent prostate cancer in an active surveillance cohort. Our findings highlight the potential utility of altered lipid profiles as additional risk markers for aggressive prostate cancer. Citation Format: Johannes Fahrmann, Jody Vykoukal, Spyridon Basourakos, Jianxiang Wang, Jennifer Dennison, Eunice Murage, Jeri Kim, Timothy C. Thompson, Samir Hanash. Metabolomics identifies a caveolin-1-associated plasma glycosphingolipid and sphingomyelin signature that differentiates aggressive from indolent prostate cancer in an active surveillance cohort [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 2503. doi:10.1158/1538-7445.AM2017-2503

Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients

BackgroundThe characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression.MethodsThree hundred seventy COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used.ResultsOne hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B.ConclusionsUnstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.

Association of the Extent of Resection With Survival in Glioblastoma

Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR) and outcome remains undefined, notwithstanding many relevant studies. To determine whether greater EOR is associated with improved 1- and 2-year overall survival and 6-month and 1-year progression-free survival in patients with GBM. Pubmed, CINAHL, and Web of Science (January 1, 1966, to December 1, 2015) were systematically reviewed with librarian guidance. Additional articles were included after consultation with experts and evaluation of bibliographies. Articles were collected from January 15 to December 1, 2015. Studies of adult patients with newly diagnosed supratentorial GBM comparing various EOR and presenting objective overall or progression-free survival data were included. Pediatric studies were excluded. Data were extracted from the text of articles or the Kaplan-Meier curves independently by investigators who were blinded to each other's results. Data were analyzed to assess mortality after gross total resection (GTR), subtotal resection (STR), and biopsy. The body of evidence was evaluated according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria and PRISMA guidelines. Relative risk (RR) for mortality at 1 and 2 years and progression at 6 months and 1 year. The search produced 37 studies suitable for inclusion (41 117 unique patients). The meta-analysis revealed decreased mortality for GTR compared with STR at 1 year (RR, 0.62; 95% CI, 0.56-0.69; P < .001; number needed to treat [NNT], 9) and 2 years (RR, 0.84; 95% CI, 0.79-0.89; P < .001; NNT, 17). The 1-year risk for mortality for STR compared with biopsy was reduced significantly (RR, 0.85; 95% CI, 0.80-0.91; P < .001). The risk for mortality was similarly decreased for any resection compared with biopsy at 1 year (RR, 0.77; 95% CI, 0.71-0.84; P < .001; NNT, 21) and 2 years (RR, 0.94; 95% CI, 0.89-1.00; P = .04; NNT, 593). The likelihood of disease progression was decreased with GTR compared with STR at 6 months (RR, 0.72; 95% CI, 0.48-1.09; P = .12; NNT, 14) and 1 year (RR, 0.66; 95% CI, 0.43-0.99; P < .001; NNT, 26). The quality of the body of evidence by the GRADE criteria was moderate to low. This analysis represents the largest systematic review and only quantitative systematic review to date performed on this subject. Compared with STR, GTR substantially improves overall and progression-free survival, but the quality of the supporting evidence is moderate to low.

Systems biology approaches for inflammatory bowel disease: emphasis on gut microbial metabolism.

Although the prevalence of main idiopathic forms of inflammatory bowel disease (IBD) has risen considerably over the last decades, their clinical features do not allow accurate prediction of prognosis, likelihood of disease progression, or response to specific therapy. Through a better understanding of the molecular pathways involved in IBD and the promise of more targeted therapies, the personalized approach to the management of IBD shows potential. To achieve this, there remains a significant need to better understand the disease process at cellular and molecular levels for any given individual with IBD. The complexity of biological functional networks behind the etiology of IBD highlights the need for their comprehensive analysis. In this, omics technologies can generate a systemic view of IBD pathogenesis on which to base novel, multiple pathway-integrated therapies. Omics sciences have just started to contribute here by generating gene, protein expression, metabolite data at global level and large scale, and more recently by offering new opportunities to explore gut functional ecology. In particular, there is much expectation regarding the putative role of the gut microbiome in IBD. No doubt it will provide additional insights and lead to the development of alternative, hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD. This review discusses perspectives of relevance to clinical translation with emphasis on gut microbial metabolic activities.

Multi-scale analysis of imaging features and its use in the study of COPD exacerbation susceptible phenotypes.

We propose a novel framework for exploring patterns of respiratory pathophysiology from paired breath-hold CT scans. This is designed to enable analysis of large datasets with the view of determining relationships between functional measures, disease state and the likelihood of disease progression. The framework is based on the local distribution of image features at various anatomical scales. Principal Component Analysis is used to visualise and quantify the multi-scale anatomical variation of features, whilst the distribution subspace can be exploited within a classification setting. This framework enables hypothesis testing related to the different phenotypes implicated in Chronic Obstructive Pulmonary Disease (COPD). We illustrate the potential of our method on initial results from a subset of patients from the COPDGene study, who are exacerbation susceptible and non-susceptible.