tbuckley/cabot-search huggingface dataset:
Expression of osteopontin and markers of inflammation in patients with hepatocellular cellular carcinoma.
Authors: Steve Scaglione, Danyelle Martin, Jasmin Sandhu, Kyle Carey, Scott Cotler, William Adams, Nil Guler, Paul Kuo, Thomas Layden, Jawed Fareed
Journal: Journal of Clinical Oncology (2015)

e15122 Background: No biomarkers exist that can diagnose Hepatocellular carcinoma (HCC). Liver cirrhosis is characterized by chronic inflammation which is a well-known factor in the development of HCC. Osteopontin (OPN) has been shown to be elevated in inflammatory states and HCC. Methods: Blood samples from 19 normals, 51 cirrhotics and 27 HCC patients were analyzed. OPN levels by ELISA (R&D systems) and the Biochip Array technology (Randox-Co. Antrim, Northern Ireland) were used to measure IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFN gamma, TNF alpha, IL-1 alpha, IL-1 beta, MCP1and EGF. Multiple nonparametric comparisons were used without adjustment to the type 1 error to determine significance between the HCC or cirrhotic group and the normal group. Results: Compared to healthy controls, HCC patients had higher levels of serum IL-6 (median = 5.68, IQR = 22.56, p < .0001), IL-8 (median = 7.57, IQR = 37.41, p < .0001), IL-10 (median = 0.92, IQR = 0.85, p < .0092), TNFa (median = 2.9, IQR = 2.9, p = .001), IL-1a (median = 0.12, IQR = 0.115, p = .038). Cirrhotic patients had higher levels of IL-6 (median = 2.9, IQR = 5.98, p < .0001), IL-8 (median = 6.42, IQR = 12.75, p < .0001), VEGF (median = 10.21, IQR = 16.98, p < .0001), IFN-gamma (median = 0.35, IQR = 0.59, p = .001), TNFa (median = 2.8, IQR = 1.42, p < .0001), IL-1a (median = 0.14, IQR = 0.18, p = .03), EGF (median = 3.52, IQR = 7.68, p < .0001) compared to healthy controls. No differences in inflammatory markers were seen between HCC patients and cirrhotics. In HCC patients, increased levels of IL-8 was correlated with IL-6, and IL-8 was correlated with TNFa. AFP was significantly higher in the HCC group compared to the cirrhotic group (median = 5.50, IQR = 13.60; p = 0.3). Similarly, OPN levels were significantly increased in cirrhotic (median = 104.31ng/mL, IQR = 96.46; p = 0.022) and HCC patients (median = 151.56, IQR = 113.16; p < .0001) compared to the normal group. Tumor size was also shown to correlate with OPN levels (r = .400; p = .035). Conclusions: Inflammatory markers were elevated in cirrhotic patients and HCC patients compared to normal, but no difference in HCC versus cirrhotic patients. OPN levels were only associated with tumor size. AFP was the only biomarker that differentiated HCC from cirrhotics.
Abstract P015: Biomarkers Representing Key Aging-related Biological Pathways Are Associated With Subclinical Atherosclerosis: the Framingham Study
Authors: Cecilia Castro-Diehl, Rachel Q. Ehrbar, Ramachandran S. Vasan, Vanessa Xanthakis
Journal: Circulation (2019)

Background: Increased oxidative stress, telomere attrition, endothelial dysfunction and alterations in insulin-like growth factor-1 are key molecular mechanisms of aging. We hypothesized that biomarkers representing these aging-related biological pathways are associated with measures of subclinical atherosclerosis. Methods and Results: We evaluated up to 2,314 Framingham Offspring Study participants attending routine examination cycles (mean age 58 yrs, 55% women) with available biomarkers of key aging-related pathways: leukocyte telomere length [expressed by terminal restriction fragment; TRF]; urinary concentrations of creatinine corrected isoprostanes [an index of systemic oxidative stress]; circulating concentrations of insulin-like growth factor [IGF-1]; and asymmetrical dimethylarginine [ADMA; a marker of endothelial dysfunction]. We related each biomarker as independent variable to the presence of subclinical atherosclerosis (dependent variable) defined as presence of coronary artery calcium (CAC modeled as [ln(CAC+1)]), and carotid intimo-medial thickness (IMT; defined as the average of standardized values of common carotid and internal carotid artery IMT) using multivariable linear regression models adjusting for age, sex, body mass index, systolic blood pressure, diabetes, smoking status, hypertension, and total cholesterol/HDL. In multivariable-adjusted models, higher ADMA levels were associated with higher CAC values (β ADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.09,0.41]). Shorter TRF length and lower IGF-1 values were associated with higher IMT values (β TRF -0.08; 95%CI [-0.14, -0.01] and β IGF-1 -0.04; 95%CI [-0.08, -0.01]). Levels of isoprostanes were not associated with either CAC or IMT. Conclusions: We observed differential patterns of associations between aging-related biomarkers and measures of subclinical atherosclerosis. Additional studies are warranted to elucidate the molecular mechanisms that underlie these association patterns.
The impact of pathologic downstaging with neoadjuvant chemotherapy on survival of patients with muscle-invasive bladder cancer.
Authors: Alberto Martini, John R Heard, Nikhil Waingankar, Rachel Jia, John P. Sfakianos, Matthew Galsky
Journal: Journal of Clinical Oncology (2019)

491 Background: Achieving a pathologic complete response (pCR) with neoadjuvat chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been correlated with improved survival. Such findings have served as justification for using pCR as an intermediate endpoint for clinical trials and perpetuated the notion that NAC only benefits patients achieving a pCR. The impact of downstaging (pDS) on outcomes of patients with MIBC treated with NAC has been underexplored. Methods: The National Cancer Database (NCDB) was queried to identify patients with MIBC (cT2-4N0M) treated with platinum-based NAC. A multivariable Cox model including either pDS or pCR and adjusted for potential confounders was generated and c-indices were computed to evaluate whether the inclusion of pDS or pCR was more informative in predicting overall survival (OS). Results: Overall 2,010 patients from NCDB met inclusion criteria. The median follow-up for survivors was 36 months with a 5-year OS of 47% (95% CI 44, 50%). Overall, 694 (43.5%) patients achieved pDS; 139, 201, 291, 49 and 14 downstaged of 1, 2, 3, 4 and 5 categories, respectively. The 5-year OS rate for patients who achieved pDS was 70%. A pCR was achieved by 306 (15%) of the patients, the 5-year OS rate in this group was 84%. In the NCDB, pDS and pCR emerged as predictors of OS: HR:0.36 (95% CI: 0.30,0.44, p&lt;0.001) and 0.25 (95% CI: 0.18,0.25, p&lt;0.001), respectively. The cindex of the model including pDS was 72 vs. 70 of the model with pCR. Conclusions: pDS represents a more informative endpoint in predicting OS with respect to pCR in patients receiving NAC for MIBC.
Treatment of locally advanced or metastatic urothelial carcinoma: Analysis of expert and community healthcare provider practice trends.
Authors: Kristen Rosenthal, Matt D. Galsky, Matthew I. Milowsky, Daniel Peter Petrylak, Jonathan E. Rosenberg, Kevin Obholz, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2019)

389 Background: With new indications for immune checkpoint inhibitors (ICI), treatment (Tx) decisions for patients (pts) with locally advanced (LA) and metastatic (m) urothelial carcinoma (UC) are becoming more complex. Methods: In Jan 2018, 5 UC experts developed an online tool to provide specific Tx recommendations for 318 case variations based on key factors. Healthcare providers (HCP) enter pt information and their intended Tx to see expert Tx choices for that case. We compared intended Tx of HCPs vs expert recommendations for 388 cases entered in the tool from Feb 1-Aug 15, 2018, before the FDA label change for ICI requiring PD-L1 testing for cisplatin-ineligible pts. Pearson chi-squared and Fischer’s exact tests were used. Results: In LA UC, experts chose cisplatin-based chemotherapy (CT) for 94% of eligible pts vs 59% of HCP ( P &lt; .0001). In pts ineligible for any platinum (Plt)-based CT, experts selected pembrolizumab for all cases vs only 10% of HCP ( P &lt; .0001). In pts with untreated mUC, experts picked cisplatin-based CT in 93% of eligible cases vs 60% of HCP ( P &lt; .0001) and experts chose pembrolizumab for 91% of pts ineligible for any Plt-based CT vs 22% of HCP ( P = .0001). For cisplatin-ineligible pts with either LA UC or mUC who may be able to tolerate carboplatin, there was more variability in expert and HCP Tx choices (Table) prior to the updated ICI indications. For pts who progressed after 1 or 2 lines of CT (including Plt CT), experts chose pembrolizumab for 99% of cases vs 28% of HCP ( P &lt; .0001); 22% of HCP were uncertain of Tx. Although pembrolizumab was the preferred ICI by experts for these 2nd and 3rd line cases, 31% of HCP chose a different ICI. Conclusions: Tx patterns between experts and HCP differed significantly for UC across multiple settings, particularly with integration of ICIs into clinical practice. As treatment indications for ICI continue to evolve, HCP can benefit from an online tool with expert guidance to help navigate complex Tx choices. [Table: see text]
Cancer Vaccines: Steering T Cells Down the Right Path to Eradicate Tumors
Authors: Patrick A. Ott, Catherine J. Wu
Journal: Cancer Discovery (2019)

Lack of tumor T-cell infiltration is a barrier to the efficacy of immune checkpoint inhibitors and other immunotherapies in patients with cancer. Because of their ability to activate and augment tumor-specific T cells, vaccines are an attractive approach to direct T-cell responses into the tumor.
Metabolomics investigation of human colorectal cancer tissue, adjacent mucosa, and stool collected from CRC patients.
Authors: Dustin George Brown, Elizabeth Ryan, Erica Borresen, Joanne O'Malia, Sangeeta Rao
Journal: Journal of Clinical Oncology (2015)

e14688 Background: Metabolomics is an emerging analytical tool that has been applied to cancer biomarker and pathway discovery across several cancer types. Cancer metabolomic studies have revealed variable levels of amino acids, nucleosides, and carbohydrates in tissue that imply perturbations of the pentose-phosphate pathway, glycolysis, and TCA cycle catabolic pathways. Metabolite profile distinctions have been reported between colorectal cancer (CRC) patients and healthy controls. Limited evidence exists for differential expression of metabolites in CRC tissue when compared to adjacent healthy mucosa, and we hypothesize that metabolite profile differences occur across tumor locations in the colon that are involved in CRC pathogenesis. Methods: The goal of this study was to identify metabolite profile distinctions between tumor and non-tumor tissue collected from 17 recently diagnosed CRC patients during colonic resection surgery. Three different tumor locations were determined from pathology reports, and were used to correlate the metabolite differences in tissue with their expression in matched stool samples. Stool samples were self-collected by 13 patients just prior to surgery. These samples were analyzed by metabolomic analysis using GC-MS, LC-MS, and UPLC-MS platforms. Results: Nineteen Metabolites showed significant (p ≤ .05) differences between tumor and non-tumor tissue, involving lipids, carbohydrates, and amino acids when analyzed by matched t-test. Eighty-six metabolites were significantly (p ≤ .05) different across 3 locations within the colon after linear regression analysis. Interestingly, one-hundred and sixty-six stool metabolites showed distinctions across tumor location. Conclusions: Metabolome distincitons between tumor and non-tumor tissue in the same individual provides an opportunity for future studies with larger sample sizes to identify biomarkers of CRC pathogenesis by location and potentially inform prognosis and treatment.
Germline heterozygous <i>BLM</i> mutations and prostate cancer risk.
Authors: Elisa Ledet, Emmanuel S. Antonarakis, Colin Pritchard, William B. Isaacs, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2019)

321 Background: The BLM gene encodes a RecQ DNA helicase that is involved in homologous recombination. Biallelic BLM inactivation leads to Bloom syndrome, an inherited genetic disorder marked by chromosomal instability and multiple cancer susceptibilities. Conflicting studies have suggested that heterozygous BLM mutation carriers may have an increased risk of various cancers. Here we explored the role of germline pathogenic BLM mutations in prostate cancer. Methods: Prostate cancer patients with heterozygous BLM mutations were assembled from Tulane Cancer Center (TCC), Johns Hopkins Hospital (JHH) and University of Washington (UW). BLM germline mutations were identified either through commercial germline testing (Invitae), the UW-BROCA panel, or whole-exome sequencing. Corresponding tumor tissue was analyzed by DNA sequencing for somatic alterations. Population level control data were obtained from the Genome Aggregation Database (gnomAD). Results: 6 BLM germline carriers were identified among 985 advanced prostate cancer case; 2/295 TCC patients, 2/172 JHH patients, and 2/518 UW patients. Overall, pathogenic BLM mutations were detected in 0.609% (6/985) of prostate cancer cases. All mutations were loss-of-function truncating lesions (splicing or nonsense alterations). No Ashkenazi BLM mutations were observed. The population frequency of pathogenic or likely pathogenic BLM alterations detected in gnomAD was 0.025% (31/124,589). Compared to gnomAD controls, the relative risk of BLM mutations in prostate cancer patients was 24.3 (95% CI 10.2 to 58.2; P &lt; 0.0001). One family had a pathogenic splice variant in BLM that cosegregated with disease in three of three cases with lethal/high risk prostate cancer. Tumor DNA sequencing was possible in 5 of 6 BLM carriers; no case demonstrated LOH or additional somatic BLM mutations. Interestingly, 2/5 cases on tumor sequencing also had bi-allelic BRCA2 inactivation. Conclusions: Germline BLM mutations may play a role in prostate cancer risk. Given the role of BLM in chromosomal stability and evidence of concurrent BRCA2 inactivation in a subset of cases, larger cohorts and functional analyses will be critical for better understanding the role of BLM in prostate cancer.
The quality of prostate cancer applications available on smartphones.
Authors: Danny Landau, Kaitlyn Steininger
Journal: Journal of Clinical Oncology (2015)

e17786 Background: In 2012, our group opted to looks at prostate cancer directed applications available on smartphone application stores. We found that of 18 available applications, the majority of free applications offered level one evidence. It was applications that required payment that had questionable data. We decided to search newly available applications to see if there have been changing patterns in availability. Methods: The terms prostate cancer was entered into an iPhone application store and the results analyzed for the level of data provided. 65 applications were found. Five of these were applications looked at in 2012. Results: Of the 60 new applications, four were unrelated to prostate cancer and were not looked at. Of the remaining, 34 were free and 22 required payment with an average cost of $6.17 (range $0.99-49.99). Within the free applications; 13/34 for were medical journals written at or near a medical providers level, one application was from a pharmaceutical company, two applications advertised specific medical centers or physicians. The other remaining applications were a mix of staging guides, calendars, tools to calculate prognosis, or social networking sites. The information provided from these free applications, all supported high levels of evidence when they claimed to provide advice for patients with prostate cancer. Of the applications that required payment, six were geared toward training medical professionals, three provided supportive care that did not have a solid base behind them, 11 applications were PSA calculators/ staging guides. The other applications included supportive care information. Conclusions: Most applications available through the iPhone application store had solid evidence behind them. However, many of these applications were written at a provider’s level, leaving patients with limited resources from this store or with information that can be difficult to interpret without a physician’s guidance. The paid applications did have a few aps that provided questionable data, that could confuse of mislead patients.
Alkaline phosphatase (ALP) value at diagnosis of CRPC and response to primary androgen deprivation therapy may predict metastasis in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Mori Keiichiro, Takahiro Kimura, Shin Egawa
Journal: Journal of Clinical Oncology (2019)

294 Background: Numerous therapeutic options are available for metastatic castration-resistant prostate cancer (mCRPC). However, current therapeutic options remain inadequate for non-metastatic CRPC (nmCRPC); furthermore, there is a paucity of clear evidence to show who may be targeted for aggressive therapy among nmCRPC patients. Therefore, the objective of this retrospective study was to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of nmCRPC patients who may benefit from aggressive therapy. Methods: A total of 115 patients with CRPC who had no metastasis at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University Hospital. The primary outcome measure was metastasis-free survival (MFS) from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox model. Results: The median observation period after diagnosis of CRPC in these patients was 30 months. Kaplan-Meier analysis revealed a median MFS of 76 months in these patients. Multivariate analysis demonstrated that low ALP values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS ( P = 0.011, and 0.031, respectively). Conclusions: Study results suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict metastasis in patients with nmCRPC. Further prospective studies will be required in more patients to confirm our findings. Univariate/multivariate analysis of factors contributing to MFS in nmCRPC patients. [Table: see text]
New and Emerging Tobacco Products and the Nicotine Endgame: The Role of Robust Regulation and Comprehensive Tobacco Control and Prevention: A Presidential Advisory From the American Heart Association
Authors: Aruni Bhatnagar, Laurie P. Whitsel, Michael J. Blaha, Mark D. Huffman, Suchitra Krishan-Sarin, John Maa, Nancy Rigotti, Rose Marie Robertson, John J. Warner
Journal: Circulation (2019)

The advent of new tobacco products such as electronic cigarettes and the dramatic rise in their use, especially by adolescents and young adults, are significant public health concerns. Electronic cigarettes have become the most popular tobacco products for youth and adolescents in the United States and are attracting youth to new avenues for nicotine addiction. Although these products may have benefit by helping some smokers quit or to move to a less harmful product, the long-term health effects of these products and the net public health effect associated with their use remain unclear and widely debated. There is increasing concern that the use of newer tobacco products may catalyze transition to the use of other tobacco products or recreational drugs, particularly in young adults. Therefore, there is urgent need for robust US Food and Drug Administration regulation of all tobacco products to avoid the significant economic and population health consequences of continued tobacco use. Although the American Heart Association acknowledges that the ultimate endgame would be an end to all tobacco and nicotine addiction in the United States, it supports first minimizing the use of all combustible tobacco products while ensuring that other products do not addict the next generation of youth and adolescents. The endgame strategy needs to be coordinated with the long-standing, evidence-based tobacco control strategies that have significantly reduced tobacco use and initiation in the United States.
Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis
Authors: Nishant Gupta, Hye-Seung Lee, Lisa R. Young, Charlie Strange, Joel Moss, Lianne G. Singer, Koh Nakata, Alan F. Barker, Jeffrey T. Chapman, Mark L. Brantly, James M. Stocks, Kevin K. Brown, Joseph P. Lynch, Hilary J. Goldberg, Gregory P. Downey, Angelo M. Taveira-DaSilva, Jeffrey P. Krischer, Kenneth Setchell, Bruce C. Trapnell, Yoshikazu Inoue, Francis X. McCormack
Journal: European Respiratory Journal (2019)

Introduction The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. Methods MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV 1 ; 51–70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. Results In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean± se FEV 1 slope −17±3 versus −3±3 mL·month −1 ; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (−17±3 versus −1±2 mL·month −1 ; p&lt;0.0001) and post-menopausal patients (−3±3 versus 6±3 mL·month −1 ; p=0.04) exhibited a beneficial response in mean± se FEV 1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV 1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D &gt;600 pg·mL −1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. Conclusions In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV 1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.