tbuckley/cabot-search huggingface dataset:
Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer
Authors: Alexander W Wyatt, Matti Annala, Rahul Aggarwal, Kevin Beja, Felix Feng, Jack Youngren, Adam Foye, Paul Lloyd, Matti Nykter, Tomasz M Beer, Joshi J Alumkal, George V Thomas, Robert E Reiter, Matthew B Rettig, Christopher P Evans, Allen C Gao, Kim N Chi, Eric J Small, Martin E Gleave
Journal: JNCI Journal of the National Cancer Institute (2017)

Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. Methods: We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Results: Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53, PTEN, RB1, APC, CDKN1B, BRCA2, and PIK3R1. In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Conclusions: Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.
Multiple neoplasms consist of hematological malignancies and gastrointestinal cancer
Authors: Kazuhiko Natori, Daisuke Nagase, Susumu Ishihara, Akiko Shibuya, Yurika Mitsui, Yasunobu Kuraishi, Motohiro Kato, Kazuho Arai, Haruka Izumi
Journal: Annals of Oncology (2017)
Association between progression-free survival and health-related quality of life in oncology: A systematic review and regression analysis.
Authors: Bruno Kovic, Xuejing Jin, Lehana Thabane, Gordon Guyatt, Michael Donald Brundage, Feng Xie
Journal: Journal of Clinical Oncology (2017)

6574 Background: The goal of cancer care is to improve not only survival duration but also health-related quality of life (HRQoL). Progression-free survival (PFS) has become an important surrogate outcome in assessing efficacy of new cancer drugs, but the relationship between improved PFS and HRQoL is not clear, particularly in the absence of an overall survival (OS) benefit. The objective of this study was to examine the relationship between PFS and HRQoL through a systematic review and analysis of published evidence. Methods: We searched MEDLINE, Embase, and Cochrane databases for randomized controlled human trials addressing oncology treatments published since 2000. We utilized the difference in median PFS time duration between treatment groups, with eligible trials being those reporting no significant OS benefit. We calculated and compared HRQoL between treatment groups using the difference in standardized mean incremental area under the curve adjusted to per month values. Weighted simple regressions were used to examine the PFS-HRQoL association, separately for physical, emotional, and global HRQoL domains. Results: 35,960 citations were identified, with 42 final articles reporting 30 clinical trials being eligible for inclusion. The 30 trials involved 10,731 patients across 12 types of cancer using 6 different instruments. 67% of all trials had improved PFS, and 56%, 54%, and 62% of trials had improved physical, global, and emotional HRQoL, respectively. The PFS with physical domain (n = 18) regression coefficient (slope) β = -0.205 (95% CI; -0.649 to 0.239), with emotional domain (n = 13) β = 0.775 (95% CI; -0.048 to 1.598), and with global domain (n = 24) β = 0.094 (95% CI; -0.271 to 0.459). Conclusions: Our systematic review and analyses revealed weak and nonsignificant association between PFS and HRQoL. In the absence of OS benefit, when longer PFS doesn’t correspond to better HRQoL, using PFS as the proxy for efficacy for oncology drugs is problematic.
Geographic Differences in Persistent Organic Pollutant Levels of Yellowfin Tuna
Authors: Sascha C.T. Nicklisch, Lindsay T. Bonito, Stuart Sandin, Amro Hamdoun
Journal: Environmental Health Perspectives (2017)

Background: Fish are a source of persistent organic pollutants (POPs) in the human diet. Although species, trophic level, and means of production are typically considered in predicting fish pollutant load, and thus recommendations of consumption, capture location is usually not accounted for. Objectives: Yellowfin tuna (Thunnus albacares) are harvested from across the world's oceans and are widely consumed. Here, we determined geographic variation in the overall mass, concentration, and composition of POPs in yellowfin and examined the differences in levels of several POP congeners of potential relevance to human health. Methods: We sampled dorsal muscle of 117 yellowfin tuna from 12 locations worldwide, and measured POP levels using combined liquid or gas chromatography and mass spectrometry according to U.S. Environmental Protection Agency standard procedures. Results: POP levels varied significantly among sites, more than 36-fold on a mass basis. Individual fish levels ranged from 0.16 to 138.29ng/g wet weight and lipid-normalized concentrations from 0.1 to 12.7μM. Levels of 10 congeners that interfere with the cellular defense protein P-glycoprotein, termed transporter interfering compounds (TICs), ranged from 0.05 to 35.03ng/g wet weight and from 0.03 to 3.32μM in tuna lipid. Levels of TICs, and their individual congeners, were strongly associated with the overall POP load. Risk-based analysis of several carcinogenic POPs indicated that the fish with the highest levels of these potentially harmful compounds were clustered at specific geographic locations. Conclusions: Capture location is an important consideration when assessing the level and risk of human exposure to POPs through ingestion of wild fish. https://doi.org/10.1289/EHP518
Gefitinib (’Iressa’, ZD1839) inhibits the expression of COX-2 and the growth of experimental head and neck squamous-cell carcinoma
Authors: Mariana S. De Lorenzo, Mindy Chang, Baoheng Du, Erik G. Cohen, Agnieszka Kazior, Charles Miller, Jay O. Boyle, Kotha Subbaramaiah, Andrew J. Dannenberg
Journal: Cancer Research (2004)

4645  Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are believed to contribute to the growth of head and neck squamous-cell carcinoma (HNSCC). In this study, we investigated the antitumor properties of gefitinib (‘Iressa’, ZD1839), an orally active EGFR-TKI (EGFR tyrosine kinase inhibitor), in experimental HNSCC. Studies were carried out in 1483 cells, an EGFR overexpressing human HNSCC cell line. Initially, we evaluated whether gefitinib inhibited the growth of 1483 xenografts in nude mice. Gefitinib at doses of 10, 50, and 100 mg/kg/day administered by oral gavage caused dose-dependent inhibition of tumor growth. Tumor growth was almost completely inhibited by 100 mg/kg/day gefitinib. To determine whether growth inhibition reflected a change in cell proliferation, immunohistochemistry for Ki-67 was carried out. Treatment with 100 mg/kg/day gefitinib caused more than a 60% decrease in cell proliferation in 1483 xenografts. Subsequently, in vitro studies were performed to further elucidate the mechanism underlying the growth inhibitory effect of gefitinib. Gefitinib caused dose- and time-dependent inhibition of 1483 cell growth with an IC50 of 1 μM. Growth inhibition was a consequence of reduced DNA synthesis and a G0/G1 cell cycle arrest. These inhibitory effects were associated with a marked reduction in levels of phospho-Rb and cyclin D1. Selective inhibitors of COX-2 also suppress the growth of HNSCC. Activation of EGFR signaling has been observed to induce COX-2 in vitro. It was of interest, therefore, to determine whether treatment with gefitinib suppressed the expression of COX-2 in vitro and in vivo. Gefitinib caused dose-dependent inhibition of EGF-mediated induction of COX-2 in 1483 cells in vitro. Moreover, acute treatment of mice bearing 1483 xenografts caused nearly complete suppression of intratumoral COX-2 expression. Taken together, these results support the evaluation of gefitinib in the treatment of HNSCC. Inhibition of COX-2 expression is likely to contribute to the antitumor activity of gefitinib.
The Public Health Service Action Plan for Women's Health: STDs-Reply
Authors: Agnes H. Donahue
Journal: JAMA (1992)

<h3>In Reply.</h3> —As a goal-driven, comprehensive blueprint for improving the health of all women, the PHS Action Plan for Women's Health addresses a wide range of age-specific issues and conditions, including STDs. Although the one-page space limitation in the<i>JAMA</i>article did not permit discussion of every women's health issue, the Action Plan identifies educational, preventive, and research initiatives for lowering the STD rate among women. For example, the Centers for Disease Control (CDC) is addressing STD morbidity, including the complications of pelvic inflammatory disease, ectopic pregnancy, infertility, cervical cancer, and immune deficiencies. A number of prevention projects, including screening programs, have been implemented through grants to state and local health departments for chlamydia, gonorrhea, and syphilis control. The CDC has developed STD prevention messages for incorporation into behavior-based school curricula. And STD prevention messages are being implemented in a variety of clinical service delivery settings throughout the country, including
Association between androgen receptor (AR) expression, Ki-67, and the 21-gene recurrence score in early breast cancer.
Authors: Francisco Emilio Vera-Badillo, Martin Chang, Gordana Kuruzar, Alberto Ocana, Arnoud J. Templeton, Bostjan Seruga, Mustafa Al-Mubarak, Robyn Goldstein, Philippe L. Bedard, Ian Tannock, Eitan Amir
Journal: Journal of Clinical Oncology (2014)

547 Background: AR expression is a favorable prognostic factor in estrogen receptor (ER) positive and ER negative breast cancer. Here we explore the association between AR, Ki67, and the 21-gene recurrence score (RS). We hypothesized that ER-positive breast cancers with high AR expression will be associated with a low Ki67 and RS. Methods: Sequential patients with lymph node negative, ER positive and HER2 negative breast cancer who had surgery at Mount Sinai Hospital, Toronto between January 2010 and October 2013 and in whom the RS was requested were identified. Archival tissue was sectioned and stained for AR (AR441 clone, Dako) and Ki67 (MIB-1 clone, Dako) and then visualized by protein polymer (MACH4, Biocare) and DAB chromogen. AR was scored using the Allred system and Ki67 by manual count (using the Ki67 working group recommendations) by a single pathologist. Associations between RS and AR, age, grade, mitotic score, Ki67, and the extent of ER and progesterone receptor (PgR) expression were assessed using linear regression. Ki67 was assessed as a continuous and dichotomous variable (using a cut off of 14%). Statistical significance of this exploratory study was defined as p<0.10. Results: Seventy cases satisfied criteria for analysis. Median age was 59.5 years, mean tumor size was 1.8 cm (range 0.6-3.9 cm), 24% were grade 1, 66% grade 2 and 10% grade 3. Most tumors had high AR expression (median Allred score = 8, 97% had score ≥4). Median RS was 15 (range 1-53). AR expression showed a modest positive correlation with ER (R=0.37), but no correlation with PgR (R=0.09) or Ki67 (R=-0.18). In univariable analysis, AR (p=0.01), ER (p<0.001) and PgR (p<0.001) had significant negative associations with the RS. Ki67 had a non-significant positive association with RS (p=0.11 and p=0.16 for continuous and cut off analyses, respectively). Age (p=0.93), grade (p=0.40) and mitotic count (p=0.23) showed no association with RS. Multivariable analysis showed similar associations with RS (AR [p=0.07], ER [p=0.05], PgR [p=0.001]). Conclusions: AR is not associated with proliferative index (Ki67) but is associated with lower probability of disease recurrence (Low RS).
Limitations Concerning the Association of Physician Sex and Patient Outcomes—Reply
Authors: Yusuke Tsugawa, Anupam B. Jena, Ashish K. Jha
Journal: JAMA Internal Medicine (2017)

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Functional melanoma‐risk variant <i> <scp>IRF</scp> 4 </i> rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas
Authors: D.C. Gibbs, S.V. Ward, I. Orlow, G. Cadby, P.A. Kanetsky, L. Luo, K.J. Busam, A. Kricker, B.K. Armstrong, A.E. Cust, H. Anton‐Culver, R.P. Gallagher, R. Zanetti, S. Rosso, L. Sacchetto, D.W. Ollila, C.B. Begg, M. Berwick, N.E. Thomas
Journal: British Journal of Dermatology (2017)

Breslow thickness is considered to be the most important prognostic tumor feature in melanoma patients and is associated with age, sex, and phenotypic risk factors for melanoma such as number of nevi. However, its association with inherited genetic variants in recently identified melanoma risk loci is largely unknown.

In a Western Australian Melanoma Health Study (WAMHS) study, published in the British Journal of Dermatology, IRF4 rs12203592, OCA2 rs1800401 and TP53 rs1042522 were significantly associated (P < 0.05) with Breslow thickness; however, these associations did not pass false discovery.

This article is protected by copyright. All rights reserved.
The Prevalence and Causes of Vision Loss in Indigenous and Non-Indigenous Australians
Authors: Joshua Foreman, Jing Xie, Stuart Keel, Peter van Wijngaarden, Sukhpal Singh Sandhu, Ghee Soon Ang, Jennifer Fan Gaskin, Jonathan Crowston, Rupert Bourne, Hugh R. Taylor, Mohamed Dirani
Journal: Ophthalmology (2017)
High Expression of ARMCX1 Predicts Poor Survival in Intensively Treated Older Acute Myeloid Leukemia Patients (≥ 60 years)
Authors: Jan-Henrik Mikesch, Christina Sauerland, Tobias Herold, Dennis Görlich, Eike Bormann, Wolfgang Hartmann, Christoph Schliemann, Bernhard J Wörmann, Wolfgang Hiddemann, Karsten Spiekermann, Matthias Stelljes, Utz Krug, Carsten Muller-Tidow, Thomas Büchner, Wolfgang E Berdel, Maria Francisca Arteaga
Journal: Blood (2016)
Outcomes according to tumor RAS and BRAF mutation status in patients treated with cetuximab in 1st-line treatment of unresectable metastatic colorectal cancer (mCRC): Updated results from EREBUS cohort
Authors: Denis Smith, Antonio Sa-cunha, Magali Rouyer, Eric François, Alain Monnereau, Edwige Yon, Emmanuelle Bignon, Pernelle Noize, Cécile Droz-Perroteau, Nicholas Moore, Annie Fourrier-réglat
Journal: Annals of Oncology (2017)
A pilot study to evaluate the levels of inter-alpha inhibitor proteins (IAIPs) in metastatic cancer patients on chemotherapy.
Authors: Peter C. Kurniali, John A Gerlach, Yow-Pin Lim, Joseph Qiu, Sarah Siemiontkowski, Anas Al-Janadi
Journal: Journal of Clinical Oncology (2014)

e22138 Background: Inter-alpha Inhibitor protein family (IAIP) is a group of structurally related serine protease inhibitors produced in the liver and found at relatively high concentrations in human plasma. IAIPs have a significant role in systemic inflammation and function as an endogenous immunomodulator. Significant reduction of IAIPs level is found in decompensated septic patients due to rapid excretion through kidney. Although IAIPs correlate with several pro and anti-inflammatory cytokines in septic patients, the relationship in cancer patients is not well understood. Since many cancers may represent a systemic inflammatory state, we are interested in finding the relationship between IAIPs and malignancy, as well as exploring their potential as prognostic markers. Methods: A total of 25 blood samples (8 healthy controls and 17 cancer patients) were collected at a single time point. Plasma was used for the quantitative analysis of IAIPs (competitive ELISA using MAb 69.26), albumin, pre-albumin, CRP, and cytokines (BioRad). Additional data collected included percent of weight loss, cancer type, and BMI. Cancer types included in this analysis were lung, breast, and gastrointestinal, and lymphoma. Results: Cancer patients had a higher median level of IAIPs compare to healthy control, although it did not reach statistical significance due to small sample size (400.6 vs. 255.2 mg/L, p=0.12). In cancer patients, we found that IAIPs level was positively correlated with BMI (r2=0.34, p=0.01) and inversely correlated with albumin (r2=0.24, p=0.04), IL-2 (r2=0.26, p=0.03), and MIP-1ß (r2=0.39, p=0.006). Conclusions: Increased IAIPs level found in advanced stages of cancer patients might be due to the systemic inflammatory condition. An inverse correlation of IAIPs with pro-inflammatory cytokines (IL-2 and MIP-1ß) as well as albumin is consistent with the inflammatory state in these patients. IAIPs level might be a useful biomarker to predict disease severity and host response. To further evaluate the relationship between IAIPs and metastatic cancer, we will perform longitudinal study in patients with metastatic cancer before and during chemotherapy, and at disease progression.
Comparative Assessment of the Different American College of Rheumatology/European League Against Rheumatism Remission Definitions for Rheumatoid Arthritis for Their Use as Clinical Trial End Points
Authors: Michael E. Mack, Elizabeth Hsia, Daniel Aletaha
Journal: Arthritis & Rheumatology (2016)

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have defined remission using Boolean- or index-based criteria (i.e., a Simplified Disease Activity Index [SDAI] score of ≤3.3). We undertook this study to compare definitions of remission to inform choice of end points for future rheumatoid arthritis (RA) clinical trials, and we also included in our comparison the remission criterion of a score of ≤2.8 on the Clinical Disease Activity Index (CDAI).We performed post hoc analyses on clinical remission rates using data from 2 infliximab trials (the ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset] and ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy] trials) and 1 golimumab trial (the GO-FORWARD trial). We investigated stringency of the different remission definitions, their power to discriminate between active drug and comparator, and aspects of their internal and external validity. We also investigated population determinants of discriminatory power for a particular remission end point.In patients with early RA (the ASPIRE trial), ACR/EULAR Boolean, CDAI, and SDAI remission rates at 6-7 months were 4-6% for methotrexate (MTX) alone versus 11-14% for infliximab plus MTX. In patients with MTX-refractory active RA (the ATTRACT and GO-FORWARD trials), remission rates were ≤1% for comparator (add-on of placebo) versus 4-6% for add-on of infliximab in the ATTRACT trial and ≤3% for comparator (add-on of placebo) versus 11-13% for add-on of golimumab in the GO-FORWARD trial. Existing remission cut points of different measures were generally comparable, with the Boolean criteria being somewhat more stringent than the SDAI and CDAI criteria. Remission rates were similar across definitions, as was average statistical power (CDAI, 55.6%; Boolean, 59.9%; SDAI, 62.6%).Remission is an ambitious primary end point for RA clinical trials, to be reserved for selected scenarios based on power considerations. The ACR/EULAR definitions are interchangeable, with slightly higher stringency of Boolean criteria over index-based criteria.
R-COMP Vs. R-CHOP As First-Line Treatment for De Novo Diffuse Large B-Cell Lymphoma in Patients Older Than 60 Years: Preliminary Results from a Prospective Randomized Phase 2 Study from the Spanish Group Geltamo
Authors: Juan-Manuel Sancho, Francisco Gual, Rubén Fernández-Alvarez, Esther González-García, Carlos Grande, Carmen Jiménez-López, Norma C Gutierrez, María-José Peñarrubia, Ana Batlle, Eva González-Barca, Jose-Maria Guinea-de-Castro, Eva Gimeno, Francisco-Javier Peñalver, Miguel A Fuertes, Jorge Gayoso, José-Ángel Hernández-Rivas, José-María Moraleda, Lluis Virgili, Alejandro Martín
Journal: Blood (2016)