tbuckley/cabot-search huggingface dataset:
Abstract P5-04-24: Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents
Authors: L Bathurst, L Liao, C Crozier, N Lyttle, R Marcellus, J Bayani, R Al-awar, J Bartlett, M Spears
Journal: Cancer Research (2019)

Abstract Background: Approximately 70% of all breast cancers are estrogen receptor positive (ER+) at diagnosis and are dependent on estrogen signaling for tumour growth and proliferation. Some ER+ breast cancers can be effectively treated with adjuvant endocrine therapies including tamoxifen, but despite favorable improvements in overall survival, resistance to endocrine therapy is common and has been associated with dysregulation of several signaling pathways. These pathways can be targeted with specific inhibitors, many of which are currently under clinical investigation. However currently there is a lack of predictive biomarkers to identify which patients should receive treatment with targeted therapy. The goal of this study was to determine whether alterations in specific signaling pathways can be identified and used to stratify breast cancer cell lines to the most effective experimental treatments. Methods/Results: Fifteen ER+/HER2- cell lines were characterized using a NanoString PAM50-like assay as well as next generation sequencing and were then stratified according to alterations in three key signaling pathways: CCND/CDK, PI3K/AKT/mTOR and FGFR. High-throughput small-molecule screenings were performed to identify the IC50 values of 24 inhibitors across the strata. Variation in inhibitor sensitivity was observed between cell lines based on molecular alterations. Cell lines with a PIK3CA mutation in combination with a CDK-pathway alteration were more sensitive to CDK inhibitors (50 to 120nM) than cell lines with alterations in the CDK-pathway alone or PIK3CA mutations alone (170nM to &amp;gt;5000nM). In addition, cell lines with the dual alterations demonstrated stronger synergy between CDK and PI3K-pathway inhibitors compared to either alteration alone. Conclusions: The results suggest that stratification according to molecular alterations in specific signaling pathways may predict sensitivity to targeted inhibitors in a panel of ER+/HER2- luminal breast cancer cell lines. Work is ongoing to identify the optimal synergistic inhibitor combinations for each strata. The ultimate goal is to translate this work into a novel personalized medicine approach, using molecular stratification based on a combination of molecular events in a functional pathway as opposed to single genes. Citation Format: Bathurst L, Liao L, Crozier C, Lyttle N, Marcellus R, Bayani J, Al-awar R, Bartlett J, Spears M. Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-24.
Abstract P3-01-07: Enabling HER2 and androgen receptor (AR) protein expression and localization in circulating tumor cells (CTCs) of ER(+/-)HER2(-) metastatic breast cancer (MBC) patients (pts)
Authors: P Ontiveros, C Landaverde, R Graf, MK Levin, S Hippely, Y Wang, M Landers, R Dittamore, JA O'Shaughnessy
Journal: Cancer Research (2019)

Abstract Background: Upregulation of HER2 and AR are mechanisms of acquired resistance to endocrine therapy, and are being investigated as treatment-guiding biomarkers. However, measurement of these proteins and their localization requires metastatic biopsies, which are costly, invasive, and prone to under-sampling which limits their utility to guide treatment in late stage metastatic patients. A CTC-based test could expand the clinical utility of these biomarkers. Here we utilized the Epic Sciences CTC platform for CTC detection and characterization. MBC blood samples were characterized for CTC prevalence, HER2 and AR expression at time of disease progression. Material and methods: HER2 and AR expression levels were determined based on model cell lines. A total of 72 blood samples were acquired from ER(+/-)/HER2(-) patients (by standard tissue pathology) at disease progression. 72 samples were analyzed for HER2 and 64 were analyzed for AR using the Epic Platform. Single-cell whole genome sequencing was performed to assess clonality and inter-patient heterogeneity of CTCs detected. Results: 55/72 (76.4%) of patients had CTCs detected across two slides. 13/72 (18.1%) had at least one HER2(+) CTC, 14/64 (21.9%) had at least one AR(+) CTC, and 7/64 (10.9%) had at both AR(+) and HER2(+) CTCs detected on replicate slides. HER2 expression on individual CTCs showed distinctive cytoplasmic membrane staining, and AR expression on individual CTCs showed frequent nuclear localization. Most patient samples showed heterogeneous expression of these markers at disease progression indicating subclonal sensitivity to targeted therapies. Subsequently, these cells will be individually sequenced to better determine the clonality of resistance. Conclusions: CTCs are detected in most MBC pts upon disease progression, with expression of known endocrine therapy resistance markers, HER2 and AR, observed that CTCs could guide subsequent therapy selection. Prospective evaluation of HER2 and AR on MBC pts' CTCs as predictive biomarkers of benefit from inhibitors of these proteins is needed. Citation Format: Ontiveros P, Landaverde C, Graf R, Levin MK, Hippely S, Wang Y, Landers M, Dittamore R, O'Shaughnessy JA. Enabling HER2 and androgen receptor (AR) protein expression and localization in circulating tumor cells (CTCs) of ER(+/-)HER2(-) metastatic breast cancer (MBC) patients (pts) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-07.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
Authors: Dieter Haffner, Francesco Emma, Deborah M. Eastwood, Martin Biosse Duplan, Justine Bacchetta, Dirk Schnabel, Philippe Wicart, Detlef Bockenhauer, Fernando Santos, Elena Levtchenko, Pol Harvengt, Martha Kirchhoff, Federico Di Rocco, Catherine Chaussain, Maria Louisa Brandi, Lars Savendahl, Karine Briot, Peter Kamenicky, Lars Rejnmark, Agnès Linglart
Journal: Nature Reviews Nephrology (2019)

Abstract X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.
Abstract P1-12-01: Withdrawn
Authors: V Bjelic-Radisic, A Bottomley, F Cardoso, D Cameron, E Brain, K Kuljanic, RA de Costa, T Conroy, V Deville, E Inwald, S Serpentini, M Pinto, E Bleiker, J Arrares, F Duhoux, J Weiss, O Morag, G Lindviksmoen Astrup, K Tomaszweksi, G Velikova, K Pogoda, E Nagele, B Bliem, P Sinai, M Sprangers, N Aaronson, E Greimel
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Bjelic-Radisic V, Bottomley A, Cardoso F, Cameron D, Brain E, Kuljanic K, de Costa RA, Conroy T, Deville V, Inwald E, Serpentini S, Pinto M, Bleiker E, Arrares J, Duhoux F, Weiss J, Morag O, Lindviksmoen Astrup G, Tomaszweksi K, Velikova G, Pogoda K, Nagele E, Bliem B, Sinai P, Sprangers M, Aaronson N, Greimel E. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-12-01.
Association of Primary Care Clinic Appointment Time With Clinician Ordering and Patient Completion of Breast and Colorectal Cancer Screening
Authors: Esther Y. Hsiang, Shivan J. Mehta, Dylan S. Small, Charles A. L. Rareshide, Christopher K. Snider, Susan C. Day, Mitesh S. Patel
Journal: JAMA Network Open (2019)

<h3>Importance</h3> As the clinic day progresses, clinicians may fall behind schedule and experience decision fatigue. However, the association of time of day with cancer screening rates is unknown. <h3>Objective</h3> To evaluate the association of primary care clinic appointment time with clinician ordering and patient completion of breast and colorectal cancer screening. <h3>Design, Setting, and Participants</h3> Retrospective, quality improvement study of 33 primary care practices in Pennsylvania and New Jersey from September 1, 2014, to August 31, 2016. Participants included adults eligible for breast or colorectal cancer screening. Data analysis was conducted from April 24, 2018, to November 8, 2018. <h3>Exposures</h3> Clinic appointment time during each patient's first primary care physician visit in the study period. <h3>Main Outcomes and Measures</h3> Primary outcome was clinician ordering of the screening test during the visit. Secondary outcome was patient completion of the tests within 1 year of the visit. <h3>Results</h3> Among the 19 254 patients eligible for breast cancer screening, the mean (SD) age was 60.2 (6.9) years; 19 254 (100%) were female, 11 682 (60.7%) were white, and 5495 (28.5%) were black. Screening test order rates were highest at 8amat 63.7%, decreased throughout the morning to 48.7% at 11am, increased to 56.2% at noon, and then decreased to 47.8% at 5pm(adjusted odds ratio [OR] for overall trend, 0.94; 95% CI, 0.93-0.96;<i>P</i> &lt; .001). Trends in screening test completion rates were similar beginning at 33.2% at 8amand decreasing to 17.8% at 5pm(adjusted OR, 0.95; 95% CI, 0.94-0.97;<i>P</i> &lt; .001). Among the 33 468 patients eligible for colorectal cancer screening, the mean (SD) age was 59.6 (7.4) years; 18 672 (55.8%) were female, 22 157 (66.2%) were white, and 7296 (21.8%) were black. Screening test order rates were 36.5% at 8am, decreased to 31.3% by 11am, increased at noon to 34.4%, and then decreased to 23.4% at 5pm(adjusted OR, 0.94; 95% CI, 0.93-0.95;<i>P</i> &lt; .001). Trends in screening test completion rates were similar beginning at 28.0% at 8amand decreasing to 17.8% at 5pm(adjusted OR, 0.97; 95% CI, 0.96-0.98;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Clinician ordering of cancer screening tests significantly decreased as the clinic day progressed. Patient completion of cancer screening tests within 1 year of the visit was also lower as the primary care appointment time was later in the day. Future interventions targeting improvements in cancer screening should consider how time of day may influence these behaviors.
Abstract P5-04-27: Investigating the incidence of ESR1 gene amplification in breast cancers resistant to multiple endocrine agents
Authors: AK Turnbull, C Martinez-Perez, S Mok, M Tanioka, A Fernando, L Renshaw, J Keys, A Wheless, A Garrett, J Parker, X He, AH Sims, LA Carey, CM Perou, JM Dixon
Journal: Cancer Research (2019)

Abstract Background: Around 70% of all breast cancers (BCs) are estrogen receptor positive (ER+), but some do not respond to endocrine therapy (ET) and many eventually develop resistance. ESR amplification (ESRA) linked to an increase in ESR1 gene expression is known to occur in some cancers that are endocrine resistant. However, the incidence of ESRA has been the object of debate and its clinical significance remains unclear. This study aimed to investigate the incidence of ESRA in BCs resistant to multiple sequential ETs and optimise a fluorescence in-situ hybridisation (FISH) methodology to robustly detect ESRA. Methods: Two unique cohorts have been studied: (A) 20 post-menopausal women with ER+ BC with acquired resistance to letrozole, subsequently treated with up to 4 different lines of ET. Serial RNA and DNA from 3-5 cancer samples per patient (58 samples from 20 patients) were analysed by Ribo0-RNAseq and DNA exome sequencing; (B) 18 post-menopausal women who developed ER+ BC recurrences on 1st line adjuvant letrozole, then on 2nd line tamoxifen and subsequently on 3rd line exemestane. Tissues were collected at the time of each surgery. We have optimised a FISH method to assess ESRA in these tissues. Results: In cohort A, 6/20 patients developed ESR1 gene amplification (ESRA) at some point during treatment. In 5 of these cases, ESRA was only found while on 2nd or 3rd line exemestane but was not present on acquired resistance to previous letrozole or tamoxifen. 1 patient had ESRA at the time of first recurrence on letrozole. The FISH method showed concordance with the genomic analysis. This suggests that ESRA may be associated with BCs that are treated with and then become resistant to exemestane. ESRA is also evident in samples from Cohort B, which includes 18 exemestane resistant cases. The complete analysis is ongoing. Conclusions: · ESRA can be seen in ER+ recurrent BCs. · ESRA may be associated with BCs treated with 2nd or 3rd line exemestane. · The frequency of ESRA in endocrine and exemestane resistance can now be ascertained using an optimised FISH-based method, which is more cost-effective than alternative genomic and biochemical methods. Citation Format: Turnbull AK, Martinez-Perez C, Mok S, Tanioka M, Fernando A, Renshaw L, Keys J, Wheless A, Garrett A, Parker J, He X, Sims AH, Carey LA, Perou CM, Dixon JM. Investigating the incidence of ESR1 gene amplification in breast cancers resistant to multiple endocrine agents [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-27.
Abstract P4-08-35: Young age at diagnosis is associated with worse prognosis in the luminal A breast cancer subtype. A retrospective institutional cohort study
Authors: Z Liu, Z Sahli, Y Wang, AC Wolff, L Cope, CB Umbricht
Journal: Cancer Research (2019)

Abstract Background: Breast cancer (BCA) presents with distinct molecular subtypes, each associated with different patterns of relapse, drug sensitivity, and prognosis. Although age at diagnosis is a recognized independent prognostic risk factor, its relative importance among molecular subtypes is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among BCA patients of different immunohistochemical subtypes (LuminalA, LuminalB, Her2, Triple-negative). Methods: We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital from January 2000 - December 2016, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41-60, and &amp;gt; 60 years, and multivariable analysis was performed using Cox regression. To explore age-related differences in gene expression, we identified differentially expressed genes (DEG) between age groups among BCA subtypes in the TCGA dataset. Finally, we identified key driver genes within DEG using a weighted gene co-expression network analysis. Results: Our cohort included 3,524 patients with a median follow-up of 85.1 months. LuminalA breast cancer patients had significantly lower 5-year Disease Free Survival (DFS) and Distant Metastasis-Free Survival (DMFS) in the ≤ 40 year age group compared to the 40-60 year age group (HR=2.69, 95%CI: 1.72 - 4.23 and HR=2.95, 95%CI: 1.78 - 4.90, respectively), while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger predictor of 5- year DFS and 5-year DMFS than tumor grade or proliferative index (Ki67) in LuminalA BCA patients, but not other subtypes. Gene expression data were obtained from 1097 BCA TCGA patients, divided into two groups (≤40y, n=36; &amp;gt;40y, n=455). We identified 374 DEG between ≤40y and &amp;gt;40y LuminalA BCA subsets. The DEG were enriched in 7 pathways, and the WGCNA analysis identified two modules of co-expressed genes. No age group-specific DEG were identified in non-LuminalA subtypes. Conclusion: Age at diagnosis may be an important prognostic factor in LuminalA BCA and may improve risk stratification and personalized therapy. Prospective studies are needed to further evaluate the prognostic value of age in this subset of BCA patients. Citation Format: Liu Z, Sahli Z, Wang Y, Wolff AC, Cope L, Umbricht CB. Young age at diagnosis is associated with worse prognosis in the luminal A breast cancer subtype. A retrospective institutional cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-35.
On the Ethical Criteria for Health-Promoting Nudges: The Importance of Conceptual Clarity
Authors: J. S. Blumenthal-Barby
Journal: The American Journal of Bioethics (2019)

In his article “Ethical Criteria for Health-Promoting Nudges: A Case-by-Case Analysis,” Bart Engelen (2019) synthesizes a growing literature on the ethics of nudging and outlines nine criteria for ...
Updated Report of a Phase I/II Multicenter Study of Forodesine, a Purine Nucleoside Phosphorylase Inhibitor, in Japanese Patients with Relapsed Peripheral T-Cell Lymphoma
Authors: Hirohiko Shibayama, Kensei Tobinai, Kunihiro Tsukasaki, Toshiki Uchida, Yoshinobu Maeda, Hirokazu Nagai, Mitsutoshi Kurosawa, Youko Suehiro, Kiyohiko Hatake, Kiyoshi Ando, Isao Yoshida, Michihiro Hidaka, Tohru Murayama, Yoko Okitsu, Norifumi Tsukamoto, Masafumi Taniwaki, Junji Suzumiya, Kazuo Tamura, Takahiro Yamauchi, Ryuzo Ueda
Journal: Blood (2017)
Review of Sunita Puri, <i>That Good Night: Life and Medicine in the Eleventh Hour</i>
Authors: Jori Felice Bogetz, Danielle F. Jonas
Journal: The American Journal of Bioethics (2019)

"Review of Sunita Puri, That Good Night: Life and Medicine in the Eleventh Hour." The American Journal of Bioethics, 19(5), pp. W1–W2
Junior doctors need more supervision, according to GMC survey
Authors: Emilie Green
Journal: BMJ (2012)

Evidence from a survey suggests that junior doctors often fulfil tasks outside of their competencies, jeopardising patient safety.

The seventh annual national trainee survey was conducted by the General Medical Council and was published on the 16 July. Foundation, core, higher specialty, and military trainees were all eligible to participate.

Most (95%) of UK doctors responded to the online survey, which aims to provide insight into the existing system, and elicit changes that will improve medical education.

Respondents were generally satisfied with their training, and satisfaction has increased from 78% to 80% over the past year. Similarly, 74% of participants rated their practical …
Abstract 12040: Pediatric Heart Network Echocardiographic Z Scores: Comparison to Other Published Models
Authors: Leo Lopez, Peter C Frommelt, Steven D Colan, Felicia Trachtenberg, Mario Stylianou, Aarti Bhat, Kristin M Burns, Meryl S Cohen, Andreea Dragulescu, Lindsay R Freud, Michele Frommelt, Irene D Lytrivi, Joseph Mahgerefteh, Brenda Ni, Ricardo Pignatelli, Ashwin Prakash, Ritu Sachdeva, Jonathan H Soslow, Christopher Spurney, Carolyn Taylor, Poonam P Thankavel, Thor Thorsson, Justin T Tretter, Luciana Young, L. LuAnn Minich
Journal: Circulation (2018)

Introduction: Different allometric methods have resulted in variable Z scores for an echo measurement. The Pediatric Heart Network (PHN) recently established a database of echo measurements from 32...
Abstract P4-16-08: A regional audit of 6-hour monitoring for administration related reactions during the first administration of subcutaneous trastuzumab
Authors: S Karmali, N Hughes, A Kinneally, J Kroes, J Cook, M Killian, T Shafiq, D O'Mahony, B Bird, M O'Connor, S O'Reilly, R Galiauskas, CG Murphy
Journal: Cancer Research (2019)

Abstract Introduction In 2012, Subcutaneous Trastuzumab (TSC) was introduced as an alternative to Intravenous Trastuzumab (TIV) for HER2+ breast cancer. The pivotal HannaH study demonstrated that TSC was non-inferior to TIV, was preferred by patients, and serious administration related reactions (ARRs) were not reported. However, the Summary of Product Characteristics (SPC) advises that patients be observed for ARRs for 6 hours post-first administration (and 2 hours post-subsequent administrations), similar to TIV. Aim To assess the frequency and tolerability of ARRs during the 6-hour observation period post first administration of TSC in patients with HER2+ breast cancer. Method: A retrospective audit of TSC was conducted in Southwest Ireland across five centers from 2014-2016. Patient charts were reviewed to record ARRs reported on the first-administration or at subsequent visit. In addition a subset of patients were interviewed regarding their recollection of ARRs with first or subsequent injections. Results: The study is ongoing having identified 192 patients. These centers have administered 2111 TSC injections in total, associated with 4998 hours of observation as per SPC. From the 385 injections given over the first two TSC administrations, 13 injections (3.4%) were associated with ARRs within 24 hours. Nine patients (2.3%) experienced injection site reactions immediately post injection, one injection site pain (0.3%), and one experienced petechiae on subsequent exposure (0.3%). Three patients experienced pyrexia and dry cough 24 hours post-injection and were hospitalized for respiratory tract infection. There were no reactions experienced between 2 and 6 hours post-first injection. There were no serious ARRs. Telephone interviews are ongoing and these results will be reported. Conclusion: ARRs related to TSC are usually immediate, mild and self-limiting. Observing patients for 6 hours post-first injection and 2 hours post-subsequent injections represents an inefficient use of healthcare resources. Citation Format: Karmali S, Hughes N, Kinneally A, Kroes J, Cook J, Killian M, Shafiq T, O'Mahony D, Bird B, O'Connor M, O'Reilly S, Galiauskas R, Murphy CG. A regional audit of 6-hour monitoring for administration related reactions during the first administration of subcutaneous trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-08.