tbuckley/cabot-search huggingface dataset:
Abstract P3-06-20: Druggable genomic landscape of primary and metastatic breast cancers
Authors: SQ Sun
Journal: Cancer Research (2019)

Abstract Background: Several studies (e.g. The Pan-Cancer Atlas) have examined the druggable genomic landscape of breast cancers and other malignancies using The Cancer Genome Atlas (TCGA). However, TCGA is representative of newly-diagnosed, treatment-naïve breast cancers, whereas genomic profiling is typically used to inform therapy for metastatic and/or pre-treated breast cancers. Here, we characterize the druggable genomic landscape of breast cancers using AACR Genomics Evidence Neoplasia Information Exchange (GENIE), a multi-institutional pragmatic cancer genomics registry. Methods: We obtained mutation, copy-number amplification (CNA), and fusion data from GENIE, which contains de-identified genomic records from 4506 breast carcinoma and carcinoma-in-situ (CIS) tumors. We used Clinical Interpretation of Variants in Cancer (CIViC) to label the potential druggability of these mutations, CNAs, and fusions. Further, we plan to assess variations in the druggable genomic landscape of breast tumors as a function of tumor characteristics (e.g. histology, tumor mutation burden), patient characteristics (age, sex, ethnicity), and genomics assay characteristics (e.g. PCR vs. hybridization capture). Results: In GENIE, we identified 19932 mutations, 9334 copy number amplifications (CNA), and 987 fusions in 4506 breast tumors. CNAs suggesting potential druggability were relatively common (e.g. ERBB2 amplifications in 9.9% of tumors), whereas fusions suggesting potential druggability were relatively rare (e.g. NTRK fusions in 0.1% of tumors). Mutations suggesting potential druggability were identified in ERBB2 (3.5% of tumors) and mismatch repair genes [MLH1, MSH2, MSH3, MSH6, PMS1, PMS2] (3.7% of tumors). Conclusion: GENIE can be used to infer druggability across a cohort of breast tumors likely to be considered for approved systemic therapy at tertiary academic centers. This may inform use of genomic assays and/or design of clinical trials for patients with breast tumors. *The author would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors. Citation Format: Sun SQ. Druggable genomic landscape of primary and metastatic breast cancers [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 P3-06-20.
Abstract P1-06-11: Microsatellite instability in triple negative breast cancers
Authors: K Kurata, M Kubo, H Mori, H Kawaji, Y Motoyama, L Kuroki, M Yamada, K Kaneshiro, M Kai, M Nakamura
Journal: Cancer Research (2019)

Abstract Background:Microsatellite instability (MSI) is a phenotype resulting from defect in mismatch repair genes. The Food and Drug Administration approved anti-programmed death 1 (PD-1) immune checkpoint inhibitor for any solid tumor with MSI-high (MSI-H). Some tumors had good response to PD-1 blockade and it is a promising treatment for a part of refractory breast cancers. Our goal was to determine the frequency of MSI in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes. Patients and Methods:This study included 228 patients with primary TNBC underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue. Tumor and control DNA were amplified by polymerase chain reaction at the following 5 microsatellite markers: NR-21, BAT-26, BAT-25, NR-24, MONO-27. We classified the tumors as microsatellite stable(MSS), MSI-low or MSI-H. Results: The mean age of patients was 59 years (range: 30-89) and all were women. T1 tumors were 57.9% and N0 were 67.5%. Meanwhile, the tumors with nuclear grade 3 were 66.2% and high Ki-67 (&amp;gt; 30%) were 66.7%. Among the 228 tumors, 222 tumors (97.4%) revealed MSS, of which 6 (2.6%) revealed MSI and 2 (0.9%) were MSI-H. Among the MSI tumors, T and N factor were showed as follows: T1: 2 tumors, T2: 3 tumors, T3: 1 tumor, N0: 5 tumors and N1: 1 tumor. Of two MSI-H tumors, one showed T1N0 and another showed T2N0. The both of them showed nuclear grade 3, high Ki-67 (&amp;gt; 30%) and had common following instable markers: NR-21, BAT-26 and BAT-25. Conclusions: Our results demonstrated that the frequency of MSI-H was 0.9% (2/228). MSI might not be useful as a biomarker for immune check point inhibitors. MSI should be combined with another biomarker such as tumor mutational burden in TNBC. Citation Format: Kurata K, Kubo M, Mori H, Kawaji H, Motoyama Y, Kuroki L, Yamada M, Kaneshiro K, Kai M, Nakamura M. Microsatellite instability in triple negative breast cancers [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 P1-06-11.
Abstract P1-08-19: 10-year conditional recurrence risks, overall and relative survival for breast cancer patients in the Netherlands: Taking account of event-free years
Authors: MC van Maaren, LJ Strobbe, ML Smidt, M Moossdorff, PM Poortmans, S Siesling
Journal: Cancer Research (2019)

Abstract Background Survival estimates valid at the time of diagnosis are of limited value for (ex-)breast cancer patients who survived several years, as it includes information on already deceased patients. This study analyzed the 10-year conditional risk of recurrent breast cancer in specific prognostic subgroups according to T and N stage and breast cancer subtypes. Secondly, we investigated 10-year conditional overall (OS) and relative survival (RS), adjusted for confounding. Patients and methods We selected all women diagnosed in 2005 with operated T1-2N0-1 breast cancer from the Netherlands Cancer Registry. Patients were classified into T1N0, T1N1, T2N0 and T2N1 stage. Ten-year conditional recurrence rates were calculated for every year from diagnosis for patients without an event (local (LR), regional recurrence (RR), distant metastasis (DM) or death). Ten-year conditional OS was calculated using multivariable Cox regression. RS was estimated by dividing patient survival rates by those of the general Dutch population. Results We included 7,969 patients: 52.3% had T1N0, 15.3% T1N1, 19.9% T2N0 and 12.5% T2N1 stage. For T1N0, 10-year LR rates changed from 4.6% at diagnosis to 0.5% in year 10. RR rates decreased from 2.3% to 0.2% and DM rates decreased from 7.8% to 0.6%. For T2N1 stage, the LR, RR and DM rates decreased from 6.2% to 0.8%, 5.2% to 0.4% and 19.6% to 1.5%, respectively. Of all patients, 1,702 patients (21.4%) had an unknown breast cancer subtype and were consequently excluded from the analyses according to subtype. Of the remaining 6,267 patients, 3,774 (60.2%) had luminal A, 1,465 (23.4%) had luminal B, 314 (5.0%) had HER2 positive and 714 (11.4%) had triple negative disease For the luminal A subtype, LR, RR and DM rates ranged from 3.9% to 0.4%, 1.7% to 0.5% and 7.3% to 1.1%, while for triple negative these rates ranged between 5.6% to 0.7%, 4.9% to 0.2% and 16.7% to 0%, respectively. Differences between subgroups attenuated over time and all recurrence rates became ≤1.5% in year 10. Ten-year OS and RS, adjusted for confounding, showed diminishing risk differences between subgroups over time. Conclusion Differences in recurrence rates, OS and RS between prognostic subgroups decreased as years passed by. These results highlight the importance of taking into account disease-free years to more accurately predict (ex-)breast cancer patients' prognosis over time. Citation Format: van Maaren MC, Strobbe LJ, Smidt ML, Moossdorff M, Poortmans PM, Siesling S. 10-year conditional recurrence risks, overall and relative survival for breast cancer patients in the Netherlands: Taking account of event-free years [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 P1-08-19.
Assisted dying: Association for Palliative Medicine responds
Authors: Iain Lawrie, Amy Proffitt, Derek Willis, Rob George
Journal: BMJ (2019)

As the world’s largest association representing doctors in palliative medicine, we (current officers of the Association for Palliative Medicine (APM)) are saddened and dismayed by the recent blog and opinion article in The BMJ .12 Anonymous pieces are the most difficult to respond to, as often the motives for the original piece are not obvious.

The Royal College of Physicians’ recent independent and anonymous poll about assisted dying confirms that, in line with the APM survey of 2014, 4% of palliative care physicians are in favour, 16% are undecided, and 80% remain opposed to medicine’s involvement in ending patients’ lives. …
Patterns of Texting and Driving in a US National Survey of Millennial Parents vs Older Parents
Authors: Jennifer Gliklich, Rie Maurer, Regan W. Bergmark
Journal: JAMA Pediatrics (2019)

Patterns of Texting and Driving in a US National Survey of Millennial Parents vs Older ParentsThe national US motor vehicle fatality rate has recently increased, with distracted driving being a potential underlying cause. 1 Texting and driving is prevalent, associated with an increased risk of motor vehicle crashes, 2 and more common among younger drivers. 3Millennials (born 19813 Millennials (born -1996)), 4 known for their significant cell phone and technology use, are becoming parents.Little is known about parent driving behavior associated with crash risk and the influence of such behavior on children's subsequent driving habits. 5The aim of this study was to characterize the texting and driving patterns of millennial vs older parents.
Expenditures and Health Care Utilization Among Adults With Newly Diagnosed Low Back and Lower Extremity Pain
Authors: Lily H. Kim, Daniel Vail, Tej D. Azad, Jason P. Bentley, Yi Zhang, Allen L. Ho, Paras Fatemi, Austin Feng, Kunal Varshneya, Manisha Desai, Anand Veeravagu, John K. Ratliff
Journal: JAMA Network Open (2019)

Low back pain (LBP) with or without lower extremity pain (LEP) is one of the most common reasons for seeking medical care. Previous studies investigating costs in this population targeted patients receiving surgery. Little is known about health care utilization among patients who do not undergo surgery.To assess use of health care resources for LBP and LEP management and analyze associated costs.This cohort study used a retrospective analysis of a commercial database containing inpatient and outpatient data for more than 75 million individuals. Participants were US adults who were newly diagnosed with LBP or LEP between 2008 and 2015, did not have a red-flag diagnosis, and were opiate naive prior to diagnosis. Dates of analysis were October 6, 2018, to March 7, 2019.Newly diagnosed LBP or LEP.The primary outcome was total cost of care within the first 6 and 12 months following diagnosis, stratified by whether patients received spinal surgery. An assessment was performed to determine whether patients who did not undergo surgery received care in accordance with proposed guidelines for conservative LBP and LEP management. Costs resulting from use of different health care services were estimated.A total of 2 498 013 adult patients with a new LBP or LEP diagnosis (median [interquartile range] age, 47 [36-58] years; 1 373 076 [55.0%] female) were identified. More than half (55.7%) received no intervention. Only 1.2% of patients received surgery, but they accounted for 29.3% of total 12-month costs ($784 million). Total costs of care among the 98.8% of patients who did not receive surgery were $1.8 billion. Patients who did not undergo surgery frequently received care that was inconsistent with clinical guidelines for LBP and LEP: 32.3% of these patients received imaging within 30 days of diagnosis and 35.3% received imaging without a trial of physical therapy.The findings suggest that surgery is rare among patients with newly diagnosed LBP and LEP but remains a significant driver of spending. Early imaging in patients who do not undergo surgery was also a major driver of increased health care expenditures. Avoidable costs among patients with typically self-limited conditions result in considerable economic burden to the US health care system.
Molecular Subtyping of Clinically Localized Urothelial Carcinoma Reveals Lower Rates of Pathological Upstaging at Radical Cystectomy Among Luminal Tumors
Authors: Yair Lotan, Stephen A. Boorjian, Jingbin Zhang, Trinity J. Bivalacqua, Sima P. Porten, Thomas Wheeler, Seth P. Lerner, Ryan Hutchinson, Franto Francis, Elai Davicioni, Robert S. Svatek, Chun-Liang Chen, Peter C. Black, Ewan A. Gibb
Journal: European Urology (2019)
So you think you know anatomy
Authors: Annabel Ferriman
Journal: BMJ (2012)

Discovering the anatomical drawings of Leonardo da Vinci for the first time is a bit like finding out that Lucian Freud was the man who unravelled the mysteries of DNA or that David Hockney was the pioneer of antibiotics.

It turns out that Leonardo, whom most of us know as the painter of the Mona Lisa and The Last Supper , was also the most advanced anatomist of his generation and of many generations to follow.

Among the firsts that Leonardo achieved was the first accurate depiction of the spine, the first descriptions of cirrhosis of the liver, and the first drawing of the appendix.

Sadly for him, his genius as an anatomist was never …
A different way to learn differentials
Authors: Michael Hallahan
Journal: BMJ (2011)

PicturingED—for iPhone, iPod Touch, and iPad

Available from the iTunes app store. Free

Rating: \**\*|\*

The days of learning medicine from textbooks alone are gone. Modern teaching techniques and the concept of individual learning styles have revolutionised education, and technology allows us to access these resources anywhere, anytime. PicturingED, a medical smartphone application, combines both superbly.

PicturingED aims to help medical students and …
Abstract P4-07-09: Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032
Authors: S Cocco, A Leone, G Buonfanti, MJ Sisalli, A Budillon, M De Laurentiis
Journal: Cancer Research (2019)

Abstract Abundant preclinical evidences indicate that stress-induced autophagy in tumor cells is predominantly cytoprotective and that inhibition of autophagy can enhance tumor cell death by diverse anticancer therapies. A major negative regulator of autophagy is the mammalian target of rapamycin (mTOR), activated downstream of PI3KAKT pathway. mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells, while the combination of PI3K-AKT/mTOR and autophagy inhibitors shown synergistic effect on increased apoptosis and reduced autophagy (Takeuchi H. 2005). This project aimed to characterize the role of autophagy in Breast Cancer models exposed to new potent Genentech PI3K/AKT inhibitors GDC0068 (Ipatasertib) and GDC0032 (Taselisib) currently in phase III clinical trials on TNBC and ER+ patients. However, the efficacy of PI3K/AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. In order to investigate the role of autophagy as possible mechanisms of resistance, Ipatasertib and Taselisib have been evaluated in breast cancer cell lines characterized by different receptors profile: TNBC, HER2/c-erb-2 and luminal A cell lines. Our results showed that both drugs are able to induce G1/S cell cycle block and increase of autophagy signaling measured by p62 level and LC3 II/LC3 I ratio and by the percentage of cells exhibiting LC3 positive puncta. In addition, apoptosis increase was also evaluated by measuring positive annexin V staining, by flow cytometry technique, and apoptosis markers, such as PARP and cleaved caspase 3, by immunoblot assay. Furthermore, the supplement of pharmacologic inhibitors of autophagy, such as hydroxichloroquine, were able to reduce cell viability evaluated by both short- and long-term assays in cell lines exposed to Ipatasertib and Taselisib. 3D breast cancer models are ongoing to confirm the synergic effect of PI3K/AKT inhibitors and hydroxychloroquine, in order to provide a new therapeutic combinatorial approach potentially translatable to patients. Citation Format: Cocco S, Leone A, Buonfanti G, Sisalli MJ, Budillon A, De Laurentiis M. Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032 [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 P4-07-09.
Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke
Authors: Henry Ma, Bruce C.V. Campbell, Mark W. Parsons, Leonid Churilov, Christopher R. Levi, Chung Hsu, Timothy J. Kleinig, Tissa Wijeratne, Sami Curtze, Helen M. Dewey, Ferdinand Miteff, Chon-Haw Tsai, Jiunn-Tay Lee, Thanh G. Phan, Neil Mahant, Mu-Chien Sun, Martin Krause, Jonathan Sturm, Rohan Grimley, Chih-Hung Chen, Chaur-Jong Hu, Andrew A. Wong, Deborah Field, Yu Sun, P. Alan Barber, Arman Sabet, Jim Jannes, Jiann-Shing Jeng, Benjamin Clissold, Romesh Markus, Ching-Huang Lin, Li-Ming Lien, Christopher F. Bladin, Søren Christensen, Nawaf Yassi, Gagan Sharma, Andrew Bivard, Patricia M. Desmond, Bernard Yan, Peter J. Mitchell, Vincent Thijs, Leeanne Carey, Atte Meretoja, Stephen M. Davis, Geoffrey A. Donnan
Journal: New England Journal of Medicine (2019)

The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.
Abstract P5-06-02: Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer
Authors: RE Ellsworth, PJ Kostyniak, L-H Chi, CD Shriver, NS Costantino, DL Ellsworth
Journal: Cancer Research (2019)

Abstract Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues — 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), hexachlorobenzene (HCB), and mirex — assayed by high resolution gas chromatography were abundant in breast tissue. p,p′-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p′-DDE and HCB were significantly correlated (P &amp;lt; 0.001) with patient age at mastectomy, and levels of p,p′-DDE were correlated (P &amp;lt; 0.05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government. Citation Format: Ellsworth RE, Kostyniak PJ, Chi L-H, Shriver CD, Costantino NS, Ellsworth DL. Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer [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 P5-06-02.
What are the biggest challenges international medical graduates face when starting work in the NHS?
Authors: Sophia Bourne
Journal: BMJ (2018)

Dear Sophia, what are the biggest challenges that international medical graduates face when starting work in the NHS?

Marcus Dawson, sixth year medical student, Medical University Sofia, Bulgaria

International medical graduates (IMGs) make a substantial contribution to healthcare in the United Kingdom. As of July 2017, over one third (37%) of doctors on the General Medical Council list of registered medical practitioners had gained their primary medical qualification outside the UK.1

Taking your first step on the career ladder in the UK is daunting for all medical graduates, and those who …
Author Correction: Developing and adopting safe and effective digital biomarkers to improve patient outcomes
Authors: Andrea Coravos, Sean Khozin, Kenneth D. Mandl
Journal: npj Digital Medicine (2019)

The original version of the published Article mistakenly omitted the second affiliation for the first Author, Andrea Coravos. The first Author’s affiliation has been updated to include Harvard-MIT Center for Regulatory Science, Boston, MA, USA. This has been corrected in the HTML and PDF version of the Article.
Human natural killer cells mediate adaptive immunity to viral antigens
Authors: Rana Nikzad, Laura S. Angelo, Kevin Aviles-Padilla, Duy T. Le, Vipul K. Singh, Lynn Bimler, Milica Vukmanovic-Stejic, Elena Vendrame, Thanmayi Ranganath, Laura Simpson, Nancy L. Haigwood, Catherine A. Blish, Arne N. Akbar, Silke Paust
Journal: Science Immunology (2019)

Adaptive immune responses are defined as antigen sensitization-dependent and antigen-specific responses leading to establishment of long-lived immunological memory. Although natural killer (NK) cells have traditionally been considered cells of the innate immune system, mounting evidence in mice and nonhuman primates warrants reconsideration of the existing paradigm that B and T cells are the sole mediators of adaptive immunity. However, it is currently unknown whether human NK cells can exhibit adaptive immune responses. We therefore tested whether human NK cells mediate adaptive immunity to virally encoded antigens using humanized mice and human volunteers. We found that human NK cells displayed vaccination-dependent, antigen-specific recall responses in vitro, when isolated from livers of humanized mice previously vaccinated with HIV-encoded envelope protein. Furthermore, we discovered that large numbers of cytotoxic NK cells with a tissue-resident phenotype were recruited to sites of varicella-zoster virus (VZV) skin test antigen challenge in VZV-experienced human volunteers. These NK-mediated recall responses in humans occurred decades after initial VZV exposure, demonstrating that NK memory in humans is long-lived. Our data demonstrate that human NK cells exhibit adaptive immune responses upon vaccination or infection. The existence of human memory NK cells may allow for the development of vaccination-based approaches capable of establishing potent NK-mediated memory functions contributing to host protection.