tbuckley/cabot-search huggingface dataset:
PSMA heterogeneity analysis in patients with metastatic castrate-resistant prostate cancer (mCRPC): Imaging versus CTCs.
Authors: Michael J. Morris, Nicholas J. Vogelzang, A. Oliver Sartor, Alison A. Armour, Richard Adam Messmann, Michael Groaning, Adam Robarts, Anthony W. Tolcher, Michael S. Gordon, Hani M. Babiker, Phillip Kuo, Megan Kearney, Adam Jendrisak, Yipeng Wang, Mark Andrew Landers, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2018)

272 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, making it an ideal imaging and therapeutic target of interest. The utility of the PSMA-targeted imaging agent 99m Tc-EC0652 is being evaluated, along with biomarker analysis of circulating tumor cells (CTCs), in pts with mCRPC in a PSMA-targeted chemotherapeutic study. We now report the PSMA heterogeneity via CTC vs. imaging in the pt population treated to date. Methods: Patients were enrolled in 1 of 2 cohorts: mCRPC taxane naïve or taxane exposed. A total of 48 pts evaluated at the time of the data cut had baseline CT &amp; bone scans performed in addition to a 99m Tc-EC0652 SPECT/CT as a measure of imaging-based PSMA expression. 40 of 48 pts provided pre-treatment blood samples evaluable for CTC biomarker analysis, which included PSMA expression &amp; were given percent homologous recombination deficiency (%HRD) scores. Four of the best and four of the worst responders were evaluated in more detail for imaging and CTC-based biomarker analysis as it related to clinical outcome. Results: 35 of 40 pts (88%) had detectable CTCs in their samples. 15 of the 35 (43%) pts had PSMA-positive CTCs. The 4 “non-responders” were on study for an average of 41 days and the 4 “responders” for an average of 256 days. Each group contained 2 taxane exposed &amp; 2 taxane naïve patients. Of the 335 bone lesions analyzed by MDP, CT, 99m Tc-EC0652, 333 (99.4%) were characterized as PSMA pos based on their 99m Tc-EC0652 SPECT/CT scan. Of the 26 soft tissue lesions analyzed by CT, all were characterized as PSMA pos based on their 99m Tc-EC0652 SPECT/CT scan. Seven (26.9%) of those lesions were CT positive (observed on CT scan). Each group had 2 pts that were CTC-based PSMA pos &amp; 2 that were PSMA neg . Their percent homologous recombination deficiency (%HRD) scores were of 0.60 [0.333, 1.0] for “non-responders” &amp; 0.01 [0.0, 0.039] for “responders”. Conclusions: PSMA-based imaging showed a high percentage of positive lesions whereas CTC-based PMSA positivity is lower by comparison (43%). The discordance between the imaging results &amp; CTC-based biomarkers, &amp; the relative therapeutic predictive value, requires additional exploration. Clinical trial information: NCT02202447.
Signaling function of PRC2 is essential for TCR-driven T cell responses
Authors: Marc-Werner Dobenecker, Joon Seok Park, Jonas Marcello, Michael T. McCabe, Richard Gregory, Steven D. Knight, Inmaculada Rioja, Anna K. Bassil, Rabinder K. Prinjha, Alexander Tarakhovsky
Journal: The Journal of Experimental Medicine (2018)

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell-driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases.
HIGHER QUANTITATIVE PERICARDIAL DELAYED HYPERENHANCEMENT IN PATIENTS WITH RECURRENT PERICARDITIS AFTER A YEAR OF MEDICAL THERAPY IS ASSOCIATED WITH FREQUENT RELAPSES
Authors: Beni Rai Verma, Chandra Ala, Kimi Sato, Arnav Kumar, Vivek Menon, Rory Hachamovitch, Deborah Kwon, Allan Klein
Journal: Journal of the American College of Cardiology (2018)
Guideline: USPSTF recommends against menopausal estrogen for primary prevention of chronic conditions
Authors: Susan M. Ott
Journal: Annals of Internal Medicine (2018)

Source Citation US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318:2224-33. 29234814
Prevention of Contrast-Associated Acute Kidney Injury
Authors: Mitchell H. Rosner
Journal: New England Journal of Medicine (2018)

Contrast-associated acute kidney injury signifies a severe and usually reversible decline in kidney function that may develop within 72 hours after intravascular administration of iodinated contrast material.1 The condition is usually defined as an increase in the serum creatinine level of more than 0.5 mg per deciliter (44 μmol per liter) or an increase of at least 25% in the level from baseline. Contrast-associated acute kidney injury occurs most commonly after contrast-enhanced computed tomography, coronary angiography, or percutaneous coronary interventions, circumstances in which the volume of contrast material that is administered is large or the administration is intraarterial. The incidence . . .
Clinical impact of tumour-infiltrating B-cells in periampullary adenocarcinoma in relation to adjuvant chemotherapy.
Authors: Sebastian Lundgren, Richard Fristedt, Jacob Elebro, Emelie Karnevi, Bjorn Nodin, Carl Fredrik Warfvinge, Patrick Micke, Jakob Eberhard, Bobby Tingstedt, Karin Jirstrom
Journal: Journal of Clinical Oncology (2018)

330 Background: The prognostic significance of tumour-infiltrating lymphocytes of the B lineage in solid cancers has only recently begun to receive attention. Herein, we explored the relationship between B cell and plasma cell density and survival in patients with periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological type. Methods: Immunohistochemistry was applied to quantify the abundance of B cells (CD20+), and plasma cells (CD138+) in tissue microarrays with tumours from a retrospective consecutive cohort of 175 patients who had undergone pancreaticoduodenectomy for periampullary adenocarcinoma. Cox regression was applied to calculate univariable and multivariable hazard ratios (HR) for recurrence and death within five years up until March 2017. Multivariable HRs were adjusted for established clinical parameters. Results: High CD20+ cell density was an independent prognostic factor for a prolonged overall survival in both intestinal-type (HR 0.32; 95% CI 0.12-0.86) and pancreatobiliary-type (HR 0.38; 95% CI 0.23-0.66) tumours. CD138+ was an independent prognostic factor in pancreatobiliary-type tumours (HR 0.51; 95% CI 0.32-0.82) only. A significant positive interaction was seen between adjuvant chemotherapy and CD20+ cells in relation to OS for PB-type tumours (p interaction = 0.027). Conclusions: These results demonstrate that dense infiltration into the tumour by cells of the B lymphocyte lineage confers an improved prognosis in periampullary adenocarcinoma including pancreatic cancer. The impact of B cells in the local anti-tumour response is gradually being unravelled, and their potential influence on adjuvant chemotherapy response in the more aggressive pancreatobiliary-type tumours may be clinically relevant and merits further study.
STRAIN ECHOCARDIOGRAPHY PREDICTS DIFFERENCES IN OUTCOMES BETWEEN TRANSAPICAL AND TRANSFEMORAL TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Mirette Fahim, Cristina Pislaru, Vuyisile Nkomo, Patricia Pellikka, Ahmed Elamragy, Mera Fahim, Hesham Taha, Mackram Eleid, Kevin Greason, Sorin Pislaru
Journal: Journal of the American College of Cardiology (2018)
Nationwide analysis of genitourinary expert opinions on active surveillance for localized prostate cancer.
Authors: Shearwood McClelland, Kiri A Sandler, Catherine Degnin, Yiyi Chen, Timur Mitin
Journal: Journal of Clinical Oncology (2018)

29 Background: The ProtecT trial has provided Level 1 evidence supporting active surveillance for prostate cancer patients with low-risk and intermediate risk disease. The impact of these findings on the opinions of North American genitourinary (GU) experts regarding the role of active surveillance for these patients has not been previously examined. Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to knowledge about and personal opinions on the role of active surveillance in patients with low-risk and intermediate-risk (Gleason 3+4) disease. Opinions regarding active surveillance were correlated with practice patterns using Fisher’s exact test. Results: Analysis was conducted on 42 radiation oncologist respondents. Forty percent have been in practice for 20+ years; 90% practice at an academic center. Forty-five percent see 20+ patients/month in consultation. More than 95% recommended active surveillance for Gleason 6 disease, while only 17% recommended active surveillance for Gleason 3+4 disease. There were no significant demographic differences between supporters or opponents of active surveillance regarding monthly patient volume, practice type, self-identification as an expert brachytherapist, belief in advanced imaging techniques, or preferred default EBRT dose/fractionation for low-risk or intermediate-risk disease. However, opposition to active surveillance for Gleason 3+4 disease approached significance for experts having practiced 10+ years versus &lt; 10 years (p = 0.085). Conclusions: Active surveillance is well-regarded among North American GU experts for low-risk but not intermediate-risk prostate cancer, despite the results of the ProtecT trial providing Level 1 evidentiary support for active surveillance in both risk groups. There were no significant differences between experts supporting versus opposing active surveillance for either low-risk or intermediate-risk disease. These preferences may affect the design of future clinical studies, influencing the adoption of active surveillance in North American clinical practice.
Liposomal Grb2 antisense oligodeoxynucleotide (BP1001) in patients with refractory or relapsed haematological malignancies: a single-centre, open-label, dose-escalation, phase 1/1b trial
Authors: Maro Ohanian, Ana Tari Ashizawa, Guillermo Garcia-Manero, Naveen Pemmaraju, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gautam Borthakur, Michael Andreeff, Marina Konopleva, Miranda Lim, Sherry Pierce, Susan O'Brien, Yesid Alvarado, Srdan Verstovsek, William Wierda, Hagop Kantarjian, Jorge Cortes
Journal: The Lancet Haematology (2018)
GPs are spending several days a week on CCG duties
Authors: Helen Jaques
Journal: BMJ (2012)

General practitioners on the boards of clinical commissioning groups are spending up to four days a week setting up their organisation, show data obtained under the Freedom of Information Act.

In three areas of England GPs who are board members of clinical commissioning groups are spending up to four days a week setting up the commissioning group, show the findings from the research organisation …
Only five in 1000 doctors prompt performance concerns
Authors: Caroline White
Journal: BMJ (2013)

Just five in every 1000 NHS doctors prompt concerns about their performance that are sufficient to warrant outside help, analysis of 11 years of data has indicated.1

However, doctors who are in the late stages of their career are six times more likely to be referred for remedial help than those at earlier stages, the analysis shows.

The findings, published in BMJ Quality & Safety , are based on analysis of referrals of NHS doctors in England by employing organisations and by doctors themselves to the National Clinical Assessment Service (NCAS). The data cover the period from April 2001, when NCAS was established, to March 2012.

Over the 11 years, 6179 doctors …
GMC is creating climate of fear, GPs say
Authors: Abi Rimmer
Journal: BMJ (2015)

The General Medical Council is creating a climate of fear, delegates at the BMA’s Local Medical Committees (LMCs) conference in London on Friday 22 May said. Delegates voted unanimously for a motion saying that the regulator had created a climate in which “doctors practise in fear for their registration.”

The motion demanded that GPs who were being investigated for alleged misdemeanours by the GMC were …
Signet ring cell gastric carcinoma: A descriptive analysis of a unique county population.
Authors: Mital Patel, Neha Patel, James H. Tabibian, Nora Ostrzega
Journal: Journal of Clinical Oncology (2018)

32 Background: Signet ring cell type gastric carcinoma (SRCC) is an uncommon epithelial malignancy of the stomach, with data from the United States (US) being particularly scarce. Compared to other gastric carcinoma types, it has a female predominance, younger age at diagnosis, and late presentation, making treatment particularly challenging. Recent reports suggest this disease may be increasing among even younger patients, for reasons which remain unclear. We aimed to examine the occurrence, features, and outcomes of SRCC in a predominantly minority Los Angeles County patient population. Methods: We identified all patients diagnosed with SRCC at Olive View-UCLA Medical Center (OVMC) from 2004-2017. Clinico-demographic, imaging, and pathologic data were reviewed and analyzed and compared descriptively to available Surveillance, Epidemiology, and End Results (SEER) data. Results: Sixty-six cases of SRCC were identified, of which 77% were Latino, 9% White, 6% Armenian, and the remaining 8% other. Mean age at SRCC diagnosis was 52 years, and 37 (56%) of patients were female. H. pylori infection was present in 35% (43% diagnosed by serum antibody, 35% by pathology, 9% by stool antigen, and 13% by combination). Follow-up was available for 91% of patients. Median survival was 1 year, and 5-year survival was 7%, markedly lower than the 31% reported in SEER. Seventy-two percent of patients were deceased or on hospice within 2 years of diagnosis. Conclusions: In this first US study to assess the clinical epidemiology of SRCC in a predominantly minority population: 1) the mean age of diagnosis was younger than reported in previous studies (55-61 years), 2) the proportion of males was high compared to SEER data, and 3) survival was considerably lower than previously reported. Insofar as the patient population in this study serves as a microcosm of surrounding underserved communities, it is likely that SRCC may be more common than expected in this vulnerable patient population, and that significant clinical differences may exist in presentation and outcomes of SRCC. In light of these differences, further research is needed to examine potential environmental and/or genetic risk factors or disparities which may be operational.
RCSEng Training the Trainers
Authors: Daniel Westacott
Journal: BMJ (2011)

The Training the Trainers course is organised by the Royal College of Surgeons of England and run at various locations in the United Kingdom. This report concerns the course run at the Welsh Institute for Minimal Access Therapy in Cardiff. The course takes place over two consecutive days.

The course is targeted at specialty trainees in years 3-8 and consultants who are interested in improving their teaching technique and understanding the principles behind teaching, learning, and the potentially testing relationship between trainer and trainee.

As a senior house officer, I found myself delivering small group teaching to undergraduates and foundation doctors and wanted to be able to plan and deliver these sessions more effectively. Furthermore, …
CORRELATION BETWEEN TRANSTHORACIC ECHOCARDIOGRAPHY AND CARDIAC MAGNETIC RESONANCE IMAGING IN THE ASSESSMENT OF LEFT VENTRICULAR FUNCTION IN PATIENTS WITH REPAIRED TETRALOGY OF FALLOT
Authors: Tam Doan, Shailendra Upadhyay, Ji Hyun Lee, Brooke Davey, Olga Toro-Salazar
Journal: Journal of the American College of Cardiology (2018)
Oxidative Phosphorylation as an Emerging Target in Cancer Therapy
Authors: Thomas M. Ashton, W. Gillies McKenna, Leoni A. Kunz-Schughart, Geoff S. Higgins
Journal: Clinical Cancer Research (2018)

Abstract Cancer cells have upregulated glycolysis compared with normal cells, which has led many to the assumption that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma, and endometrial carcinoma, and that this can occur even in the face of active glycolysis. OXPHOS inhibitors could therefore be used to target cancer subtypes in which OXPHOS is upregulated and to alleviate therapeutically adverse tumor hypoxia. Several drugs including metformin, atovaquone, and arsenic trioxide are used clinically for non-oncologic indications, but emerging data demonstrate their potential use as OXPHOS inhibitors. We highlight novel applications of OXPHOS inhibitors with a suitable therapeutic index to target cancer cell metabolism. Clin Cancer Res; 24(11); 2482–90. ©2018 AACR.
Expression of immune genes and a signature of PD-1 inhibition resistance in basal-like pancreatic adenocarcinoma (PDAC) subtypes.
Authors: Ranjit Joseph, Kyla Collins, Dante S. Bortone, Benjamin Garrett Vincent, Jen Jen Yeh, Autumn Jackson McRee
Journal: Journal of Clinical Oncology (2018)

277 Background: PDAC is a lethal disease with poor survival even when detected at an early stage. Recurrence rates after surgical resection remain high. Recently, two distinct molecular subtypes of PDAC (basal-like and classical) have been identified with basal-like tumors demonstrating inferior outcomes. We hypothesize that differences in tumor immunogenicity may contribute to this aggressive biology and predict response to immune checkpoint inhibitors. Methods: RNA sequencing was performed on formalin-fixed paraffin embedded samples of 60 resected PDAC patients. We evaluated previously published immune gene expression signatures comprised of 1400 genes and used a single sample classifier to determine molecular subtypes. Results: Table 1 summarizes patient characteristics in our cohort. There were 35 classical and 25 basal-like tumors. PFS was significantly shorter in patients with basal-like compared to classical subtypes (9 vs 15 mo, p = 0.006). In a multivariable model with molecular subtype, lymph node and margin status, subtype was the only independent predictor of PFS (p=0.028). Unsupervised clustering identified two distinct immune groups that were associated with molecular subtypes (p=0.038) with higher expression of immune genes in basal-like tumors. Basal-like tumors were significantly associated with an immunosuppressive signature (p&lt;0.001) and a signature associated with non-response to PD-1 inhibition in melanoma (p=0.001). Conclusions: This is the first study to show that basal-like pancreatic cancers are associated with increased immune gene expression and may help explain their inferior prognosis. We hypothesize that this reflects an increase in immunosuppressive cells in basal-like tumors that may predict decreased response to immune check point inhibitors. [Table: see text]
“Frictionless trade” of drugs must continue after Brexit, warn European organisations
Authors: Rory Watson
Journal: BMJ (2018)

Over a dozen pan-European healthcare organisations are warning the UK and the EU that Brexit will be highly damaging to the care of patients and the wider medical sector if negotiators fail to tackle key concerns.

The organisations, which range from the European Brain Council to the European Federation of Pharmaceutical Industries and Associations, sent a five point statement setting out their concerns to EU health ministers last December. The statement focused on access to drugs, research collaboration, reciprocal healthcare arrangements, cooperation on pandemics, and professional training and education.

As the Brexit negotiations entered a critical phase, the organisations met in Brussels on 21 February to …
IMPACT OF HIGH-SENSITIVITY C-REACTIVE PROTEIN ON 5-YEAR CLINICAL OUTCOMES IN PATIENTS WITH CHRONIC TOTAL OCCLUSION LESION
Authors: Seung-Woon Rha, Jae Kyeong Byun, Byoung Geol Choi, Se Yeon Choi, Ahmed Mashaly, Yoonjee Park, Won Young Jang, WooHyeun Kim, Eun Jin Park, Ja Yeon Choi, Jin Oh Na, Cheol Ung Choi, Hong Euy Lim, Eung Ju Kim, Chang Gyu Park, Hong-Seog Seo, Dong Joo Oh
Journal: Journal of the American College of Cardiology (2018)
Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy
Authors: Daniel Kotlarz, Benjamin Marquardt, Tuva Barøy, Way S. Lee, Liza Konnikova, Sebastian Hollizeck, Thomas Magg, Anna S. Lehle, Christoph Walz, Ingo Borggraefe, Fabian Hauck, Philip Bufler, Raffaele Conca, Sarah M. Wall, Eva M. Schumacher, Doriana Misceo, Eirik Frengen, Beint S. Bentsen, Holm H. Uhlig, Karl-Peter Hopfner, Aleixo M. Muise, Scott B. Snapper, Petter Strømme, Christoph Klein
Journal: Nature Genetics (2018)
MORTALITY IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST UNDERGOING A STANDARDISED PROTOCOL INCLUDING THERAPEUTIC HYPOTHERMIA
Authors: Andreas Schaefer, Florian Zauner, Jan-Thorben Sieweke, Joern Tongers, L. Christian Napp, Jens Treptau, Ulrike Flierl, Johann Bauersachs
Journal: Journal of the American College of Cardiology (2018)