tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibition in elderly non-small cell lung cancer patients.
Authors: Kristen Marrone, Jiajia Zhang, Josephine Louella Feliciano, Patrick M. Forde, Christine L. Hann, Ronan Joseph Kelly, David S. Ettinger, Michelle Turner, Valerie Rowe, Sarah Bonerigo, Kellie Nicole Smith, Valsamo Anagnostou, Victor E. Velculescu, Julie R. Brahmer, Jarushka Naidoo
Journal: Journal of Clinical Oncology (2018)

137 Background: Age-related changes in the immune system are dynamic and complex. Use of anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer (NSCLC), with median patient age of 71, has rapidly become standard of care. Understanding how senescent remodeling of the immune system may affect outcomes with anti-PD-1/PD-L1 therapy is poorly understood. Although trends in phase III clinical trials of anti-PD-1/PD-L1 therapy suggest a potential lack of clinical efficacy in patients ≥ 75 years of age, the proportion of treated patients in this age range was low. The use and outcomes of these agents in this population treated in clinical practice has not been reported. Methods: The Johns Hopkins Upper Aerodigestive Diseases Malignancies and Immunotherapy Database was queried for all patients treated with anti-PD-1/PD-L1 agents as part of a clinical trial or as standard of care, from 2007 to 2017. Patients ≥ 75 years old were assessed for demographic, response, toxicity and survival data as of September 2017. Results: Of the 275 patients in our database, 144 NSCLC patients had received an anti-PD-1/PD-L1 agent alone or in combination with another immune checkpoint inhibitor (52%). Of those 144 patients, 20 patients were ≥ 75 years of age at time of anti-PD-1/PD-L1 therapy initiation (14%), with a median age of 81 years (range: 75-90). Of those 20 patients, 19 received anti-PD1 monotherapy (95%); 1 patient received combination anti-PD-1 with an anti-KIR. 14 of the 20 patients (70%) received therapy in second line or beyond; 6 received anti-PD-1 monotherapy as first line therapy. No significant difference in median survival for 1st line or ≥2nd line group was seen (12.7m vs 15.3m; p = 0.92). A median of 5.5 doses were administered (range 1-24). Reasons for off therapy included: progressive NSCLC (9; 45%), consent withdrawal (1; 5%) and adverse events (6; 30%) with 4 patients who remain on therapy (20%). Conclusions: Anti-PD-1/PD-L1 therapy is now standard of care in NSCLC, a malignancy of the elderly. Translational evaluation of how immune system senescent remodeling affects outcome and toxicity is needed. Further analysis of immunologic and genomic data will be presented and compared to the overall population in our database at the time of presentation.
Tumor-infiltrating lymphocytes in androgen receptor-positive, triple-negative breast cancer.
Authors: Roberto Antonio Leon-Ferre, Mei-Yin Polley, Heshan Liu, Victoria Cafourek, Judy Caroline Boughey, Krishna R. Kalari, Vivian Negron, Minetta C. Liu, James N. Ingle, Fergus Couch, Daniel W. Visscher, Matthew P. Goetz
Journal: Journal of Clinical Oncology (2018)

5 Background: Triple-negative breast cancer (TNBC) is an immunogenic breast cancer subtype, with a greater percentage of tumors containing tumor-infiltrating lymphocytes (TILs) compared to non-TNBC. TILs are prognostic for recurrence and predictive for chemotherapy benefit in TNBC, but not in estrogen receptor (ER)-positive tumors. A subset of TNBC expresses the androgen receptor (AR), and resembles ER-positive breast cancer in terms of demographics (older age) and clinical course (later recurrences that tend to involve bone). However, little is known regarding the association between TILs and AR expression in TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, patients who met criteria for TNBC (ER/PR &lt; 1% and HER2-negative) by centralized-pathology review were included as previously published [Leon-Ferre et al, Breast Cancer Res Treat 2017]. Stromal TILs in these tumors were quantified on full-face hematoxylin and eosin sections from the surgical specimen, following the 2014 TIL Working Group recommendations [Salgado et al, Ann Oncol 2014]. The expression of AR [EPR1535(2), Abcam] was scored as a continuous variable (1% increments), and categorized as absent (0%), low (1-25% ), low-moderate (26-50%) moderate (51-75%) and high (&gt; 75%) and correlated with TIL density. Results: 605 patients met criteria for TNBC. The median age was 56 years. Most tumors were T1-2 (95%), N0-1 (86%), and high grade (88%). The median stromal TIL content was 20% (0-90%). Tumor tissue was available for AR staining in 509/605 patients. 165 (32%) tumors expressed AR as follows: low: 12%, low-moderate: 7%, moderate: 5%, and high: 8%. Apocrine tumors (n = 30) expressed AR most frequently (86%) and at higher levels (AR high: 50%). For all 509 tumors, the median stromal TIL content according to AR expression was AR absent: 20%, AR low: 20%, AR low-moderate: 15%, AR high: 10%. AR and stromal TILs (both as continuous variables) demonstrated a weak inverse correlation (correlation coefficient -0.1064, p = 0.017). Conclusions: AR expression in TNBC is associated with lower levels of stromal TILs. Additional data correlating the AR, stromal TILs and outcomes in this cohort will be presented at the meeting.
I am due to finish my GP vocational training scheme in August 2006. I am interested in working in France for up to six months. How and where can I work in France without being fluent in French?
Authors: James Sherifi
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Sex Differences in the Presentation and Perception of Symptoms Among Young Patients With Myocardial Infarction
Authors: Judith H. Lichtman, Erica C. Leifheit, Basmah Safdar, Haikun Bao, Harlan M. Krumholz, Nancy P. Lorenze, Mitra Daneshvar, John A. Spertus, Gail D’Onofrio
Journal: Circulation (2018)

Background: Some studies report that women are less likely to present with chest pain for acute myocardial infarction (AMI). Information on symptom presentation, perception of symptoms, and care-seeking behaviors is limited for young patients with AMI. Methods: We interviewed 2009 women and 976 men aged 18 to 55 years hospitalized for AMI at 103 US hospitals participating in the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients). Structured patient interviews during the index AMI hospitalization were used to collect information on symptom presentation, perception of symptoms, and care-seeking behaviors. We compared patient characteristics and presentation information by sex. Multivariable hierarchical logistic regression was used to evaluate the association between sex and symptom presentation. Results: The majority of women (87.0%) and men (89.5%) presented with chest pain (defined as pain, pressure, tightness, or discomfort). Women were more likely to present with ≥3 associated symptoms than men (eg, epigastric symptoms, palpitations, and pain or discomfort in the jaw, neck, arms, or between the shoulder blades; 61.9% for women versus 54.8% for men, P &lt;0.001). In adjusted analyses, women with an ST-segment–elevation AMI were more likely than men to present without chest pain (odds ratio, 1.51; 95% confidence interval, 1.03–2.22). In comparison with men, women were more likely to perceive symptoms as stress/anxiety (20.9% versus 11.8%, P &lt;0.001) but less likely to attribute symptoms to muscle pain (15.4% versus 21.2%, P =0.029). Approximately 29.5% of women and 22.1% of men sought medical care for similar symptoms before their hospitalization ( P &lt;0.001); however, 53% of women reported that their provider did not think these symptoms were heart-related in comparison with 37% of men ( P &lt;0.001). Conclusions: The presentation of AMI symptoms was similar for young women and men, with chest pain as the predominant symptom for both sexes. Women presented with a greater number of additional non–chest pain symptoms regardless of the presence of chest pain, and both women and their healthcare providers were less likely to attribute their prodromal symptoms to heart disease in comparison with men.
Erythema Nodosum–like Eruption in the Setting of Sorafenib Therapy
Authors: Emily L. Coleman, Shawn E. Cowper, Stacey M. Stein, Jonathan S. Leventhal
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Use of Facebook and Twitter leads to 28 GMC complaints against doctors
Authors: Abi Rimmer
Journal: BMJ (2014)

Doctors’ use of the social networking websites Facebook and Twitter has led to 28 complaints to the General Medical Council since 2009, figures obtained by BMJ Careers have shown.

From 2009 to 2013 the GMC received 27 complaints about doctors that referred to Facebook and one about a doctor’s activity on Twitter. The GMC provided the data in response to a freedom …
NHS reform will be most difficult over next six months, says Lansley
Authors: Helen Jaques
Journal: BMJ (2012)

The next six months of transition to the new set up of clinical commissioning groups (CCGs) is going to be a “very tough time” for GPs, the health secretary for England, Andrew Lansley, has said.

Speaking at a conference in London for leaders of CCGs, Mr Lansley said that the period between the passing of the Health and Social Care Bill and its full implementation would be a difficult transition. 

“The mechanics of …
Abstract P4-03-13: Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance
Authors: Z Madak Erdogan, E Kulkoyluoglu
Journal: Cancer Research (2018)

Abstract The majority of breast cancer-specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are initially responsive to endocrine therapy yet become endocrine-resistant. There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway profiling, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tamoxifen (4-OH-Tam) and Selinexor (SXR), a highly selective XPO1 inhibitor that is currently in clinical trials for leukemia and prostate cancer, inhibited Akt phosphorylation by changing the phosphorylation status and localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that metabolic pathways and consequently metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and induce autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for combined targeting of ERα and XPO1 in the clinic to reduce cancer recurrences. Citation Format: Madak Erdogan Z, Kulkoyluoglu E. Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-13.
Activity of VERU-111, an novel oral α and β tubulin inhibitor, against paclitaxel sensitive and resistant prostate cancer.
Authors: Robert H. Getzenberg, James T. Dalton, Duane D. Miller, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2018)

302 Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.
What are the equivalent qualifications to MRCPsych? I have done my MD in psychiatry in India—am I eligible to apply for the post of specialist registrar in psychiatry?
Authors: Rahul Rao
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
Abstract P2-13-01: Differential efficacies of DNA damaging agents in basal-like TNBC subtypes
Authors: CV Shaffer, AJ Robles, AL Risinger, SL Mooberry
Journal: Cancer Research (2018)

Abstract New approaches are needed to improve long term survival for patients with metastatic triple negative breast cancer (TNBC). Women with metastatic TNBC have a worse 3-year survival compared to women with metastatic HER2+ or ER/PR+ disease.1 Identifying the molecular vulnerabilities of TNBC subtypes could provide for optimal treatment strategies. Gene expression analyses of TNBC patient samples by Lehmann and Bauer, et al. identified 6 subtypes of TNBC.2 Based on the analysis of laser dissected tumor samples, the number of tumor subtypes was reduced from 6 to 4.3 Both analyses identified two types of basal-like cancers, basal-like 1 (BL1) and basal-like 2 (BL2).2,3 The BL1 subtype is defined by the amplified expression of genes involved in cell division and DNA damage response, and RNA polymerase.2 BL2 cancers express high levels of genes involved in growth factor signaling, glycolysis, and gluconeogenesis.2 They show that cell lines representative of the BL1 and BL2 subtypes of TNBC are more sensitive to cisplatin than cell lines representing the other TNBC subtypes. The BL1 or BL2 categorization, however, failed to predict sensitivity to olaparib.2 BL1 and BL2 representative cell lines responded differently when treated with veliparib; BL1 cells were more sensitive than BL2 cells.2 We investigated the response of BL1 and BL2 cells to a variety of DNA damaging agents to determine if the BL1 or BL2 subtype was predictive of sensitivity to a particular drug. DNA damaging agents, including alkylating agents, anti-metabolites, topoisomerase inhibitors, and PARP inhibitors were tested in cells resenting the BL1 and BL2 subtypes. HCC1806 cells (BL2) were found to be selectively sensitive to gemcitabine when compared to HCC1937 cells (BL1). The panel of drugs and cell lines was expanded to further understand the sensitivity of BL1 and BL2 subtypes to a variety of DNA damaging agents. Our goal is to provide preclinical evidence for the informed use of specific DNA damaging agents in the treatment of patients with BL1 or BL2 subtypes of TNBCs. 1. Li, X. et al. Breast Cancer Res. Treat. 161, 279–287 (2017). 2. Lehmann, B. D. et al. J. Clin. Invest. 121, 2750–2767 (2011). 3. Lehmann, B. D. et al. PLoS One 11, e0157368 (2016). Citation Format: Shaffer CV, Robles AJ, Risinger AL, Mooberry SL. Differential efficacies of DNA damaging agents in basal-like TNBC subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-13-01.
ETIOLOGIES, TRENDS AND PREDICTORS OF EARLY READMISSION AFTER VENTRICULAR TACHYCARDIA ABLATION: AN ANALYSIS OF 4,614 PATIENTS
Authors: Charan Yerasi, Anil Kumar Jonnalagadda, Byomesh Tripathi, Sandeep Banga, Varun Miryala, Saifuldeen Al-Qaisi, Sina Nafisi, Anantharam Kalya
Journal: Journal of the American College of Cardiology (2018)
Physician assistants are not a “lifeline,” GPs say
Authors: Matthew Limb
Journal: BMJ (2016)

Physician assistants in primary care are not a “lifeline” to save general practice and will divert attention from the need for more GPs, local medical committees (LMCs) have said.

Delegates at a special BMA conference of LMCs were not persuaded that physician assistants were the solution to their workload concerns.

Roberta King, of Dorset LMC, argued that it would take many years to increase GP …
A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.
Authors: Izak Faiena, Nazy Zomorodian, Begonya Comin-Anduix, Ankush Sachadeva, Adrian Bot, Fariouz Kabinnivar, Jonathan W. Said, Gardenia Cheung-Lau, Jia Pang, Mignonette Macabali, Paula Cabrera, Paula Kaplan-Lefko, Beata Berent-Maoz, Sandy Liu, Allan J. Pantuck, Arie S. Belldegrun, Karim Chamie, Alexandra Drakaki
Journal: Journal of Clinical Oncology (2018)

653 Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF &amp; IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses &amp; antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.
New pension arrangements could force general practices to cap locum use, warns BMA
Authors: Helen Jaques
Journal: BMJ (2013)

Changes to pension regulations that require general practices to pay the employers’ element of locum GPs’ pension contributions could limit practices’ ability to employ locums, the BMA has warned.

From 1 April general practices in England will receive a 0.15% increase in their annual global sum payment that they will be expected to give to the locum GPs they employ. Locums will use this money to pay the 14% employer superannuation element of their pension contributions to the NHS Commissioning Board, which will pass the money on to the NHS Pension Scheme administrator.

Previously the employer element of locum doctors’ pension contributions …