tbuckley/cabot-search huggingface dataset:
Foretinib Overcomes Entrectinib Resistance Associated with the <i>NTRK1</i> G667C Mutation in <i>NTRK1</i> Fusion–Positive Tumor Cells in a Brain Metastasis Model
Authors: Akihiro Nishiyama, Tadaaki Yamada, Kenji Kita, Rong Wang, Sachiko Arai, Koji Fukuda, Azusa Tanimoto, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Noritaka Furuya, Takayoshi Kinoshita, Seiji Yano
Journal: Clinical Cancer Research (2018)

Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1 The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation.Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases. Clin Cancer Res; 24(10); 2357-69. ©2018 AACR.
Myasthenia gravis and Guillain-Barré syndrome adverse events with immune checkpoint inhibitors.
Authors: Catherine R. Garcia, Jessica N Cox, John L. Villano
Journal: Journal of Clinical Oncology (2018)

37 Background: Immune checkpoint inhibitors (ICI) have provided landmark breakthrough achieving success in prolonging survival in multiple cancer types. As a new class of therapy immune related serious adverse drug reactions (sADRs) have had limited reporting. This includes neurologic based, with reports limited to clinical trials and case-based. Ours is the largest database analysis to date reporting neurological adverse events after ICI therapy. Methods: We analyzed the FDA Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, and ipilimumab two years prior their FDA approval to September 2017, to include all cases reported with Guillain-Barré syndrome (GBS), Myasthenia gravis, ocular myasthenia, and myasthenic syndrome after the usage of ICI. Results: A total 35,726 cases were reported in FAERS. We identified a total of 263 cases of which 121 (46%) were GBS, 112 (42.6%) myasthenia gravis, 22 myasthenic syndrome (8.4%), and 8 (3%) ocular myasthenia. The mean age in our study was 66 years, with 63% being male. The majority of the cases were reported in the United States (49%), followed by Japan (10%), France (6%), and Australia (5.7%). Over 30% of patients presented more than one significant symptom. Around 20% of these patients were taking more than one immune checkpoint inhibitor, combining ipilimumab with either nivolumab or pembrolizumab. A significantly higher proportion of patients with GBS taking more than one ICI (28.1%, p = 0.013). Nivolumab was the most common ICI in patients with myasthenia gravis, myasthenic syndrome, and ocular myasthenia, while ipilimumab was the most common in patients with GBS. Sixty four percent of these patients required hospitalization, 17% were reported as life threatening events, 7% resulted in disability, and 22% died. Conclusions: Neurological adverse events associated with ICI are relatively uncommon, but can have serious clinical consequences. Recognizing and detailing neurological immune syndromes in relation to ICI therapy are essential in the oncological and neurological practice due to the growing usage of these agents in cancer treatment.
Experience of a single “epileptic” fit
Authors: David Parkins
Journal: BMJ (2004)

<i>There seem to be no hard and fast rules about what specialties doctors with epilepsy, or those who experience a single grand mal seizure, should go in for. Although</i> David Parkins9s <i>experience was over 20 years ago, many doctors in a similar position are still dictated to about what they can and cannot do, with little evidence base to back up these decisions</i>
Proportion of trainees going straight to specialty training fell again this year
Authors: Abi Rimmer
Journal: BMJ (2013)

The proportion of doctors in training who moved straight from the foundation programme into specialty training fell again in 2013.

Figures from the UK Foundation Programme Office show that the proportion of foundation year 2 doctors who moved into a specialty training post in August 2013 was 64%, down from 67% in 2012 and 71% in 2011.

The proportion still seeking employment as a doctor in the UK …
BASELINE NUTRITIONAL STATUS PREDICTS LONG-TERM AMPUTATION-FREE SURVIVAL IN PATIENTS UNDERGOING ENDOVASCULAR THERAPY
Authors: Keiko Mizobuchi, Kentaro Jujo, Yuichiro Minami, Issei Ishida, Shintaro Haruki, Hiromu Kadowaki, Kazuki Tanaka, Madoka Akashi, Motoko Kametani, Masashi Nakao, Jyunichi Yamaguchi, Nobuhisa Hagiwara
Journal: Journal of the American College of Cardiology (2018)
Patient safety must be greater priority than doctors’ freedom of movement, GMC says
Authors: Ingrid Torjesen
Journal: BMJ (2012)

Patient safety must take precedence over the right of doctors to work in other countries in Europe, the General Medical Council has said.

The GMC made its position clear after a council meeting earlier this week to discuss proposed changes to European Union law governing how doctors and other professionals move around the European Economic Area (EEA) to work.

The EU’s Recognition of Professional Qualifications Directive is designed to support the free movement of doctors …
How can I find more information on career opportunities in allied areas such as medical ethics or medical law?
Authors: Catriona Richardson
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>
Adenoviral E1A-Associated Protein p300 Is Involved in Acute Myeloid Leukemia With t(11; 22)(q23; q13)
Authors: Kohmei Ida, Issay Kitabayashi, Tomohiko Taki, Masafumi Taniwaki, Keiko Noro, Masao Yamamoto, Misao Ohki, Yasuhide Hayashi
Journal: Blood (1997)
Management of Gait Impairments in Chronic Unilateral Upper Motor Neuron Lesions
Authors: Jorik Nonnekes, Nathalie Benda, Hanneke van Duijnhoven, Frits Lem, Noël Keijsers, Jan Willem K. Louwerens, Allan Pieterse, Bertjo Renzenbrink, Vivian Weerdesteyn, Jaap Buurke, Alexander C. H. Geurts
Journal: JAMA Neurology (2018)

Gait impairments are common in patients with chronic supratentorial upper motor neuron lesions and are a source of disability. Clinical management aimed at improving the gait pattern in these patients is generally perceived as a challenging task because many possible abnormalities may interact. Moreover, a multitude of treatment options exist, ranging from assistive devices and muscle stretching to pharmacologic and surgical interventions, but evidence is inconclusive for most approaches and clear treatment guidelines are lacking.Gait deviations in adults with a chronic supratentorial upper motor neuron lesion can approximately be reduced to the following 3 groups of primary deficits: (1) imbalance of muscle strength, length, and activity around the ankle and tarsal joints leading to pes equinovarus or pes equinus; (2) calf muscle weakness; and (3) overactivity of proximal leg muscles.A stepwise treatment algorithm emphasizes medical-technical interventions, which are based on evidence when available and otherwise reflect practice-based experience.
Overseas doctors warning
Authors: Jayaprakash A Gosalakkal
Journal: BMJ (2005)

EDITOR—Peter Trewby has brought this debate to the mainstream.1 I notice, however, that another of his articles was published a year ago. Has anything changed since then? Not a lot, it seems from the heart rending stories we have been hearing in our ethnic minority discussion groups. I am against such drastic measures as stopping the Professional and Linguistic Assessments Board (PLAB) tests, which some seem to be advocating. I can understand the emotional reasons for making such a demand, but it does have the …
What hoops does a fully qualified UK general practitioner have to jump through to work as a fully qualified family practitioner in the United States?
Authors: Zain Khalpey
Journal: BMJ (2004)

Have a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone ([www.bmjcareers.com/advicezone][1]) 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. [1]: http://www.bmjcareers.com/advicezone
High salaries and drug costs push US health spending above 10 comparable nations
Authors: Janice Hopkins Tanne
Journal: BMJ (2018)

The United States spends nearly twice as much as 10 similar countries on healthcare because of high salaries for doctors and nurses, costly drugs, and high administrative costs, a study published in JAMA has found.1

The reasons often blamed for high US spending—more use of health services, too many specialists, too much in-hospital care, insufficient social services, and low quality of care—were not the culprits.

The study, by researchers from the London School of Economics (UK), Harvard University Global Health Institute (USA), and Harvard School of Public Health (USA), compared the US with 10 other high income countries: the United Kingdom, Canada, Germany, Australia, Japan, Sweden, France, the Netherlands, Switzerland, and Denmark. They used …
WPA‐WHO Africa Mental Health Forum – recommendations and position statement
Authors: Bernard Janse van Rensburg, Dinesh Bhugra, Shekhar Saxena
Journal: World Psychiatry (2018)

The WPA Action Plan 2017-20201 has been released by H. Herrman, new WPA President, during the recent World Congress of Psychiatry in Berlin. An agreement that could assist in achieving the objectives of that Action Plan in an African context has been produced during the WPA-World Health Organization (WHO) Africa Mental Health Forum meeting that took place in November 2016 in Cape Town, South Africa. In particular, the agreement can be helpful with regard to the Action Plan's enabling activities, aimed at supporting psychiatrists to promote mental health and improve care capacity, and its partnership and collaboration activities, aimed to expand the reach and effectiveness of partnerships with service providers, service beneficiaries and policy makers. From the vision stated by M. Moeti in her presentation, the proceedings and the concluding remarks by the co-chairs of the Forum, the following position statement was drafted on a continental alliance for integrated mental health care in Africa: In order to achieve the communicated vision, objectives and targets for achieving the potential of mental health for all and integrated mental health care in Africa, we will need to work together with collective strength and active collaboration. Such an alliance for integrated mental health care in Africa, with emphasis on public mental health, includes: individual and collective psychiatrists, as well as all members of the multidisciplinary mental health team (psychologists, nurses, social workers, occupational therapists); other health professionals in primary and specialist health care; community mental health workers and self-help resources; our patients and their families; the public at large through the media; training institutions; as well as governments’ Ministries of Health and private service providers of mental health care services. While different countries and groups may have different entry points, strengthening of this alliance must be sought within countries nationally, provincially and locally, but also on subcontinental and continental levels. The full report on the Forum can be obtained from the WPA website. Bernard Janse van Rensburg1, Dinesh Bhugra2, Shekhar Saxena3 1President, South African Society of Psychiatrists; 2WPA Immediate Past-President; 3Director, WHO Department of Mental Health and Substance Abuse
Abstract P6-09-06: The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast: An analysis from the National cancer data base
Authors: GD Lewis, Y Xing, T Patel, M Schwartz, AA Rodriguez, AC Chen, A Farach, SS Hatch, EB Butler, JC Chang, BS Teh
Journal: Cancer Research (2018)

Abstract Purpose/Objectives: Invasive micropapillary carcinoma (IMPC) is an uncommon variant of breast cancer, accounting for &amp;lt;2% of all cases. Previous studies demonstrated that this subtype often presents with hormone receptor (HR) positive disease, resulting in survival outcomes similar to invasive ductal carcinoma. However, many of these studies were conducted prior to the availability of HER2 testing. In this study, we aim to determine the impact of molecular marker status (including HER2 status) on survival outcomes of invasive micropapillary carcinoma. Materials/Methods: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven IMPC diagnosed from 2007-2012. Only patients with known estrogen receptor (ER) status, progesterone receptor (PR) status and HER2 status were included in the analysis. Cox multivariate regression was used to determine prognostic factors. Results: Overall, 865 patients met inclusion criteria. The median follow-up was 2.5 years. Out of all patients, 651 (75.3%) had HR+, HER2 negative disease, 128 (14.8%) had HR+, HER2+ disease, 41 (4.7%) had HR negative, HER2+ disease, and 45 (5.2%) had triple negative disease. Patients with triple negative disease were more likely to have poorly differentiated/undifferentiated histology (66.7%), lymphovascular invasion (73.3%), stage 3 disease (37.8%), undergone mastectomy (68.9%), and positive surgical margins (15.6%). On Cox multivariate regression, those with triple negative disease had worse overall survival (hazard ratio 7.28, P&amp;lt;0.001). Other prognostic factors associated with worse overall survival included African American descent (hazard ratio 2.24, P=0.018), comorbidity score of 1 (hazard ratio 2.50, P=0.011), comorbidity score ≥2 (hazard ratio 3.27, P=0.06), and ≥3 positive lymph nodes (hazard ratio 3.23, P=0.007). Conclusions: Similar to invasive ductal carcinoma, triple negative disease in invasive micropapillary carcinoma results in worse survival outcomes. This is the largest and first study to characterize molecular status (including HER2 status) in IMPC patients, as well as its impact on survival outcomes. Citation Format: Lewis GD, Xing Y, Patel T, Schwartz M, Rodriguez AA, Chen AC, Farach A, Hatch SS, Butler EB, Chang JC, Teh BS. The impact of molecular status on survival outcomes for invasive micropapillary carcinoma of the breast: An analysis from the National cancer data base [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 P6-09-06.
The age of adolescence…and young adulthood
Authors: Janet E McDonagh, Anne-Emmanuelle Ambresin, Kirsten Arntz Boisen, Helena Fonseca, Pia Jakobsson Kruse, Anne Meynard, Susanne Stronski, Pierre-Andre Michaud, Yusuke Leo Takeuchi
Journal: The Lancet Child & Adolescent Health (2018)
Immune checkpoint molecule expression measured using circulating cell-free RNA isolated from the blood of metastatic prostate cancer patients.
Authors: Kanthi Athreya Kollengode, Erwin Grussie, Genevieve Danenberg, Joshua L. Usher, KATHLEEN DANENBERG, Peter Danenberg, Jacek K. Pinski
Journal: Journal of Clinical Oncology (2018)

380 Background: Recent studies have identified panels of immune-related genes linked to progression and survival. Expressions usually are measured using RNA from tissue samples. The aim of the present study was to utilize circulating RNA (cfRNA) isolated from hormone-naïve (HN) and castrate-resistant prostate cancer (CRPC) patients to measure gene expressions of PD-L1, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), T-cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte activated gene 3 (LAG-3). Androgen receptor (AR) and AR-variant 7 (AR-v7) expressions were also measured in these samples to test for any possible relationships with the immune checkpoint genes. Methods: Blood samples were collected from 53 metastatic prostate cancer patients. cfRNA was extracted from patients’ plasma and reverse transcribed into complementary DNA. The gene expressions (mRNA levels) of the above genes were determined by quantitative reverse transcription-PCR. Beta-actin was used to normalize gene expressions to total RNA content. Results: Each of the immune signatures tested (PD-L1, TIM-3, LAG-3, CTLA-4) was expressed in over 50% (29/53) of the patients’ blood samples. AR was expressed in 25/53 (47%) samples. Four of these patients (8%) expressed AR-v7, indicating resistance to anti-AR drugs. Patient disease status included: 25% (13/53) CRPC, 74% (39/53) HN, and 1 unknown. Within the CRPC group, a significant negative correlation was found between TIM-3 and CTLA-4 expression (-0.833), and CTLA-4 also correlated with disease progression (0.719). Within the HN group, a significant negative correlation was measured between TIM-3 and PD-L1 (0.589). AR expression did not correlate with other targets measured among all patients or within the CRPC or HN groups. Conclusions: This study demonstrates successful quantitation of immune checkpoint gene expressions as well the AR and AR-v7 genes in plasma of prostate cancer patients. This result opens the possibility of the use of a noninvasive method to measure, monitor and track the dynamic interplay of these genes with changing disease status. Clinical trial information: NCT02853097.
Make returning to practice easier for GPs, says new RCGP chair
Authors: Abi Rimmer
Journal: BMJ (2013)

Returning to work must be made less “tortuous and difficult” for GPs, the incoming chairwoman of the Royal College of General Practitioners has said.

Speaking before she formally took on her new role on 16 November, Maureen Baker said that she planned to approach key stakeholders, including the Department of Health and NHS England, to discuss how returning to work could be made easier for GPs. She said that since the creation of the national performers list for GPs it had become more difficult for GPs who had taken a career break of more than two years to return to work.

“We now have a very tortuous and difficult process for returning back …
Clinical and genomic characterization of low-prostate-specific antigen, high-grade prostate cancer.
Authors: Brandon Arvin Virgil Mahal, David Dewei Yang, Natalie Wang, Mohammed Alshalalfa, Elai Davicioni, Voleak Choeurng, Daniel Eidelberg Spratt, Neil E. Martin, Kent William Mouw, Peter F Orio, Toni K. Choueiri, Quoc-Dien Trinh, Felix Y Feng, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2018)

59 Background: The consequences of a low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown. We sought to evaluate the clinical implications and genomic features of this entity. Methods: Clinical and transcriptomic data from 626,057 patients with N0M0 prostate cancer were collected from two national cohorts and a large transcriptome database. Multivariable Fine-Gray and Cox regressions analyzed prostate-cancer specific mortality (PCSM) and all-cause mortality, respectively. GRID data were used to analyze transcriptomic features. Results: For Gleason 8-10 disease, the distribution of PCSM was U-shaped by PSA (PSA 4.1-10.0 ng/mL = referent), with adjusted hazard ratio (AHR) 2.70 for PSA ≤2.5 ng/mL (P &lt; 0.001) versus 1.97, 1.36, and 2.56 for PSA 2.6-4.0, 10.1-20.0, and &gt; 20.0 ng/mL, respectively. In contrast, distribution of PCSM by PSA was linear for Gleason ≤7 with AHR 0.41 for PSA ≤2.5 ng/mL (P = 0.127) versus 1.38, 2.28, and 4.61 for PSA 2.6-4.0, 10.1-20.0, and &gt; 20.0 ng/mL, respectively (P Gleason*PSA interaction &lt; 0.001). Gleason 8-10, PSA ≤2.5 ng/mL disease had a significantly higher PCSM than standard high and very high-risk disease with PSA &gt; 2.5 ng/mL (AHR 2.15, P = 0.009; 47-month PCSM 13.8% versus 4.9%). Among Gleason 8-10 patients treated with definitive radiotherapy, androgen deprivation therapy (ADT) was associated with a survival benefit for PSA &gt; 2.5 ng/mL (AHR 0.87, P &lt; 0.001) but not for ≤2.5ng/mL (AHR 1.36, P = 0.084; P ADT*PSA interaction = 0.021). For Gleason 8-10 tumors, PSA ≤2.5 ng/mL was associated with a higher expression of neuroendocrine markers compared to &gt; 2.5 ng/mL (P = 0.046), with no such relationship for Gleason ≤7. Conclusions: Low-PSA, high-grade prostate cancer appears to be a unique entity that has a very high risk for PCSM, potentially responds poorly to ADT, and is associated with neuroendocrine genomic features.
Medical emergencies course for trainees
Authors: Craig Davies
Journal: BMJ (2010)

The medical emergencies course for trainees at University College London is a two day course on various medical emergencies. A course booklet was given at registration on the first morning, which contained all the slides to be presented and spaces for making notes. An additional bonus was a complimentary copy of the Oxford Handbook of Critical Care , which was given to all attendees.

Lectures were given by regional specialist consultants and several intensive care consultants. A wide range of topics were covered, from seizures and metabolic emergencies to extreme temperature management and acute renal failure. Lectures were well delivered, with some audience participation, and aimed at trainee doctors of all grades. Surprisingly, there was a real emphasis on physiology …