tbuckley/cabot-search huggingface dataset:
Metastases-directed therapy (MDT) for oligometastatic prostate cancer.
Authors: Ahmed El-Modir
Journal: Journal of Clinical Oncology (2018)

375 Background: Stereotactic ablative radiotherapy (SABR) is emerging as a treatment option for patients with oligometastatic prostate cancer. The primary aim of this approach is to prolong disease free survival and delay the initiation of systemic therapies. This retrospective study is aimed to analyse local control, biochemical progression-free survival (b-PFS), toxicity and systemic therapy-free survival in a cohort of patients treated by a single clinician. Methods: Eighteen patients (26 lesions) in patients with relapsed oligometastatic prostate cancer ( 1-3 sites) were treated with SABR, delivered using both cyberknife and VMAT. Doses used were 24 Gy in 2 or 3 fractions for spine and 30 - 40 Gy in 3 fractions for lymph nodes and other bony metastases. All patients had either a Choline or PSMA- PET scan prior to treatment. Response was assessed with PSA testing and repeat scanning when feasible. CTCAE acute and late toxicity was prospectively recorded. Results: Mean age was 68. Previous treatments for the primary prostate cancer included surgery (7 patients), surgery and salvage prostate bed radiotherapy (6 patients), radical radiotherapy (4 patients) and cryotherapy (1 patient). Twelve patients had a single metastatic site, four patients had 2 sites and two patients had 3 sites. Six patients patients were treated with a short course of androgen deprivation therapy (ADT) in addition to SABR. All patients had a fall in PSA with a mean reduction of 75%. Median pre-SABR PSA was 1.83μg/L and median post-SABR PSA was 0.28μg/L. At a median follow-up of 14 months (range 2 - 28.5), 14 patients (78%) remained systemic therapy free. Three patients with a single pelvic lymph node metastases achieved a sustained undetectable PSA level. All 8 patients who had a post-treatment PET scan showed no residual activity at the treated site. One patient experienced G2 acute bowel toxicity, otherwise there was no toxicity above G1. Conclusions: MDT using SABR for relapsed prostate cancer is a safe treatment with promising results in terms of local control, b-PFS and delaying the initiation of systemic therapies. This minimally invasive approach has the potential to improve patients' quality of life, but requires further evaluation in randomised clinical trials.
P064 Adipose tissues obtained from ra and oa patients differ in cytokine and chemokine secretion
Authors: M Plebanczyk, A Radzikowska, T Burakowski, W Maslinski, E Kontny
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rheumatoid arthritis (RA) and osteoarthritis (OA) lead to joint destruction and disability. Although both diseases are characterised by inflammation of the joints as well as systemic inflammation, their pathogenesis is different. Despite the progress in the treatment both diseases are still incurable. Articular adipose tissue (AAT) and subcutaneous adipose tissue (ScAT) are supposed to contribute to joint and systemic inflammation, respectively. Our previous work showed that AAT from RA patients synthesises factors relevant to disease pathogenesis and/or progression and this secretion is usually higher from articular than subcutaneous adipose tissue.<sup>1,2</sup> <h3>Objectives</h3> The aims of present work were (i) to investigate whether AAT obtained from OA patients is also more active than ScAT and (ii) to compare secretory activity of adipose tissues from RA and OA patients. <h3>Methods</h3> AAT and ScAT explants obtained from OA [(n=44; female (F)/male (M)=36/8; age=62 (mean) (35–71) (min-max)] and RA (n=43; F/M=35/8; age=54 (31–70)] patients during knee joint replacement surgery were cultured (100 mg/ml) for 24 hours in DMEM. Concentrations of proinflammatory (IL-6, TNF), anti-inflammatory (IL-1Ra, IL-10, TGFβ) cytokines, chemokines (CCL2, CCL5) and metalloproteinase MMP-3 was measured in culture supernatants by ELISA. <h3>Results</h3> In both diseases AAT secreted spontaneously more IL-1Ra, TGFβ and MMP-3 than ScAT while the release of other factors was minute (TNF, IL-10, CCL5) or moderate (CCL2) and did not differ between tissues. The only exception was IL-6 produced in larger quantity by AAT than ScAT from OA patients. Both adipose tissues from OA patients released significantly more TNF, IL-1Ra and CCL2 than tissues from RA patients. Moreover, AAT from OA produced more MMP-3 than respective tissue of RA patients while rheumatoid ScAT secreted more TGFβ. We did not find differences in basal secretion of IL-6, IL-10 and CCL5 between diseases. <h3>Conclusions</h3> Despite the fact, that similarly to RA the secretion of cytokines and chemokines in OA was usually higher in AAT than in ScAT, also the latter tissue released considerable quantity of tested factors and thus may contribute to systemic inflammation. Unexpectedly, our results give also evidence that basal secretory activity of adipose tissues from OA patients is usually higher than from RA patients. It is possibly caused by different anti-inflammatory treatment, stronger in RA than OA patients, with resulting poor control of inflammation in OA. <h3>References</h3> . Kontny E, et al. Ann Rheum Dis2012;71(2):262–267. . Kontny E, et al. Rheumatology2013;52:2158–2167. <h3>Acknowledgements</h3> This work was funded by the National Science Centre (grant number 2012/N/NZ5/00074). <h3>Disclosure of interest</h3> None declared
Probing glioblastoma infiltration into healthy tissue by magnetic resonance perfusion imaging: a quantitative MRI evaluation
Authors: Antoine Vallatos, Joanna Birch, Haitham Al-Mubarak, Lindsay Gallagher, Lesley Gilmour, William Holmes, Anthony Chalmers
Journal: Neuro-Oncology (2018)

The ability of tumour cells to invade healthy brain tissue is a major obstacle to successful treatment of Glioblastoma (GBM). This makes complete removal of the tumour by surgery impossible, leading to high recurrence rates, and reduces the accuracy of target volume delineation for radiotherapy planning. Providing with a wide range of imaging modalities, Magnetic Resonance Imaging (MRI) is an important tool for GBM diagnosis and characterisation. However, conventional MRI techniques fail to detect regions of low tumour cell density that may be responsible for subsequent tumour recurrence, while novel techniques are often not reliable due to a lack of robust evaluation protocols. Invading tumour cells often progress along blood vessels and recent results indicate that even individual cells can disrupt the normal function of the blood brain barrier (BBB), providing an opportunity to detect tumour invasion at its earliest stages. Our research focuses on the development of perfusion imaging techniques, and their quantitative assessment in detecting low tumour infiltration regions on mouse GBM models presenting highly invasive tumour margins. A high SNR multiple adiabatic boli Arterial Spin Labelling technique (mbASL) was implemented and optimised for rodent brain perfusion imaging and its ability to probe tumour invasion was evaluated by comparison with standard MRI techniques (T2 and diffusion weighted imaging) and immunohistochemistry sections. To achieve a quantitative MRI evaluation, multiple histological slices (HLA stain for human GBM) were cut in the MRI plane, registered and stacked to account for MRI slice thickness. This approach, leading to the production tumour density maps in the MRI plane, allows going beyond the standard evaluation tests to consider a voxel-to-voxel comparison between MRI and histology. Our results confirm the limitations of standard imaging modalities in probing low tumour densities and demonstrate the existence of a quantitative relation between glioblastoma invasion and brain perfusion.
Role of C terminal binding proteins (CtBP) in pancreatic adenocarcinoma (PDAC).
Authors: Prashant J. Joshi, Ayesha Chawla, Patrick Memari, John Stansfield, Michael Idowu, Adam Sima, Steven R. Grossman
Journal: Journal of Clinical Oncology (2018)

320 Background: Overexpression of the oncogenic transcription factors CtBP1 and 2 is common and associated with poor prognosis in ovarian, breast and prostate cancer. CtBP2 drives tumor progression through promotion of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) activity. Frequent early metastasis observed in PDAC may depend on EMT and CSC activity, prompting us to investigate the prognostic significance of CtBP1/2 in PDAC. In parallel, we determined the oncogenic contribution of CtBP2 to PDAC utilizing a transgenic KRAS mutant mouse PDAC model (CKP) that incorporated heterozygous loss of the Ctbp2 gene (CKP2). Methods: Immunohistochemistry (IHC) using CtBP1/2 antibodies was performed on 69 cases of resected PDAC from VCU Health for the period 2005-16. Clinical data included stage (84% stage 1/2; 16% stage 3/4), initial CA19-9 level, and overall survival. IHC stains were assigned an Allred score (sum of intensity and proportion) by two independent pathologists with a scale from 0-8. Cox Proportional Hazard survival models were fit for CtBP1/2 staining vs. survival. CtBP1/2 correlation with stage and CA19-9 level was tested by ANOVA. CKP mice were bred to Ctbp2 +/- mice, and survival of cohorts (n = 10 each) of CKP vs. CKP2 mice was analyzed by log-rank analysis of Kaplan-Meier survival curves. Results: CtBP1 and 2 expression was uniformly high (7-8) across all cases, including stage 1/2. Thus, no statistically significant survival difference could be derived based on CtBP1/2 expression [CtBP1 HR 1.03 (0.67-1.41) p 0.92, CtBP2 HR 0.75 (0.39-1.43) p 0.31], and no significant association of CtBP1/2 was seen with stage or CA19-9. Suggesting a possible contribution of CtBP2 in human PDAC, Ctbp2 knockout in CKP2 mice improved median survival (9.5 vs. 8.1 weeks, p &lt; 0.05), decreased mean tumor weight (750 mg vs. 400 mg, p &lt; 0.05), and also abrogated peritoneal metastases and ascites normally seen in 100% of CKP mice. Conclusions: While uniformly high CtBP expression in PDAC subverts prognostic use, CtBP may play a pathogenic role, as CKP2 mice exhibited improved survival, lower tumor burden and no peritoneal spread. Our data supports further study of CtBP inhibition as a potential therapeutic strategy in PDAC.
MA/Postgraduate Diploma in Healthcare Ethics and Law
Authors: Kathryn Leask
Journal: BMJ (2006)

Practising lawyers, law graduates, medical graduates, hospital managers, and anyone interested in healthcare ethics and medical law, including those considering a career in medicolegal work.

In 2003-5, during my first two years of specialist registrar training in clinical genetics. Some of my colleagues in clinical genetics have also done the course, but it would equally benefit doctors in any specialty.

I had always been interested in learning more about medical law and considered a career in medicolegal work before gaining a national training number in clinical genetics. The ethical aspect seemed particularly relevant to genetics and to complement my specialist training.

The master's degree takes two years, which includes 18 months completing course work followed by about six months carrying out a 12 000 to 15 000 word dissertation. All of the course material is provided and is comprehensive. Study packs are also supplied, which contain a number of relevant law reports and journal articles. There are eight modules in total, each requiring …
Prognostic implication of soluble programmed death-ligand 1 (sPDL1) and its dynamic changes during FOLFIRINOX chemotherapy in unresectable pancreatic cancer.
Authors: Hyunkyung Park, Ju-Hee Bang, Ah-Rong Nam, Ji Eun Park, Mei Hua Kim, Yung-Jue Bang, Do-Youn Oh
Journal: Journal of Clinical Oncology (2018)

306 Background: Programmed death-ligand 1 (PD-L1) expressed on a tumor or in a tumor microenvironment has an important role in the tumor escaping from the immune system. The soluble form of PD-L1 (sPD-L1) has been suggested to have an immunosuppressive activity. In pancreatic cancer, the acquisition of a sufficient amount of tumor tissue is an obstacle. In this study, we measured the serum levels of sPD-L1 and evaluated its prognostic implications in unresectable pancreatic cancer. Methods: We prospectively enrolled 60 pancreatic cancer patients who were treated with FOLFIRINOX as the first-line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment and disease progression. Serum sPD-L1 was measured using an enzyme-linked immunosorbent assay. Results: The median sPD-L1 was 1.7ng/mL (range, 0.4-5.7ng/mL). The median overall survival (OS) and progression free survival (PFS) were 10.3 months (95% CI: 8.5-12.11) and 6.5 months (95% CI: 4.9-8.1), respectively. Patients with low levels of sPD-L1 at diagnosis ( &lt; 4.6 ng/mL) showed a better OS than the patients with a high sPDL1 (OS: 12.6 vs. 8.0 months HR 2.796, P = 0.015). In the multivariable analysis, sPD-L1 and the neutrophil-to-lymphocyte ratio were independent prognostic factors for OS. During chemotherapy, more patients achieved CR(complete response)/PR (partial response) as the best response when sPD-L1 was decreased at the first response assessment. (CR+PR rate; sPDL1 decreased group vs. sPD-L1 increased group: 14/29 (48.3%) vs. 5/24 (20.8%), P = 0.038). For patients who achieved CR/PR as the best response, sPD-L1 was significantly increased at disease progression compared with the first response assessment (mean 3.5 vs. 1.9 ng/mL, P = 0.025). Conclusions: sPD-L1 at diagnosis confers a prognostic value for OS in pancreatic cancer patients treated with chemotherapy. The dynamics changes of sPD-L1 during chemotherapy correlates with disease progression
Evolutionary and genetic features of drug targets
Authors: Yuan Quan, Zhong‐Yi Wang, Xin‐Yi Chu, Hong‐Yu Zhang
Journal: Medicinal Research Reviews (2018)

Abstract In the modern drug discovery pipeline, identification of novel drug targets is a critical step. Despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. This fact is partially responsible for the situation of “more investments, fewer drugs” in the pharmaceutical industry. A series of recent researches revealed that successfully targeted genes share some common evolutionary and genetic features, which means that the knowledge accumulated in modern evolutionary biology and genetics is very helpful to identify potential drug targets and to find new drugs as well. In this article, we comprehensively summarize the links between human drug targets and genetic diseases and their evolutionary origins, with an attempt to introduce these novel concepts and their medical implications to the biomedical community.
I am interested in a career in academic intensive care. I know how to train in intensive care medicine as a dual specialty, but how would I go about developing a research interest in this area and would a base specialty other than anaesthetics be a disadvantage?
Authors: Gavin Perkins
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>
Self-reported burden in patients with localized prostate cancer treated with stereotactic body radiation therapy (SBRT).
Authors: Abigail Pepin, Nima Aghdam, Colin Johnson, Malika Danner, Marilyn Ayoob, Thomas M. Yung, Siyuan Lei, Brian Timothy Collins, Anatoly Dritschilo, Simeng Suy, John Lynch, Sean P. Collins
Journal: Journal of Clinical Oncology (2018)

51 Background: Retaining quality of life in patients treated with SBRT for prostate cancer remains paramount. As such, balancing the benefits of treatment against the effects of therapy on patients is essential. The quality of life is influenced by the disease and treatment related burden. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire that can assess burden. This study reports burden trends in patients with prostate cancer treated with SBRT. Methods: All patients with localized prostate cancer treated with SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess self-reported patient quality of life at time points before and following treatment. Initially, 267 patients (Median age of 70) responded to the ELD14 questionnaire. Approximately 30% received ADT. The specific questions reviewed for this study were focused on burden of disease and treatment. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Number of patients reporting quite a bit or very much burden from prostate cancer declined over time from 13% prior to treatment to 8% at 36 months post-SBRT. This was highest at one month post-SBRT (15%) and resolved to baseline by 6 months. Treatment burden similarly decreased over time from 10% to 3%. Patients treated with androgen deprivation therapy (ADT) experienced greater burden than others. At initial consult, 19% of patients on ADT reported quite a bit or very much burden from their illness. At one month post-SBRT, this had increased to 27% and subsequently decreased to 16% at 36 months. Of those not receiving ADT, 12% reported having quite a bit or very much burden from illness initially, 9% at one month and 6% at 36 months. Conclusions: This cross-sectional study suggests that the burden of clinically localized prostate and its treatment with SBRT improves over time. Increased burden was noted in patients receiving ADT. These findings can inform decision making in improving quality of life for patients with prostate cancer treated with SBRT.
Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea
Authors: Patrick J. Atkinson, Yaodong Dong, Shuping Gu, Wenwen Liu, Elvis Huarcaya Najarro, Tomokatsu Udagawa, Alan G. Cheng
Journal: Journal of Clinical Investigation (2018)

During development, Sox2 is indispensable for cell division and differentiation, yet its roles in regenerating tissues are less clear. Here, we used combinations of transgenic mouse models to reveal that Sox2 haploinsufficiency (Sox2haplo) increases rather than impairs cochlear regeneration in vivo. Sox2haplo cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2haplo amplified and expanded domains of damage-induced Atoh1+ transitional cell formation in neonatal cochlea. Wnt activation via β-catenin stabilization (β-cateninGOF) alone failed to induce proliferation or transitional cell formation. By contrast, β-cateninGOF caused proliferation when either Sox2haplo or damage was present, and transitional cell formation when both were present in neonatal, but not mature, cochlea. Mechanistically, Sox2haplo or damaged neonatal cochleae showed lower levels of Sox2 and Hes5, but not of Wnt target genes. Together, our study unveils an interplay between Sox2 and damage in directing tissue regeneration and Wnt responsiveness and thus provides a foundation for potential combinatorial therapies aimed at stimulating mammalian cochlear regeneration to reverse hearing loss in humans.
And so to bed...
Authors: Peter Cross
Journal: BMJ (2005)

One of the most enjoyable parts of an editor's job is choosing the right mix of articles, features, and interviews to make up an interesting selection for the forthcoming issue and sending it on its their way. In the trade this process is called putting a paper “to bed.” So it seems appropriate that this week's lead article is a piece about the importance of sleep.

Dying for a …
CORONARY SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR RELEASE IS A BIOMARKER OF ENDOTHELIAL-DEPENDENT MICROVASCULAR DYSFUNCTION
Authors: Michel Corban, Abhiram Prasad, Lisa Nesbitt, Darrell Loeffler, Lilach Lerman, Amir Lerman
Journal: Journal of the American College of Cardiology (2018)
Trials that say “maybe”: the disconnect between exploratory and confirmatory testing after drug approval
Authors: Benjamin Carlisle, Carole A Federico, Jonathan Kimmelman
Journal: BMJ (2018)

Clinical trials that explore the repurposing of drugs for off-label uses are common. But without a commitment to rigorously testing the hypotheses generated by these exploratory trials, patients are put in harm's way, argue <b>Benjamin Carlisle and colleagues</b>
Academy’s £1.6m scheme for researchers aims to tackle NHS brain drain
Authors: Matthew Limb
Journal: BMJ (2015)

Biomedical researchers will be eligible for more support under a £1.6m scheme to help them “fulfil their leadership potential” and prevent the NHS losing talent. 

The Academy of Medical Sciences’ initiative, called “Springboard,” aims to support people in the early stages of their careers as they move to establish themselves as independent researchers. It will offer mentoring, career development, and financial support to researchers, in a bid to ease the pressure that can lead many to exit the profession too soon.

Initially, 16 researchers who do not hold clinical contracts will be accepted onto the scheme, which …
Psychometric evaluation of the Caregiver Needs Screen in neuro-oncology family caregivers
Authors: Florien Boele, Lauren Terhorst, Jennifer Prince, Heidi Donovan, Jason Weimer, Frank Lieberman, Jan Drappatz, Paula Sherwood
Journal: Neuro-Oncology (2018)

The informal care demands of brain tumour patients include various issues associated with neurological and cognitive symptoms. Caregiver needs questionnaires developed for cancer populations do not include these disease-specific symptoms. Therefore, we have developed the neuro-oncology Caregiver Needs Screen (CNS) and evaluated its psychometric properties. In-depth qualitative interviews with caregivers were used to generate items, which were reviewed by experts to add or collapse items as necessary. The resulting 32-item instrument was tested in a sample of 122 neuro-oncology caregivers, along measures of depression (Center for Epidemiological Studies – Depression scale), anxiety (Profile of Mood States – Anxiety), caregiver burden (Caregiver Reaction Assessment) and mastery (Mastery Scale). Exploratory factor analysis was used to determine internal structure. Internal consistency reliability and construct validity were assessed. Six subscales were identified (neurologic symptoms; oncologic symptoms; personal communication; communicating with health care providers; resources; caregiver health). Internal consistency for the subscales ranged between α = .653 and α = .886. A floor effect was found for the personal communication subscale only. Convergent validity was verified by moderate to strong correlations between measures of caregiver wellbeing and CNS scale scores. Findings provide preliminary evidence of reliability and validity for the CNS as a measure of neuro-oncology caregiver distress as a result of common care issues. This instrument can prove useful in research setting as well as in clinical practice when assessing caregivers’ needs for supportive care.
Margaret McCartney: Direct patient care should be rewarded and cherished
Authors: Margaret McCartney
Journal: BMJ (2018)

You would be forgiven for thinking that all doctors get paid roughly the same, pro rata, for the same work. But some recent revelations have contested this belief.

One such revelation was the leaking of a letter by a public health consultant showing wide disparities in earnings among GPs: some earn well below the average of £100 000 for a full time GP in Scotland, but others earn more than £300 000.1 Sure, some people are part time, others are full time, others do a lot of on-call, and others do not. But this range is troubling. …
Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability
Authors: Britney Johnson, Laura A. VanBlargan, Wei Xu, James P. White, Chao Shan, Pei-Yong Shi, Rong Zhang, Jagat Adhikari, Michael L. Gross, Daisy W. Leung, Michael S. Diamond, Gaya K. Amarasinghe
Journal: Immunity (2018)