tbuckley/cabot-search huggingface dataset:
Human papillomavirus DNA and antibodies to human papillomaviruses 16 E2, L2, and E7 peptides as predictors of survival in patients with squamous cell cervical cancer.
Authors: P Viladiu, F X Bosch, X Castellsagué, N Muñoz, J M Escribà, E Hamsíkova, V Hofmannova, E Guerrero, A Izquierdo, C Navarro, P Moreo, I Izarzugaza, N Ascunce, M Gili, M T Muñoz, L Tafur, K V Shah, V Vonka
Journal: Journal of Clinical Oncology (1997)

PURPOSE To assess whether human papillomavirus (HPV) DNA detection in cervical cancer specimens, or antibodies to selected HPV 16 peptides are predictors of tumor recurrence and long-term survival in patients with squamous cell invasive cervical cancer. SUBJECTS AND METHODS Four hundred seventy-one cases included in two population-based case-control studies underwent follow-up evaluation. The survival and cause of death were ascertained for 410 cases (87%), with a median follow-up time of 4.6 years after diagnosis. HPV DNA was assessed using an L1 polymerase chain reaction (PCR)-based system and Southern hybridization (SH) on scraped cytologic specimens or biopsies. HPV 16 antibodies to E2, L2, and E7 peptides were detected with enzyme-linked immunosorbent assay (ELISA). RESULTS Clinical stage was the only independent prognostic factor for recurrence or survival. Although seropositivity to HPV 16 E7/3 peptide predicted a twofold excess risk of mortality (adjusted hazards ratio [HRa] = 2.0; 95% confidence interval [CI], 1.2 to 3.3), the association was restricted to stage I (HRa = 6.6; 95% CI, 1.2 to 37.6) and II (HRa = 5.9; 95% CI, 2.1 to 16.5) patients. The presence of HPV DNA (HRa = 0.9; 95% CI, 0.5 to 1.5), different estimates of the HPV viral load and the HPV type identified were not predictors of tumor recurrence or survival. CONCLUSION The presence of antibodies to HPV 16 E7 proteins is of prognostic value in early-stage cervical cancer. Our results provide strong evidence that detection and typing of HPV DNA in cervical cells or tissues is not a prognostic factor for recurrence or survival.
What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion
Authors: R. Vellucci, G. Fanelli, R. Pannuti, C. Peruselli, S. Adamo, G. Alongi, F. Amato, L. Consoletti, L. Lamarca, S. Liguori, C. Lo Presti, A. Maione, S. Mameli, F. Marinangeli, S. Marulli, V. Minotti, D. Miotti, L. Montanari, G. Moruzzi, S. Palermo, M. Parolini, P. Poli, W. Tirelli, A. Valle, P. Romualdi
Journal: Drugs (2016)

Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient.
Overexpression of the centrosomal protein aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients
Authors: C. N. Landen, A. Immaneni, M. T. Deavers, A. Thornton, J. Celestino, P. H. Thanker, L. Y. Han, D. C. Bodurka, D. M. Gershenson, W. R. Brinkley, A. K. Sood
Journal: Journal of Clinical Oncology (2005)

5039 Background: Aurora-A kinase is a serine-threonine kinase involved in centrosome regulation that is frequently amplified in cancer. Its role in ovarian carcinoma has not been fully characterized and was examined in the current study. Methods: Ovarian carcinoma cell lines (SKOV3, EG, A2780-par, OVCAR3, and HeyA8), taxane resistant ovarian cancer cells (HeyA8-MDR), and non-transformed ovarian surface epithelial cells (HIO-180) were examined for aurora-A expression by Western blot, and for activity by kinase assay. Centrosome amplification was assessed by immunofluorescence. In addition, 33 human epithelial ovarian cancer specimens, all of high stage (III-IV) and grade (2–3), were analyzed for aurora-A expression by immunohistochemistry, and disease specific survival was determined based on the level of expression. Results: All ovarian cancer cell lines except A2780-par exhibited significant aurora-A kinase overexpression compared to the non-transformed HIO-180 cell line. In addition, the taxane resistant cell line HeyA8-MDR expressed higher levels of aurora-A kinase, and had higher kinase activity, compared to its taxane sensitive HeyA8 parental line. Cell lines with aurora-A kinase overexpression also had significant centrosome amplification (as determined by immunofluorescent centrosome count per cell), indicating multiple spindle formation units and aneuploidy. Of the 33 human ovarian cancer specimens examined, 30 (90.9%) exhibited Aurora-A kinase overexpression. Those patients with the greatest Aurora-A overexpression in the tumor (the highest quartile) had significantly worse survival compared to the remaining cohort (median survival 1.54 v. 2.34 years, p=0.033 by log rank analysis). Conclusions: Aurora-A kinase is overexpressed in the majority of ovarian cancer cell lines and human samples. Overexpression is associated with centrosome amplification and decreased patient survival, and represents a novel potential target for therapy. No significant financial relationships to disclose.
Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?
Authors: A Rosenthal, J Luthi, M Belohlavek, K M Kortüm, F Mookadam, A Mayo, R Fonseca, P L Bergsagel, C B Reeder, J R Mikhael, A K Stewart
Journal: Blood Cancer Journal (2016)

Abstract Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.
Overexpression of I Kappa B Alpha Without Inhibition of NF-κB Activity and Mutations in the I Kappa B Alpha Gene in Reed-Sternberg Cells
Authors: Florian Emmerich, Martina Meiser, Michael Hummel, Gudrun Demel, Hans-Dieter Foss, Franziska Jundt, Stephan Mathas, Daniel Krappmann, Claus Scheidereit, Harald Stein, Bernd Dörken
Journal: Blood (1999)
PWE-177 A Systematic Review Of Antidepressants In Irritable Bowel Syndrome: A Qualitative Analysis
Authors: M Rance, L Lindner, AC Ford
Journal: Gut (2014)

<h3>Introduction</h3> Antidepressants have a mild analgesic effect and are commonly used in the management of irritable bowel syndrome (IBS); however, the quality of the clinical evidence to support the use of tricyclic antidepressants (TCAs) and selective serotonin inhibitors (SSRIs) in IBS is unclear. The aim of this literature review was to systematically identify and analyse published evidence on the efficacy of TCAs and SSRIs for IBS. <h3>Methods</h3> A systematic search of the medical literature was conducted using the PubMed, Embase, and Cochrane databases. Search terms included ‘irritable bowel syndrome’, ‘spastic colon’, ‘irritable colon’, ‘functional diseases, colon’ and a mixture of agent terms – including antidepressants, tricyclic, and SSRIs. Randomised placebo-controlled trials evaluating the efficacy of antidepressants (SSRIs and TCAs) in adult patients with IBS were eligible for inclusion. Exclusion criteria included absence of placebo arm, patients &lt;18 years of age, and dual publication. Only antidepressants available in the UK were included in this analysis. <h3>Results</h3> A total of 628 unique titles and abstracts were retrieved; 581 records were excluded upon title or abstract review and 33 upon full-text review. The final review included 14 studies: 7 reporting on TCAs, 6 on SSRIs, and 1 comparing both an SSRI and a TCA vs. placebo. Agents included in the analysis were citalopram, paroxetine, fluoxetine, imipramine, amitriptyline, trimipramine and doxepin. Overall, 797 patients were included in the 14 studies, with 240 receiving a TCA, 171 receiving an SSRI and 386 receiving placebo. Of the nine studies (475 patients) that reported IBS subtype, 50% of patients had diarrhoea-predominant IBS, 32% had constipation-predominant IBS (IBS-C) and 19% had alternating-type IBS. Treatment duration ranged from 4–12 weeks. The most common IBS-related outcome measures were for global symptom relief and improvements in abdominal pain/discomfort. Three studies reported on quality of life, while only limited data were available for treatment satisfaction. Most outcomes did not align well with those now required for FDA and EMA regulatory approval of medicines to treat IBS-C. <h3>Conclusion</h3> The evidence base for the use of antidepressants in IBS is of low quality, making estimates of effect very uncertain. Data for the efficacy of antidepressants in IBS subtypes are especially limited. Further studies are required to support the off-label use of antidepressants in IBS. Study funded by Almirall UK. <h3>Disclosure of Interest</h3> M. Rance Employee of: Almirall UK, L. Lindner Employee of: Almirall S. A., A. C. Ford: None Declared.
Deprofessionalising doctors?
Authors: D. Pereira Gray
Journal: BMJ (2002)

A patient seeing a doctor professionally in the United Kingdom has expectations of professional conduct that far exceed what is expected of citizens generally or employees of most institutions. This sense of professionalism is important to patients as it motivates doctors. The underpinnings of that professionalism, established over 150 years, have in the last 150 days all been questioned.

The medical profession in the United Kingdom first emerged through the medical royal colleges in 1505. The 1858 Medical Act united the medical profession and, almost 150 years ago, created the General Medical Council—a structure through which the profession could develop an ethical code,1 systematise education, and punish erring members. The council derives its authority from parliament; its membership includes 25% of lay members, soon to increase to 40%; it elects its own president; and it has been a model for other professions, such as the General Teaching Council.

Postgraduate education developed later, and the profession entered into a partnership with the State to regulate it. The Joint Committee on Postgraduate Training for General Practice (JCPTGP) and the Specialist Training Authority (STA) between them control postgraduate training for doctors. Both bodies have …
Abstract 3642: Structure enabled design of inhibitors of the mitotic kinase MPS1
Authors: Paolo Innocenti, Hannah Woodward, Kwai_Ming J. Cheung, Sébastien Naud, Savade Solanki, Isaac M. Westwood, Amir Faisal, Angela Hayes, Jessica Schmitt, Ross Baker, Berry Matijssen, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Spiros Linardopoulos, Julian Blagg, Rob L M van Montfort, Swen Hoelder
Journal: Cancer Research (2015)

Abstract MPS1 (also known as TTK), is a dual-specificity protein kinase that is essential for the proper attachment of chromosomes to the mitotic spindle. MPS1 expression is elevated in a variety of human cancers and is correlated with higher histological grade, aggressiveness and poor patient survival. It has been also shown that basal, PTEN-deficient and triple negative breast cancers are sensitive to MPS1 inhibition. These data together provide strong support for selective antitumour action of MPS1 inhibitors in human cancers. Here we report the discovery of pyridopyrimidines as a new class of inhibitors of MPS1 exploring a hybridization approach. Rapid structure based optimisation of the initial hits led to highly potent, selective and ligand efficient compounds. We will discuss our initial design approach and the structural features that are critical for potent biochemical and cellular inhibition as derived from SAR and co-crystal structures. Furthermore, we will report pharmacokinetic and in vivo properties of selected compounds and comment on our strategy to optimise this series towards preclinical candidates. Citation Format: Paolo Innocenti, Hannah Woodward, Kwai_Ming J. Cheung, Sébastien Naud, Savade Solanki, Isaac M. Westwood, Amir Faisal, Angela Hayes, Jessica Schmitt, Ross Baker, Berry Matijssen, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Spiros Linardopoulos, Julian Blagg, Rob L M van Montfort, Swen Hoelder. Structure enabled design of inhibitors of the mitotic kinase MPS1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3642. doi:10.1158/1538-7445.AM2015-3642
Abstract 20349: Comparison of Health Literacy by Race and Gender Among Heart Failure Patients
Authors: Hannah A Hughes, Margaret Bowers, Vickie McKee, Louise Saladino, Tenita Sawyer, D. Lupino Washington, Janet P Bettger, Bradi B Granger
Journal: Circulation (2014)

Background: Heart failure affects Blacks at a disproportionate rate compared with Whites. Effective self-management programs, including those involving technology have been shown to improve clinica...
Epigenetic Therapeutics: A New Weapon in the War Against Cancer
Authors: Nita Ahuja, Anup R. Sharma, Stephen B. Baylin
Journal: Annual Review of Medicine (2016)

The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.
An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma
Authors: A. Ari Hakimi, Ed Reznik, Chung-Han Lee, Chad J. Creighton, A. Rose Brannon, Augustin Luna, B. Arman Aksoy, Eric Minwei Liu, Ronglai Shen, William Lee, Yang Chen, Steve M. Stirdivant, Paul Russo, Ying-Bei Chen, Satish K. Tickoo, Victor E. Reuter, Emily H. Cheng, Chris Sander, James J. Hsieh
Journal: Cancer Cell (2016)
Abstract 19160: Insulin Resistance over a 10-Year Period is Associated with Coronary Atherosclerosis in HIV-Infected and Uninfected Men in the Multicenter AIDS Cohort Study
Authors: Michael Brener, Wendy S Post, Sandra Reynolds, Frank J Palella, Lisa P Jacobson, Adrian Dobs, Richard T George, Mallory Witt, Matthew Budoff, Lawrence Kingsley, Todd T Brown
Journal: Circulation (2014)

Aims: HIV infection and its treatments are associated with insulin resistance and diabetes, which may influence the risk of coronary artery disease (CAD). We investigated the degree of insulin resistance in HIV-infected and uninfected men and its association with coronary atherosclerosis. Methods: We conducted a multicenter, cross-sectional study which included 448 HIV-infected and 306 uninfected men, ages 40 to 70 years old, without a history of prior coronary revascularization from the Multicenter AIDS Cohort Study (MACS). Coronary computed tomography angiography (CTA) was performed to identify the presence of coronary artery plaque, to characterize plaque composition (calcified, non-calcified, and mixed), and to identify coronary artery stenoses &gt; 50%. Insulin resistance was evaluated by the homeostatic model assessment (HOMA-IR) measured at each semi-annual visit between 2003 and 2014. The mean HOMA-IR was calculated from all visits before participants underwent CTA. Associations between HOMA-IR and the prevalence of plaque or of stenosis &gt; 50% were assessed with logistic regression by adjusting for age, race, HIV serostatus, and CAD risk factors. Results: Mean HOMA-IR compiled over a median of 8.4 years was higher in HIV-infected than uninfected men (3.2 vs. 2.7, p = 0.002), but the prevalence of stenosis &gt; 50% was similar (17% vs. 15%, p = 0.41). In fully adjusted models comparing men in the highest and lowest tertiles of mean HOMA-IR, mean HOMA-IR was associated with the presence of stenosis &gt; 50% (OR = 2.81 [95% CI, 1.51-5.22]), but not with any particular plaque type. There was no significant interaction between HIV serostatus and associations between mean HOMA-IR and coronary stenosis. Among HIV-infected men, further adjustment for HIV disease control and severity (suppressed HIV-1 RNA, CD4 T-cell count) did not alter the association between mean HOMA-IR and the presence of stenosis &gt; 50% (OR = 2.67 [95% CI, 1.26-5.89]). Conclusions: Insulin resistance over a 10 year period was greater among HIV-infected than uninfected men and was associated with coronary artery stenosis, but not with any specific plaque type. Our findings suggest that insulin resistance is a potential mechanism mediating the increased risk of CAD among HIV-infected men.
PWE-149 Thoracoscopic-assisted oesophagectomy for early oesophageal cancer: outcomes for the first 50 resections
Authors: G Couper, M Proctor, P Lamb, A MacDonald, S Paterson-Brown, J Plevris, I Penman
Journal: Gut (2015)

<h3>Introduction</h3> Since 2005 it has been unit policy to offer patients staged with T1N0 oesophageal cancer (either unsuitable for endoscopic mucosal resection (EMR) or with features on the EMR specimen that warranted resection) or T2N0 lesions a thoracoscopic-assisted oesophagectomy (TAO). We report on the surgical outcomes and survival for patients treated with this management approach. <h3>Method</h3> Results of the first 50 patients with this approach were obtained from a prospectively gathered database. All had staging with endoscopy, computerised tomography (CT) and endoscopic ultrasound (EUS). Depending on EUS assessment, patients were listed for EMR or directly to TAO. TAO was performed using a prone position for thoracoscopic mobilisation. Median follow up was 60 months and was complete for all patients. Survival was calculated using Kaplan-Meier estimates. <h3>Results</h3> The median age was 67 years (range 46–81). There were 34 males and 16 females. 48/50 (96%) patients had a TAO. Two patients were converted at an early operative stage to an Ivor Lewis oesophagogastrectomy due to dense pleural adhesions. Stomach was used as a conduit in 49 cases with a colonic interposition in one patient. There were no chyle leaks. There were no significant haemorrhages during thoracic dissection. The median blood loss was 300 mls (range 65–1530). The median number of lymph nodes was 12 (range 4–37). There was one post-operative death. Significant complications included tracheo-oesophageal fistula in 2 patients, 1 tube-tip necrosis, 4 patients with left recurrent laryngeal nerve palsy and 4 anastomotic leaks. Final histology showed HGD in 3 cases, T1a in 18, T1b in 23, T2 in 4 and T3 in 2 patients. There were 9 squamous cell tumours, 38 adenocarcinomas and the 3 patients with HGD. When compared to final histology 48/50 patients (96%) were correctly staged preoperatively as node negative with a combination of CT and EUS. The cancer specific 5-year survival was 95% and overall 5-year survival was 84%. <h3>Conclusion</h3> Patients with T1/T2 node negative oesophageal cancer have an excellent prognosis following TAO. This can be achieved with a protocol that must include EUS and access to EMR. It is essential that preoperative staging is accurate to ensure that patients with T1 or T2 lesions who are node positive are offered neoadjuvant therapy. TAO is a safe and effective alternative to open oesophagectomy. <h3>Disclosure of interest</h3> None Declared.