tbuckley/cabot-search huggingface dataset:
PTU-166 Diagnosis of Gastro-Oesophageal Reflux Disease (Gord) by Histology of Mucosal Biopsies from Distal Oesophagus: Agreement with Prolonged PH Monitoring
Authors: R Sweis, F Chang, M Fox, A Anggiansah, A Lee, A Valdes, T Wong
Journal: Gut (2013)

<h3>Introduction</h3> Prolonged wireless pH-monitoring (Bravo) increases diagnostic yield compared to 24 hr pH-studies. Studies have shown a weak association between oesophageal acid exposure from 24 hr pH-studies and mucosal disease on distal oesophageal histology. This study assessed the association between Bravo, endoscopic findings and distal oesophageal histology. <h3>Methods</h3> From July 2009 to August 2010, 63 consecutive patients with typical reflux symptoms had endoscopy with biopsies taken from 3 &amp; 9 o’clock position at and 2cm proximal to the Z-line prior to pH capsule fixation 6cm proximal to the Z-line for prolonged (up to 96 hr) Bravo. All biopsies were assessed by the 6-parameter Zentilin histology score (Zentilin <i>et al</i> Gastroenterol 2005). GORDdiagnosis was based on “Average” acid exposure (Total Reflux; TR &gt; 5.3% time pH &lt; 4) over the time period measured and/or symptom-association (symptom index; SI &gt; 50%) <h3>Results</h3> Adequate biopsy samples were available from 57/63 patients (mean age 44 (range 17–78); 27M). 37/57(65%) patients had GORD based on either TR (n = 30) <i>or</i> SI(n = 32). 20/57(35%) were both TR &amp; SI negative (Functional Heartburn; FH). 18 FH patients had no mucosal changes, 2 had grade A oesophagitis. There was no difference in individual histology parameters between GORD vs. FH (p &gt; 0.05) apart from increased ‘intra-epithelial neutrophils’ (IEN) at the Z-line (9/37 vs. 1/20 positive; p = 0.031) and 2cm proximally (6/37 vs. 0/20 positive; p = 0.012). The combined Zentilin histology score was also higher in GORD at the Z-line (p = 0.079) and 2 cm proximally (p = 0.05). Using GORD diagnosis from 96 hr Bravo as reference, ROC analysis revealed that, although sensitivity remained poor, specificity of GORD diagnosis based on histology improved with IEN and total histology score. With increased IEN, sensitivity was 30% at the Z-line and 20% 2 cm above while specificity was 92.6% at the Z-line and 100% 2cm proximally. For the optimal Zentilin histology score of ≥7, sensitivity was 40.5% at the Z-line and 18.9% 2cm above while specificity was 95% at the Z-line and 100% 2 cm proximally. Histology corroborated GORD diagnosis (based on positive TR) in 11/30 and 20/30 patients at the Z-line and in 6/30 and 11/30 patients 2 cm proximally. <h3>Conclusion</h3> Histology lacks sensitivity as a stand-alone diagnostic test; however high IEN or total histology scores have high specificity for GORD diagnosis based on pH-study results. Thus, routine biopsy of the distal oesophagus may be sufficient to diagnose GORD and obviate the need for ambulatory pH-studies in this subgroup of patients. <h3>Disclosure of Interest</h3> None Declared.
The Prognostic Value of C-Reactive Protein and Serum Amyloid A Protein in Severe Unstable Angina
Authors: Giovanna Liuzzo, Luigi M. Biasucci, J. Ruth Gallimore, Rita L. Grillo, Antonio G. Rebuzzi, Mark B. Pepys, Attilio Maseri
Journal: New England Journal of Medicine (1994)

The pathogenesis of unstable angina is poorly understood, and predicting the prognosis is problematic. Evidence suggests that there may be active inflammation, possibly in the coronary arteries, in this syndrome. We therefore studied the prognostic value of measurements of the circulating acute-phase reactants C-reactive protein and serum amyloid A protein, which are sensitive indicators of inflammation.
Abstract 3134: Neoadjuvant chemotherapy in ER+HER2- breast cancer: Response prediction based on immunohistochemical and molecular characteristics
Authors: Esther H. Lips, Lennart Mulder, Jorma J. De Ronde, Ingrid A.M. Mandjes, Andrew A. Vincent, Marie-Jeanne T.F.D Vrancken-Peeters, Petra M. Nederlof, Jelle Wesseling, Sjoerd Rodenhuis
Journal: Cancer Research (2011)

Abstract Introduction: A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy (NAC) in ER+HER2- tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be withheld from NAC, we tested standard pathology and molecular markers in ER+HER2- breast tumors. Methods: Pre-treatment biopsies were available from 211 ER+HER2- tumors, which had been treated with NAC. mRNA expression and aCGH data were available for 132 tumors. We determined progesterone receptor (PR)expression, endocrine responsiveness, histology, proliferation, molecular subtypes and BRCAness aCGH profiles. We correlated these data with chemotherapy response using pCR rates and the neoadjuvant response index (NRI). Results: PR-negative tumors (n = 65, 30.8%) and Luminal B type tumors (n=43, 20.4%) responded significantly better to NAC than other tumors, for both pCR breast and the NRI as outcome measure (table 1). The associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate (tumors with both a positive PR and of the Luminal A type (n=58, 44 %)), the majority showed downstaging (median NRI=0.25)(table 1). For endocrine responsiveness and the BRCAness aCGH profile only an association with pCR breast was observed. Histology (lobular versus ductal) and proliferation did not show an association with chemotherapy response (table 1). Discussion: PR expression and molecular subtype are associated with a better response to NAC. However, both markers had only weak predictive power and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain patients from NAC in ER+HER2- breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3134. doi:10.1158/1538-7445.AM2011-3134
S85 Effects Of Post Exacerbation Pulmonary Rehabilitation (pepr) On Exercise Tolerance, Quality Of Life (qol) And Health Care Utilisation
Authors: S. Harlow, A. Lewko, H. Black, S. Blandford, M. Irvin-Sellers
Journal: Thorax (2014)

<h3>Background</h3> PEPR has been shown to increase exercise tolerance, improve QoL and cut the cost of healthcare through reducing 30 day readmissions and A&amp;E attendances (NICE 2010). Further research into the impact of PEPR on QoL and healthcare utilisation has been called for (NICE 2010). The feasibility of PEPR in practice has yet to be established (Jones <i>et al</i> 2013, Thorax). We secured funding to pilot PEPR in our local DGH population. Here, we present the initial five months data. <h3>Aims and objectives</h3> This study aimed to investigate the impact of PEPR on exercise tolerance, QoL and health care utilisation in a local DGH population. <h3>Methods</h3> Data were collected prospectively from successive patients referred for PEPR between December 2012 and May 2014. Outcome measures consisted of ISWT and QoL (CAT). Healthcare utilisation was measured through 30 and 90 day readmission and A&amp;E attendance rates. Descriptive statistics and significance values were calculated in SPSS (version 22) using paired t-test and Chi<sup>2</sup>. <h3>Results</h3> 64 patients were referred to PEPR. 53% (n = 34) decline to attend, 15% (n = 10) failed to complete the programme. Subsequently 31% (n = 20) patients completed PEPR which is comparable to standard PR. Exercise tolerance was significantly improved (difference between the means 46 m 95% CI +/-33 m p = 0.009). QoL was significantly improved (difference between the means 5.4 95% CI +/-3.1 p = 0.002). Table 1 demonstrates the impact of PEPR on healthcare utilisation. Both 30 and 90 day readmissions were significantly reduced. 90 day A&amp;E attendances were significantly reduced. Average LoS following readmission in the group who declined PEPR was 11 days compared to an average LoS following readmission in PEPR group of 1 day. Considering the savings associated with bed days alone and staffing expenses the cost benefit of PEPR was £21309 pa. <h3>Conclusions</h3> Results suggest PEPR in a DGH population has a significant impact on QoL and exercise tolerance with reductions in healthcare utilisation and associated cost benefits.
Abstract 184: HIPK2 downregulates Nox1 that is involved in p53Lys382 deacetylation and suppression of p53 oncosuppressor function
Authors: Rosa Puca, Lavinia Nardinocchi, Gabriellla D'Orazi
Journal: Cancer Research (2011)

Abstract .HIPK2 is a stress-induced kinase and a transcriptional co-repressor that functionally cooperates with p53 to suppress cancer. Activation of the p53 proapoptotic function requires a cascade of phosphorylations and acetylations, and HIPK2 takes part in both modifications in that it phosphorylates Ser46 and allows Lys382 acetylation. In a cDNA microarray analysis we have found that depletion of HIPK2, that strongly affects p53 transcriptional function, induces Nox1 upregulation. Nox1, a homologue of the catalytic subunit of the superoxide-generating NADPH-oxidase is often overexpressed in tumors where triggers the angiogenic switch and induces genome instability by producing oxygen reactive species (ROS). However, the involvement of Nox1 in p53 regulation has never been addressed. We found that HIPK2 downregulated Nox1-luc promoter activity and that Nox1 upregulation, following HIPK2 silencing or Nox1 overexpression, inhibited drug-induced p53 Lys382 acetylation that strongly affected p53 apoptotic activity. P53Lys382 is a target of SirT1, a NAD-dependent deacetylase that is often upregulated in tumors and inhibits p53 apoptotic function. By the use of either small interfering RNAs to target SIRT1 or the SirT1 inhibitor nicotinamide we found that Nox1-dependent inhibition of p53 transcriptional activity was SirT1-dependent. Thus, Nox1 was unable to inhibit p53 when coexpressed with a SirT1 deacetylase-defective mutant (SIRT1HY) suggesting a link between Nox1 and SirT1 activity and a novel mechanism of SirT1 activation. Finally, recovery of HIPK2 function, by the use of Doxicyclin-induced conditional interference, downregulated Nox1 expression and reduced ROS production with rescue of p53Lys382 acetylation and p53 apoptotic activity. These findings suggest that Nox1 is a novel target of HIPK2 repressor function and is linked to p53 inactivation involving SirT1 activation and probably ROS production. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 184. doi:10.1158/1538-7445.AM2011-184
Strategies for Empiric Management of Pediatric Fever and Neutropenia in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review of Randomized Trials
Authors: Paula D. Robinson, Thomas Lehrnbecher, Robert Phillips, L. Lee Dupuis, Lillian Sung
Journal: Journal of Clinical Oncology (2016)

Purpose To describe treatment failure and mortality rates with different antibiotic regimens and different management strategies for empirical treatment of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. Methods We conducted a systematic review and performed searches of MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials. Studies were included if pediatric patients had cancer or were HSCT recipients and the intervention was related to the management of FN. Strategies synthesized were monotherapy versus aminoglycoside-containing combination therapy; antipseudomonal penicillin monotherapy versus fourth-generation cephalosporin monotherapy; inpatient versus outpatient management; oral versus intravenous antibiotics; and addition of colony-stimulating factors. Results Of 11,469 citations screened, 68 studies randomly assigning 7,265 episodes were included. When compared with monotherapy, aminoglycoside-containing combination therapy did not decrease treatment failures (risk ratio, 1.13; 95% CI, 0.92 to 1.38; P = 0.23), and no difference in mortality was observed. Antipseudomonal penicillin and fourth-generation cephalosporin monotherapy were associated with similar failure and mortality rates. Outpatient management and oral antibiotics were safe in low-risk FN with no infection-related mortality observed in any patient and no significant differences in outcomes compared with inpatient management and intravenous therapy. Therapeutic colony-stimulating factors were associated with a 1.42-day reduction in hospitalization (95% CI, 0.62 to 2.22 days; P &lt; .001). Conclusion There were a moderate number of pediatric randomized trials of FN management. Monotherapy for high-risk FN and outpatient and oral management for low-risk FN are effective strategies. These findings will provide the basis for guideline recommendations in pediatric FN.
Abstract LB-420: Intratumoral de novo steroid synthesis mediates prostate cancer resistance to androgen deprivation and CYP17a1 inhibition
Authors: Changmeng Cai, Steven P. Balk
Journal: Cancer Research (2011)

Abstract Prostate cancer (PCa) that relapses after androgen deprivation therapy (ADT, medical or surgical castration), termed castration resistant prostate cancer (CRPC), has increased expression of enzymes that convert adrenal dehydroepiandrosterone (DHEA) and androstenedione to testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized at high levels by the adrenals through the sequential actions of CYP11A1 and CYP17A1; hence CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, mechanisms contributing to CYP17A1 inhibitor relapse remain to be determined. We show that castration resistant VCaP PCa xenografts synthesize androgens de novo at levels that fully restore androgen receptor (AR) activity and respond to abiratrone, and that development of abiraterone resistance is associated with markedly increased intratumoral CYP17A1 expression. Consistent with these results, we find that tumor expression of CYP17A1 is markedly increased in patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a T877A mutant AR are not CYP17A1 dependent, and that AR activity in these cells is instead mediated by upstream CYP11A1 dependent pregnenolone/progesterone synthesis. These findings indicate that CYP17A1 inhibitor resistant tumors are still steroid dependent and may respond to dose escalation, alternative CYP17A1 inhibitors, or agents blocking other steps in steroid synthesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-420. doi:10.1158/1538-7445.AM2011-LB-420
498P The significance of intratumor morphological heterogeneity in breast cancer progression and pathogenetic mechanisms
Authors: E.V. Denisov, T.S. Gerashchenko, L.A. Tashireva, D.N. Pautova, M.V. Zavyalova, N.V. Cherdyntseva, V.M. Perelmuter
Journal: Annals of Oncology (2015)
Abstract 797: Targeted next generation sequencing of FFPE lung cancer tissue.
Authors: Volker Endris, Albrecht Stenzinger, Roland Penzel, Arne Warth, Peter Schirmacher, Wilko Weichert
Journal: Cancer Research (2013)

Abstract In view of a personalized medicine, the screening of somatic mutations in an individual tumor that predict therapeutic outcome has become an increasing need in the clinical and molecular diagnostics. In most laboratories, Sanger sequencing has become an accepted standard, but due to the limited screening throughput and the increasing demand for targeted sequencing, the application of next-generation sequencing in the molecular diagnostic has turned into focus. Whole-genome or whole-exome sequencing approaches provide a comprehensive view of an individual tumor mutation load, but the current high costs and the excess of information without a direct clinical implication limit the routine use of this technology. In this study, we evaluated a targeted resequencing approach that focuses on somatic hotspot cancer mutations based on semiconductor sequencing. We especially took attention on the reliability of the method concerning sample quality, mutation type and reproducibility. We used DNA extracted from formalin-fixed, paraffin embedded (FFPE) tumor tissues (biopsy and resection) of different tumor degree and overall quality that were previously screened for the presence of EGFR mutations (exon 18-21) by Sanger sequencing. 190 amplicons covering hotspot mutations in 46 genes were generated in a multiplex PCR reaction (AmpliSeqTM), barcoded and 8 samples were run on a single IonTorrent 318 chip. We were able to successfully sequence all samples with a mean coverage rate of 670.000 reads (AQ20:560.000) and an average read depth of 2947 AQ20 reads / amplicon. In all but one sample, variant calling identified the EGFR mutation, missing only one low level 9bp insertion in exon 20. Moreover, we identified additional 43 mutations in 17 genes and uncovered three previously unknown EGFR amplifications. Taken together, amplicon-based semiconductor sequencing is a powerful and cost-effective method working with low-quality DNA material, enabling routine diagnostic next-generation sequencing. Citation Format: Volker Endris, Albrecht Stenzinger, Roland Penzel, Arne Warth, Peter Schirmacher, Wilko Weichert. Targeted next generation sequencing of FFPE lung cancer tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 797. doi:10.1158/1538-7445.AM2013-797
<i>BRAF</i> V600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF–MEK Combination Therapy
Authors: Samuel J. Klempner, Bruce Gershenhorn, Phu Tran, Thomas K. Lee, Mark G. Erlander, Kyle Gowen, Alexa B. Schrock, Deborah Morosini, Jeffrey S. Ross, Vincent A. Miller, Philip J. Stephens, Sai-Hong Ignatius Ou, Siraj M. Ali
Journal: Cancer Discovery (2016)

Abstract Neuroendocrine tumors comprise a heterogeneous group of malignancies with a broad spectrum of clinical behavior. Poorly differentiated tumors follow an aggressive course with limited treatment options, and new approaches are needed. Oncogenic BRAF V600E (BRAFV600E) substitutions are observed primarily in melanoma, colon cancer, and non–small cell lung cancer, but have been identified in multiple tumor types. Here, we describe the first reported recurrent BRAFV600E mutations in advanced high-grade colorectal neuroendocrine tumors and identify a BRAF alteration frequency of 9% in 108 cases. Among these BRAF alterations, 80% were BRAFV600E. Dramatic response to BRAF–MEK combination therapy occurred in two cases of metastatic high-grade rectal neuroendocrine carcinoma refractory to standard therapy. Urinary BRAFV600E circulating tumor DNA monitoring paralleled disease response. Our series represents the largest study of genomic profiling in colorectal neuroendocrine tumors and provides strong evidence that BRAFV600E is an oncogenic driver responsive to BRAF–MEK combination therapy in this molecular subset. Significance: BRAFV600E is an established oncogenic driver, but significant disparities in response exist among tumor types. Two patients with treatment-refractory high-grade colorectal neuroendocrine tumors harboring BRAFV600E exhibited rapid and durable response to combined BRAF–MEK inhibition, providing the first clinical evidence of efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594–600. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 561
When I use a word . . ."Well tolerated" is intolerable
Authors: J. K. Aronson
Journal: BMJ (2014)

Let me be plain. I can’t stand intolerance.

On the other hand, I’m not sure about tolerance either.

It’s not obvious, but “tolerance” comes from the Latin word ferre , to carry, whose principal parts, from different roots, are ferro , ferre , tuli , latum (see BMJ 2000;320:625). And “tolerance” carries several technical meanings.

Pharmacological tolerance can be acquired or natural. Acquired tolerance is reduced sensitivity to a drug, from previous exposure either to it or (cross-tolerance) to another drug. It should not be confused with tachyphylaxis or …
AB0570 Takayasu's Arteritis and Factors Affecting the Course and Prognosis
Authors: E.N. Scryabina, A.S. Korotin
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Late determination of the disease and high frequency of severe outcomes make Takayasu9s arteritis (TA) study an actual problem [1]. <h3>Objectives</h3> To identify factors affecting the course of TA and determining its prognosis. <h3>Methods</h3> We analyzed 283 case histories of 30 pts, treated in the department of rheumatology of Saratov Regional Hospital since 2ooo to 2013 year. Doppler ultrasound, the levels of C-reactive protein (CRP), circulating immune complexes (CIC), circulating endothelial cells (CEC), and erythrocyte sedimentation rate (ESR) were used for the diagnosis and monitoring of TA. CECs9 number was determined by method of J. Hladovec (1978)[2]. The pts were divided into 2 groups: I group-with a favorable course of the disease (n=21), II-pts with severe complications (n=9). <h3>Results</h3> There were significantly more men in II group than in I (55,5% and 9,5%),significantly greater number of damaged vessels, later onset of basic therapy (10,78±9,2 and 5,36±4,88 years, p&lt;0,05)and shorter its total duration (6,3±4,1 and 1,61±1,10 years, p&lt;0,05). Management was based on the monitoring of the patient every 3-6 months with the assessment of disease activity and the dynamics of vascular lesions. Appointment of therapy and its correction was performed according to the identified changes. After the therapy the levels of CEC and CIC in I group were significantly lower than before treatment. CEC had decreased from 8,9±7,03 to 3,3±2,01. The health of patients in I group due to the treatment remained satisfactory. In II group 11 revascularization operations had been performed and 5 patients died due to severe complications of ischemic character: myocardial infarction, stroke, thrombosis of mesenteric vessels, acute renal failure, massive bleeding in postoperative period. <h3>Conclusions</h3> The levels of CEC and CEC are the most informative markers of TA activity. There are several factors, which influence on the course of TA: sex, number and severity of damaged vessels, activity of the disease, the start date of treatment, monitoring and correction of the patient therapy based on activity of the process and the dynamics of vascular lesions, application of optimal treatment, including immunosuppressive, anti-platelet and vasoactive drugs. <h3>References</h3> A.Balbir-Gurman and Y. Braun-Moscovici. IMAJ 2012; 14: 757-759. Hladovec. J.Physiol.Bohemoslov.1978; 27: 140-144. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4132