tbuckley/cabot-search huggingface dataset:
Abstract 27: A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors.
Authors: Toshihiko Doi, Nozomi Fuse, Takayuki Yoshino, Kohei Shitara, Hideaki Bando, Hideaki Miyamoto, Susumu Koyama, Katsuya Tsukada, Atsushi Ohtsu
Journal: Cancer Research (2013)

Abstract Background: BAY 86-9766 (RDEA119) is a potent, orally administered,, allosteric inhibitor of mitogen-activated protein (MAP) kinase kinase (MEK) 1/2, a key protein in the MAP kinase signaling pathway, located downstream of RAS and RAF. We conducted a phase I study to evaluate the safety and pharmacokinetics (PK) of BAY 86-9766 in advanced/refractory Japanese cancer patients. Patients and Methods: BAY 86-9766 was administered at 30 mg bid (cohort 1) and at 50 mg bid (MTD; cohort 2) over a 28-day treatment cycle which was continued until disease progression or unacceptable toxicity. PK samples were collected after single doses (Day 1 to Day 4) and during multiple dosing through Day 22. Tumor response was assessed after every even cycle by RECIST v.1.1. Results: A total of 12 patients were enrolled, including 6 colorectal cancer, 2 GIST, and one hepatocellular cancer, carcinoid tumor, neuroendocrine tumor and leiomyosarcoma, respectively (5 patients in cohort 1: 30mg bid; 7 patients in cohort 2: 50mg bid). There were no DLTs in Cycle 1 of cohort 1 and cohort 2. The most common adverse event regardless of grade was rash acneiform in 12 subjects (100.0%), followed by elevated AST, creatine phosphokinase (CPK) or hypoalbuminemia in 9 subjects (75.0%), fever or elevated ALP in 7 subjects (58.3%), elevated ALT or decreased platelet count in 6 subjects (50.0%). Of those, the most common drug-related adverse events were rash acneiform (100.0%), followed by elevated CPK (66.7%), laboratory-others (66.7%), elevated AST (58.3%), and elevated ALP (50.0%). There were three cases of serious adverse events - thrombocytopenia, bile duct stenosis and elevated CPK - with only the elevated CPK being regarded as drug-related. There were no deaths on study. In Cohort 2, 7 out of 7 patients had elevated CPK, with 4 patients Grade 3 or higher. None of these were considered clinically significant and were not regarded as DLT's. Three patients had a positive de-challenge and re-challenge and 2 patients experienced muscle-related symptoms (neck pain and muscle weakness of the lower limb). PK parameters were comparable to the non-Japanese population. Conclusions: BAY 86-9766 was generally well tolerated at both the 30 mg bid dose and the MTD of 50 mg bid. BAY 86-9766 administration increased CPK in a majority of patients but this was manageable by dose reduction. Citation Format: Toshihiko Doi, Nozomi Fuse, Takayuki Yoshino, Kohei Shitara, Hideaki Bando, Hideaki Miyamoto, Susumu Koyama, Katsuya Tsukada, Atsushi Ohtsu. A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors. [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 27. doi:10.1158/1538-7445.AM2013-27
SAT0102 Rituximab-Induced T-Cell Depletion in Patients with Rheumatoid Arthritis: Association With Clinical Response
Authors: J. Mélet, D. Mulleman, P. Goupille, B. Ribourtout, H. Watier, G. Thibault
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Rituximab, a monoclonal antibody specifically targeting CD20, induces B-cell depletion and is effective in rheumatoid arthritis (RA). We aimed to study whether routine monitoring of lymphocyte subpopulations, especially T cells, may be useful in patients receiving rituximab for RA. <h3>Methods</h3> We examined data for all patients receiving rituximab between July 2007 and November 2012 in our centre. Peripheral blood CD3<sup>+</sup>, CD4<sup>+</sup>, CD8<sup>+</sup>, CD3<sup>-</sup>CD56<sup>+</sup> and CD19<sup>+</sup> lymphocyte counts before and during the first course of rituximab were measured by flow cytometry. Mann-Whitney non-parametric test was used to compare lymphocyte subpopulation counts before and during treatment. <h3>Results</h3> We examined data for 75 patients (64 with RA, 11 with other inflammatory diseases). Rituximab induced unexpected and substantial depletion of T cells, mainly CD4<sup>+</sup> cells, in most patients. The CD4<sup>+</sup> count was 80% of the initial count, and was ≤ 200 CD4<sup>+</sup> cells/mL in some patients. Importantly, lack of CD4<sup>+</sup> cell depletion was associated with no clinical response, so the mechanism of action of rituximab may depend at least in part on T cells. <h3>Conclusions</h3> Rituximab induces substantial T-cell depletion mainly CD4+ cells, which is associated with the clinical response in RA. Routine monitoring of T cells may be useful in the clinical setting in inflammatory diseases. <h3>Acknowledgements</h3> The authors thank Drs Saloua Mammou, Isabelle Griffoul, Emilie Ducourau, and Virginie Martaillé for helping in clinical assessment. We are indebted to Nelly Jaccaz-Vallée, Sergine Gosset, Valérie Angebeau, Laetitia Cornec, Adeline Coutellier, Corinne Depont, Vanessa Fougeray, Valérie Fuseau, Pascale Guibout, Sophie Joncheray, Céline Letot, Isabelle Romier and Elodie Vigneron for blood sampling and their commitment in taking care of patients and to Claude Gautier and Elisabeth Billant who performed blood sample staining and flow cytometry analysis. <h3>Disclosure of Interest</h3> J. Mélet: None Declared, D. Mulleman Grant/research support from: Abbott, Roche, BMS, Pfizer, UCB and MSD, Consultant for: MSD and Pfizer, P. Goupille Grant/research support from: Abbott, Roche, BMS, Lilly, Novartis, Pfizer, UCB and MSD, Consultant for: Abbott, BMS, MSD, Pfizer, UCB, B. Ribourtout: None Declared, H. Watier: None Declared, G. Thibault: None Declared
Nonsurgical Reconstruction of Thoracic Aortic Dissection by Stent–Graft Placement
Authors: Christoph A. Nienaber, Rossella Fattori, Gunnar Lund, Christoph Dieckmann, Walter Wolf, Yskert von Kodolitsch, Volkmar Nicolas, Angelo Pierangeli
Journal: New England Journal of Medicine (1999)

The treatment of thoracic aortic dissection is guided by prognostic and anatomical information. Proximal dissection requires surgery, but the appropriate treatment of distal thoracic aortic dissection has not been determined, because surgery has failed to improve the prognosis.
Abstract 2245: Fever-range whole-body thermochemotherapy (FR-WB-TT + chemo-biotherapy) can induce long-duration response in both metastatic small-cell lung cancer (SCLCA) and other chemotherapy resistant neuroendocrine cancers
Authors: Joan Marie C Bull, Theresa Dancsak, Young Su, Shuang Li, Michael D. Redwine, Terri M. King, Robert E. Brown
Journal: Cancer Research (2011)

Abstract Introduction: Metastatic small-cell lung cancer (SCLCA) often relapses quickly after chemotherapy and survival thereafter is short. Resistant neuroendocrine cancers of other origins also have a poor prognosis. Methods: A schedule-optimized Phase I-II thermochemotherapy regimen combining FR-WB-TT with cisplatin (CIS), gemcitabine (GEM), and metronomic interferon-α (IFN) was tested. The treatment regimen used an explicitly sequenced combination of CIS (60 mg/m2) given day 1 with weekly IFN (100 mcg. peginterferon-α-2). On day 3, thirty-six hours later, FR-WB-TT (6h at 40°C) was administered with GEM (600 mg/m2). GM-CSF was administered daily for 10 days beginning 1 week after GEM. The cycle was repeated every 28 days. Results: We have treated 14 patients with metastatic neuroendocrine cancer; 3 with SCLCA and 11 with other neuroendocrine cancers (4 large-cell neuroendocrine of lung, 3 pancreas, 2 prostate, 1 H&amp;N, &amp; 1 adrenal). Thirteen (93%) received prior chemotherapy. The number of treatments ranged from 1-6 (median 4). Response: Using RECIST criteria, we documented: 2 complete responses [CR; 14 %; both SCLCA, durations 45+ months (m), 52 m], 6 partial responses (PR; 43%; &amp;gt;90% tumor response; mean duration 25 m, range 8-37 m; 2 prostate, 2 pancreas, 1 H&amp;N, 1 adrenal). Three patients had stable disease (SD; 21%; all &amp;gt; 4 m duration; 2 large-cell of lung, 1 pancreas). Three patients had progressive disease (PD; 21%; 2 large-cell neuroendocrine of lung, 1 SCLCA). In summary, we observed a 57% overall response (CR + PR). Toxicity: We documented grade 2 leucopenia in twelve patients (86%), grade 2 thrombocytopenia in eight patients (57%), and grade 1 thrombocytopenia in six patients (43%). All patients developed grade 2 anemia. One patient (7%) had a small, grade 2, skin burn. We observed no neuropathy or ototoxicity. Although not formally documented, responding patients experienced increased quality of life with greatly decreased/elimination of pain, weight gain, and resumption of normal activity. Conclusion: This multimodality FR-WB-TT regimen appears to be well tolerated, and demonstrates good clinical activity of relatively long duration in metastatic SCLCA and other resistant stage IV neuroendocrine cancers. 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 2245. doi:10.1158/1538-7445.AM2011-2245
SP0005 An economist’s long-term perspective on pricing of drugs
Authors: B. Jonsson
Journal: Annals of the Rheumatic Diseases (2013)

Pricing of dugs can be divided into three phases. The first phase is the time of introduction of a new drug. If it is similar to other drugs in the market it will be “clustered” and the price is determined by the price of the other product(s) in the market. If it is sufficiently different, the producer has a degree of freedom in pricing and the decision-making is focused around assessments of value, i.e. “value based pricing”. A problem with this concept is that value is linked to the use of the product, not only the product itself, and can thus vary dependent on which patients or indications it is used for. Pricing is thus often a trade off between price and size of the market. The second phase is the period of patent protection when new competitors with similar effectiveness enter the market. During this period the price remains rather constant, as new entrances to the market compete with differentiation of the product rather than the price. There are very few examples of “penetration pricing strategies”, where a new entrant launches at a much lower price. New entrants to the market usually mean that the market growth, and payers are often complaining that there is no price competition on the market. International price comparisons are some times used to make adjustments to the prices of individual drugs on the market. The market for biologicals used for treatment of RA is a good example of this type of market. The third phase is when the patent expires for first product in the new class of drugs. Before the establishment of a single market for pharmaceuticals in Europe, the price as well as the market share good be maintained even after patent expiration, due to national price regulations. However, today the price reduction when the patent is lost often is both large and fast, similar to what have been seen in the US for a long time. Price reduction of 90% or more within a few months is not unusual. Will the same happen when biosimilars will be available for the best selling biological drugs used for treatment of RA, Ms and cancer? It is still not possible to answer this question with certainty, but there are indications that we will see significant price reductions also for these drugs, even if the production process is more complex and the regulatory requirements more demanding than for traditional generics. Pricing of drugs is important first of all as an incentive for pharmaceutical innovation. While traditional price controls have been eliminated in most markets, the link between pricing and reimbursement is the key element for the future since third party payment dominates for new drugs. The introduction of many new orphan drugs and targeted therapies for small group of patients are new feature in the market, which create new challenges for pharmaceutical pricing in the future. <h3>Disclosure of Interest</h3> None Declared
Foreseeing is not necessarily the same as intending
Authors: R. Gillon
Journal: BMJ (1999)

<i>Following the acquittal of an English doctor, Dr David Moor, who had given a dying patient a lethal dose of diamorphine, we invited two ethicists to debate the issue at the centre of the case: that of giving a drug with the intention of relieving suffering even though it may hasten death. Professor Raanan Gillon argues that the difference between intending and foreseeing is all important, while Professor Len Doyal argues that the effect of this is to raise the moral character of a clinician above the best interests of his or her patients</i>
P199 Diabetic macular oedema (DME) and obstructive sleep apnoea (OSA)--visual improvement post CPAP therapy. Proof of principle study
Authors: R. H. Mason, C. A. Kiire, A. Bolton, L. Smith, V. Chong, J. R. Stradling
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> DME is an important cause of visual loss and is more advanced in patients with coexistent OSA.<sup>1</sup>OSA is very common in individuals with DME (54%), compared to unselected patients with type II diabetes (23%)<sup>2</sup> and age matched controls (8%).<sup>3</sup> This study was designed to see if CPAP could improve vision in patients with DME and coexistent OSA, perhaps via a reduction in intermittent hypoxia and/or blood pressure oscillations. <h3>Methods</h3> 35 patients with DME (identified by ocular coherence tomography, OCT) and OSA (oxygen desaturation index &gt;10, or apnoea hypopnoea index &gt;15) were identified. Visual acuity (VA, logMAR, similar to the Snellen chart) and OCT measurements were made twice at baseline (pre-CPAP), 3 and 6 months (post-CPAP). <h3>Results</h3> 32 patients (17 males) participated; 4 withdrew. 28 have 3-month follow-up data and, 24 have 6-month data. Average (SD) age 66.6 years, (8.3), BMI 31.8 Kg/m<sup>2</sup> (6.7), HbA1c 7.5% (1.4%), ESS 7.9 (4.6), ODI 20.9 (14.8) and AHI 19.0(14.5). CPAP compliance was averaged over the 6 months and a median split into ‘high’ and ‘low’ compliers performed (&gt; and &lt;2.5 h/n). At 3 months VA improved significantly in both high (p=0.009) and low compliers (p=0.001). This was only sustained at 6 months in high compliers, p=0.004. (Low compliers p=0.52). There was no significant reduction in macular oedema at either 3 or n. <h3>Conclusions</h3> This hypothesis-generating uncontrolled study indicates that continued use of CPAP in individuals with DME and OSA was associated with sustained improvement in visual acuity. This result provides justification to perform an RCT and suggests that logMAR should be the primary endpoint whereas OCT measurements appear uninformative.
Abstract 2159: Molecular characterization of ERG mediated CXCR4 transcriptional regulation
Authors: Rajareddy Singareddy, Jason Saint John, Sreenivasa R. Chinni
Journal: Cancer Research (2011)

Abstract CXCR4 is a chemokine receptor, which has been shown to be expressed in several types of tumor cells, and mediate invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive phenotypes of prostate cancer. Previously, we and others have shown that ERG transcription factor regulates CXCR4 expression in prostate cancer cells. In prostate cancer patients ERG is expressed via chromosomal alterations resulting in fusion of androgen responsive TMPRSS2 promoter with the coding sequence of ERG transcription factor and systemic androgens regulate ERG expression. We further show that in TMPRSS2-ERG fusion positive prostate cancer cells androgens regulate CXCR4 expression via activating ERG transcription factor expression. The CXCR4 promoter contains several putative ERG/Ets transcription factor binding sites. We hypothesize that ERG binds to selective ERG/Ets binding sites in the CXCR4 promoter and activates CXCR4 expression. Using electrophoretic mobility shift assay experiments with each of the individual ERG/Ets binding sites with VCaP cell nuclear extracts and in vitro translated ERG protein, sequential ERG/Ets binding site deletions in CXCR4 promoter reporters, chromatin immunoprecipitation experiments with anti-ERG antibodies in TMPRSS2-ERG positive VCaP cells, and chemoinvasion studies with VCaP cells we show that: (a) ERG expressed in VCaP cells selectively interacts with specific ERG/Ets bindings sites in the CXCR4 promoter; (b) several Ets factor family members are expressed in VCaP cells; (c) in vitro translated ERG binding with ERG/Ets elements in CXCR4 promoter further confirms that selective ERG/Ets sites in CXCR4 promoter are active in binding with ERG; (d) ERG binds with CXCR4 gene promoter in VCaP cells; (e) androgens regulate CXCR4 expression in TMPRSS2-ERG fusion positive cells; and (f) androgen induced CXCR4 is active in chemoinvasion of prostate cancer cells. These data suggest that androgens regulate CXCR4 expression via ERG transcription factor expression and ERG factor may regulate CXCR4 expression by binding to the specific ERG/Ets responsive elements and activating CXCR4 transcription. These findings may provide a link between TMPRSS2-ERG translocations and enhanced metastasis of tumor cells via CXCR4 function in PC cells. 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 2159. doi:10.1158/1538-7445.AM2011-2159
Episodic Stupor Following Portacaval Shunt
Authors: Curtis J. Fisher, William W. Faloon
Journal: New England Journal of Medicine (1956)

SINCE the report of Gabuzda et al.1 of episodes of "impending coma" in patients with hepatic cirrhosis given ammonium-containing cation-exchange resins, and the studies of Phillips et al.2 on the precipitation of this syndrome by the ingestion of nitrogenous substances, the role of ammonia in hepatic coma has been extensively explored. As a result of these investigations the restriction of dietary protein has been recommended as a therapeutic measure in patients with hepatic cirrhosis in whom impending coma or stupor develops.The association of elevated blood ammonia with episodes of stupor occurring in several patients with portacaval shunts has also . . .
SAT0121 High incidence of demyelinising neurological disease after anti TNF-alpha treatment in a rheumatological population
Authors: A. Theibich, H. Locht, L. Drejer
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AE) are primarily infections and hypersensitivity reactions. Demyelinising neurological symptoms resembling multiple sclerosis (MS) has been described and considered a rare AE. During about 10-years use of anti TNF compounds the Danish Medicines Agency has registered 8 cases of MS like AEs. <h3>Objectives</h3> To estimate the incidence of demyelinising neurological AEs both in the central and peripheral nervous system after treatment with TNF inhibitors in a cohort of patients from a large rheumatological out-patients clinic in Copenhagen. <h3>Methods</h3> In a 2-year period from January 2010 – December 2011 approximately 500 patients were undergoing treatment with TNF-alpha blockers in our Department. We collected data on all patients who developed neurological symptoms during this time period. <h3>Results</h3> We found 6 patients with signs of demyelinising neurological disorders. Four resembling MS, 1 MS-like condition, and 1 multifocal motor neuropathy (Table). <h3>Conclusions</h3> During a relatively short time period we found a remarkably high number of neurological demyelinising AEs probably linked to anti TNF-alpha treatment. The AEs were not associated with a single anti TNF-alpha agent and therefore probably due to a class-effect. The data presented suggest that neurological AEs may be under-reported. We advocate that physicians handling patients during treatment with TNF inhibitors are aware of this potentially serious AE and report these events to the proper medicinal authorities. <h3>References</h3> Alberto Ascherio and Kassandra Munger. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention.Semin Neurol 2008; 28:17-28 David A. Hafler, Howard L. Weiner. MS: a CNS and systemic autoimmune disease. Immunol Today. 1989;10:104–107. Kollias, E Douni, G Kassiotis, et al. The function of tumor necrosis factor and receptors in models of multi-organ inflammation, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Ann Rheum Dis. 1999;58(suppl 1):132–139. M Tanno, I Nakamura, S Kobayshi et al. New-Onset demyelination induced by Infliximab Therapy in two Rheumatoid Arthritis Patients. Clin. Rheumatol. 2006;25(6):929-933. <h3>Disclosure of Interest</h3> None Declared
PWE-201 Techniques for removal of polyps from the right colon: how are we doing them?: Abstract PWE-201 Table 1
Authors: S K Butt, K Besherdas
Journal: Gut (2012)

The regulation of cutaneous inflammatory processes is essential for the human skin to maintain homeostasis in the presence of the dense communities of resident microbes that normally populate this organ. Forming the hair follicle–associated sebaceous gland, sebocytes are specialized lipid-producing cells that can release inflammatory mediators. Cytokine and chemokine expression by pilosebaceous epithelial cells (i.e., sebocytes and follicular keratinocytes) has been proposed to contribute to the common human skin disease acne vulgaris. The underlying mechanisms that drive inflammatory gene expression in acne-involved pilosebaceous epithelial cells are still unknown because almost all sebaceous follicles contain dense concentrations of bacteria yet only some show an inflammatory reaction. In this study, we hypothesized that metabolites from the abundant skin-resident microbe <i>Propionibacterium acnes</i> can influence cytokine expression from human sebocytes. We show that short-chain fatty acids produced by <i>P. acnes</i> under environmental conditions that favor fermentation will drive inflammatory gene expression from sebocytes. These molecules are shown to influence sebocyte behavior through two distinct mechanisms: the inhibition of histone deacetylase (HDAC) activity and the activation of fatty acid receptors. Depletion of HDAC8 and HDAC9 in human sebocytes resulted in an enhanced cytokine response to TLR-2 activation that resembled the transcriptional profile of an acne lesion. These data provide a new insight into the regulation of inflammatory gene expression in the skin, further characterize the contribution of sebocytes to epidermal immunity, and demonstrate how changes in the metabolic state of the skin microbiome can promote inflammatory acne.