tbuckley/cabot-search huggingface dataset:
Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial
Authors: Patrick Verschueren, Diederik De Cock, Luk Corluy, Rik Joos, Christine Langenaken, Veerle Taelman, Frank Raeman, Isabelle Ravelingien, Klaas Vandevyvere, Jan Lenaerts, Elke Geens, Piet Geusens, Johan Vanhoof, Anne Durnez, Jan Remans, Bert Vander Cruyssen, Els Van Essche, An Sileghem, Griet De Brabanter, Johan Joly, Sabrina Meyfroidt, Kristien Van der Elst, Rene Westhovens
Journal: Annals of the Rheumatic Diseases (2016)

Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year.The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639).98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals.MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed.EudraCT-number 2008-007225-39 and NCT01172639; Results.
Abstract LB-242: Identification of T-cell receptors targeting KRAS-mutated human tumors
Authors: Qiong J. Wang, Zhiya Yu, Kenichi Hanada, Nicholas P. Restifo, James C. Yang
Journal: Cancer Research (2016)

Abstract KRAS is one of the most frequently mutated proto-oncogenes in human cancers, including pancreatic and colorectal cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V. The consistency, frequency, and tumor specificity of these “neo-antigens” make them attractive therapeutic targets. Recent data associates T cells targeting mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer or cholangiocarcinoma. We successfully generated T cells from HLA-A11*01 transgenic mice and subsequently isolated HLA-A11*01-resticted T cell receptors (TCRs) highly reactive with the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs can recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBL reactive with a mutated pancreatic cell line could significantly reduce its growth in NSG mice. The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers support clinical trials with these T-cells recognizing mutated KRAS in patients with a variety of common cancer types. A phase I/II clinical trial targeting KRAS G12V and G12D mutations with TCR-engineered PBL in HLA-A1101+ patients will be starting soon in the Surgery Branch NCI. Citation Format: Qiong J. Wang, Zhiya Yu, Kenichi Hanada, Nicholas P. Restifo, James C. Yang. Identification of T-cell receptors targeting KRAS-mutated human tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-242.
Tension-type headache
Authors: Sait Ashina, Dimos D. Mitsikostas, Mi Ji Lee, Nooshin Yamani, Shuu-Jiun Wang, Roberta Messina, Håkan Ashina, Dawn C. Buse, Patricia Pozo-Rosich, Rigmor H. Jensen, Hans-Christoph Diener, Richard B. Lipton
Journal: Nature Reviews Disease Primers (2021)
ELUCIDATION OF THE MECHANISM OF INCREASED BILE SALT-INDUCED BILIARY LIND SECRETION IN MICE WITH GENETIC INACTIVATION OF BILE SALT EXPORT PUMP (BSEP)
Authors: Karin E. Gooijert, Rick Havinga, Henk Wolters, Renxue Wang, Victor Ling, Susumu Tazuma, Henkjan J. Verkade
Journal: Hepatology (2008)
Abstract 760: Identifying candidate genes that regulate tumor cell dormancy
Authors: Ryan J. Nini, Lara H. El Touny, Meera Murgai, Rosandra N. Kaplan, Jeffrey E. Green
Journal: Cancer Research (2016)

Abstract Tumor cells disseminate from the primary tumor site early in the disease process. These disseminated tumor cells may remain dormant for years and later become proliferative to cause clinical recurrence and morbidity. The goal of this study is to better understand the biological and genetic mechanisms driving this dormant to proliferative switch. We have developed a 3D culture system using the dormant murine mammary tumor cell line, D2.0R. D2.0R cells remain dormant when cultured on basement membrane extract (BME), and exit dormancy when supplemented with collagen-1 (col-1). We have characterized the gene expression profile of these cells exiting dormancy in 3D through microarray analysis, and developed a fourteen-gene dormancy signature by profile cross-referencing this expression profile to a tumor cell dormancy signature developed by Kim, R.S. et al (PLOS ONE 2012). We hypothesize that knocking down expression of genes upregulated in proliferative cells will hinder the ability of D2.0R cells to break dormancy in 3D culture supplemented with collagen-1. We have validated three genes by qPCR and are screening these upregulated genes for biological effects on proliferation by short-hairpin RNA or molecular inhibition of D2.0R cells in our 3D model. We conclude that this signature will provide useful insight into genetic drivers of the dormant to proliferative switch and potential candidates as therapeutic targets in recurrent disease. Citation Format: Ryan J. Nini, Lara H. El Touny, Meera Murgai, Rosandra N. Kaplan, Jeffrey E. Green. Identifying candidate genes that regulate tumor cell dormancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 760.
Predicting response to abiraterone acetate (AA): mRNA biomarker analysis of study COU-AA-302.
Authors: Deborah Sokol Ricci, Weimin Li, Thomas W. Griffin, Michael Gormley, Erin Henitz, Charles J. Ryan, Johann Sebastian De Bono, Gerhardt Attard, Alfons JM van den Eertwegh, Dirk L. Schrijvers, John J. Gullo, Henrik Suttmann, Joan Carles, Jose Maria Piulats Rodriguez, Robert J. Jones, Christopher Logothetis, Dana E. Rathkopf, Howard I. Scher, Eleni Efstathiou
Journal: Journal of Clinical Oncology (2014)

5058 Background: AA is metabolized to abiraterone, a CYP17 inhibitor that blocks testicular, adrenal, and tumoral androgen biosynthesis. AA is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We examined the predictive value of mRNA biomarkers in determining clinical response to AA therapy in chemo-naive pts with mCRPC. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + prednisone (P) 5 mg po BID vs placebo + P and stratified by Eastern Cooperative Oncology Group (ECOG) score 0 or 1. Co-primary end points: radiographic progression-free survival (rPFS) and overall survival (OS). 329 pts provided optional consent for biomarker analysis of pretreatment FFPE tumor samples. Of these, 110 pts were evaluable for mRNA analysis using Taqman array microfluidic cards. We tested 94 biomarkers relevant to androgen receptor (AR) signaling, steroidogenesis, and AA response or resistance. Association analysis of single biomarkers or predetermined biomarker groups with rPFS (independent review) and OS was done by Cox regression within each treatment group and stratified by ECOG score. Results: Six biomarkers (SF1, HSD17B10, SRD5A1, UBE2C, NUSAP1, ANLN) were significantly associated with rPFS in the AA (p < 0.05) but not the P (p ≥ 0.2) group; none were significant based on false discovery rate (FDR) ≥ 0.15. Higher AR expression was significantly associated with longer rPFS in the AA group, HR (95% CI): 0.80 (0.65-0.98), p = 0.03, FDR = 0.2. Androgen-regulated genes and CYP17 cofactors were associated with longer rPFS and OS in the biomarker group analysis (Table). Conclusions: This exploratory analysis shows that gene expression of androgen-regulated genes and CYP17 cofactors at the time of diagnosis may be predictive of outcome to AA therapy. The current study is limited by sample size and lack of independent validation datasets and requires confirmation in planned additional studies. Clinical trial information: NCT00887198. rPFS, AA + P OS, AA + P Biomarkers HR (95% CI) p value (FDR) HR (95% CI) p value (FDR) Androgen-regulated genes (AKR1C3, FKB5, PCNA) 0.57 (0.37-0.88) 0.01 (0.11) 0.31 (0.14-0.69) 0.004 (0.07) CYP17A1 and cofactors (CYB5A, CYP17A1, CYP3A5, DUSP5, HNF1A, NR0B1, POR) 0.43 (0.21-0.89) 0.02 (0.13) 0.33 (0.13-0.86) 0.02 (0.12)
Abstract 2086: Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer
Authors: Ravi Doddapaneni, Ketan Patel, Nusrat Chowdhury, Mandip Sachdeva
Journal: Cancer Research (2016)

Abstract Purpose: The use of Noscapine (Nos) as a chemosensitizer followed by docetaxel (DTX) treatment therapy could be a novel approach for the treatment for breast cancer and possibly reduce the adverse side effects associated with DTX based chemotherapy. The goal of this study was to examine the chemo-sensitizing effect of Nos to DTX and also tumor stromal disruption effect of Nos in mice bearing xenograft TNBC tumors. Methods: Effect of Nos chemosensitization on DTX cytotoxicity was evaluated in MDA-MB-231 cells by trypan blue dye method. Apoptosis was measured by AnnexinV/FITC method using flow cytometer. Expression of different proteins like phospho-p38, pJNK, bcl-2, α-tubulin, Akt, pAkt, survivin was evaluated by immunoblot. Alpha-tubulin binding assay was done by fluorescent microscopy. In vivo antifibrotic efficacy of Nos and uptake of coumarin-6 loaded fluorescent liposomes was evaluated by picro-sirius red staining and fluorescent microscopy respectively in xenograft breast tumors. Results: MDA-MB-231 TNBC cells were exposed at sub-therapeutic dose of Nos (4 μM) which increased the cytotoxicity of DTX by 3.0-fold. Flow-cytometric analysis showed significant increase (30 percent) of late apoptotic cells in Nos chemosensitized, DTX-treated MDA-MB-231 cells compared with DTX alone treatment. Further, chemosensitization of TNBC cells with Nos at different time intervals (6 h, 12 h and 24 h), the effect on stress transducer p38 stress activator protein kinase was significantly activated (p&amp;lt;0.01). Also, Nos (4 μM) chemosensitized cells followed by DTX treatment showed downregulation of bcl2 (2.3-fold), survivin (1.3-fold) and pAKT (1.9-fold) expression further illustrating the role of Nos in inducing apoptosis. Interestingly, at this dose of Nos (4 μM), there was no impact on alpha-tubulin. Also, in vivo studies with 100 mg/kg Nos given orally to MDA-MB-231 tumor bearing athymic nude mice revealed significant reduction in tumor collagen-1 levels in Nos treated group compared to control as determined by picro-sirius staining. In Nos treated tumors, uptake of coumarin-6 loaded fluorescent liposomes was 7-fold higher compared to controls suggesting antifibrotic role of Nos. Conclusion: In conclusion, chemosensitization with sub-therapeutic dose of oral noscapine could be a promising approach to increase anticancer activity of DTX and can further enhance uptake of liposomes suggesting that this approach may have potential in TNBC treatment. Citation Format: Ravi Doddapaneni, Ketan Patel, Nusrat Chowdhury, Mandip Sachdeva. Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2086.
PTU-209 Intra-operative swab cultures do not predict the development of anal fistula in patients undergoing emergency incision and drainage of perianal abscess: Abstract PTU-209 Table 1
Authors: MI Aslam, S Chaudhry, M Oliveira-Cunha, S Chaudhri
Journal: Gut (2015)

<h3>Introduction</h3> Routine swab cultures at the time of perianal abscess drainage remains common practice in modern day emergency colorectal surgery. We aimed to analyse the effectiveness of culture swabs to predict short term and long term outcomes of perianal abscess drainage. <h3>Method</h3> 350 consecutive patients from January 2008 to December 2010 undergoing incision and drainage (I&amp;D) of perianal abscesses with packing of wound in community were analysed for readmission, follow up outpatient visit, repeat procedure for ongoing symptoms and presence of anal fistula at follow up examination under anaesthesia (EUA). Patients with inflammatory bowel disease and known anal fistula disease were excluded. Inter-group comparative analyses were made for patients with and without intra-operative culture swabs and for the microbial growth. <h3>Results</h3> Overall fistula formation rate after I and D was 12% at 36 month follow up. No statistical significant differences were found between the different groups for rate of readmission, presence of fistula and number of outpatient consultations (P &gt; 0.05). There was no significant difference in fistula rates for patients with positive microbial growth and negative microbial growth (10% vs. 8%, p = 0.12). No significant variation was observed for different types of organisms and rate of fistula formation. (See Table 1). <h3>Conclusion</h3> Routine swab cultures do not influence short and long term outcome associated with I&amp;D of perianal abscess. <h3>Disclosure of interest</h3> None Declared.
Malignant hemangioendothelioma and microangiopathic hemolytic anemia
Authors: J. Chatiwala, M. Maroules, A. Karippot
Journal: Journal of Clinical Oncology (2008)

21520 Background: Hemangioendothelioma of the spleen is a rare vascular tumor. It consists of anastomosing networks of aberrant capillaries lined by malignant endothelial cells. They develop frequently, and multicentrically, within the reticulo-endothelial system, especially in the spleen and liver. Some appear to have extramedullary hemopoietic potential. We report a case, in which the presenting feature was microangiopathic hemolytic anemia. Case report: A 66-year old man with history of CAD, diabetes, CRF, atrophic left kidney status post recent renal artery stent, was admitted to the hospital with nausea, vomiting, malaise and somnolence. On examination, he appeared weak and mildly jaundiced. Work-up revealed hemolytic anemia, thrombocytopenia, DIC, elevated ammonia level. Extensive work-up showed liver findings suggestive of cirrhosis and multiple lesions in spleen. Chest x-ray showed pulmonary vascular congestion, the peripheral smear showed Howell jolly bodies and schistocytes consistent with hyposplenism and DIC. Bone marrow and liver biopsy showed no evidence of metastasis. Patient suffered a cardiopulmonary arrest and died. Autopsy showed softened friable liver with areas of hemorrhage and blood lakes. There was spindle cell proliferation with poor preservation. Immunoperoxidase stains showed the spindle cells to be positive with vascular markers CD31, CD34, and Factor VII, and positive with vimentin, negative with cytokeratin, desmin and actin. The spleen showed similar vascular spindle cell proliferation and findings favor malignant hemangioendothelioma. Conclusions: The purpose is to describe the association of hemolytic anemia, thrombocytopenia, red blood cell fragmentation, erythrophagocytosis and extramedullary hematopoiesis associated with hemangioendothelioma. It is suggested that hemolysis may have been due to mechanical trauma sustained by the red blood cells on passage through the tumor's abnormal vasculature, that was precipitated by the alteration in coagulation cascade by renal artery stent. The tumor deposits in liver and spleen showed hematopoietic potential which is a well-recognized feature of the malignant hemangioendothelioma. In addition, groups of tumor cells showed evidence of phagocytic activity by virtue of their hemosiderin content. No significant financial relationships to disclose.
Abstract 3249: Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer
Authors: Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams
Journal: Cancer Research (2016)

Abstract Aberrant myelopoiesis is commonly observed in patients with solid cancers. This results in the production of myeloid-derived suppressive cells (MDSCs) which promote tumor growth and metastasis. However, the molecular mechanisms underlying MDSC development have remained poorly understood. The transcription factor IRF8 is integral for overseeing myelopoietic fate; high IRF8 expression during normal myelopoiesis favors monocytic differentiation and directly inhibits granulocytic differentiation. We recently showed that tumor-derived STAT3/5-activating cytokines downregulate the expression of IRF8 in myeloid cells leading to the accumulation of MDSCs in the periphery, which are primarily granulocytic. However it is unclear if MDSC production is a consequence of IRF8 downregulation in the periphery or upstream in the bone marrow during myelopoiesis. To that end, we utilized a novel mouse model expressing an IRF8-EGFP fusion protein which allowed us to investigate changes in IRF8 expression during both orthotopic and spontaneous mammary tumor growth and progression. Our results showed that: 1) the total granulocyte-monocyte progenitor (GMP) fraction, as with the peripheral MDSC population, was responsive to tumor burden and greatly expanded with increasing tumor size, and 2) IRF8 expression within the total GMPs significantly decreased during tumor growth, reflecting the expansion of a newly defined primarily IRF8lo granulocyte progenitor (GP) population, and 3) tumor-induced GPs were hyper-responsive not only to G-CSF, but also M-CSF to generate a ‘biased’ granulocytic MDSC-like phenotype. Expression of IRF8 in other progenitor populations was not affected, suggesting that IRF8lo GMPs/GPs are a key source of the peripheral MDSC response. Lastly, genetically enforced IRF8 expression in myeloid progenitors of the bone marrow constrained aberrant myelopoiesis during tumor growth, resulting in delayed autochthonous tumor growth and reduced spontaneous lung metastasis. Altogether, these data reinforce the notion that modulation of IRF8 in myeloid progenitors is an early consequence of the neoplastic process and a potential target for therapeutic intervention. NIH R01CA140622 NIH T32CA085183 Citation Format: Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams. Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3249.
Are preoperative oesophageal pH and manometry studies necessary prior to laparoscopic nissen fundoplication?
Authors: P Sanjay, A Woodward
Journal: Endoscopy (2005)

Aims: The indications for use of preoperative ph and manometry studies prior to antireflux surgery vary. We have conducted a retrospective review to determine the usefulness of ph and manometry studies in patients considered for antireflux surgery.
Nolan: A randomized, phase II study to estimate the effect of prophylactic naproxen (N) or loratadine (L) vs no intervention on bone pain in 600 patients (pts) with early-stage breast cancer receiving chemotherapy (chemo) and pegfilgrastim (PEG).
Authors: Jeffrey J. Kirshner, Andrew S Guinigundo, Linda Vanni, Cathy L Maxwell, Maureen Reiner, Jacob Garcia, Phuong Khanh H. Morrow
Journal: Journal of Clinical Oncology (2016)

10021 Background: Mild-to-moderate bone pain is the most commonly reported adverse event (AE) associated with PEG. Both N (an NSAID) and L (an antihistamine) are used in the clinic to reduce this AE, but data on the efficacy of these interventions are limited. Methods: In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I–III breast cancer and ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemo with PEG support starting in cycle 1 were randomized 1:1:1 to receive prophylactic N, L, or no prophylaxis (NP). Pts received N (500 mg BID) or L (10 mg QD) for 5 days beginning the day of PEG administration in each of the first 4 chemo cycles. PEG (6 mg) was administered in each cycle 24–72 hours after chemo. Primary endpoint: all-grade bone pain in cycle 1 from AE reporting. Results: Pts enrolled: 600. White 83.0%, black 14.1%, Asian 1.2%. Mean (SD) age: 54.2 (11.1) years. Stage I/II/III: 25.6%/50.1%/24.4%. Difference (95% CI) in all-grade bone pain in cycle 1: NP vs N –6.3% (–16.7%, 4.1%), NP vs L –4.1% (–14.5%, 6.3%), N vs L 2.2% (–8.0%, 12.4%). See table for additional results. Conclusions: Levels of all-grade and grade 3/4 bone pain were comparable in the N, L, and NP groups, but there was a trend toward lower pain with N and L. Both N and L had tolerable toxicity; L was associated with fewer AEs, and fewer pts discontinued L. Clinical trial information: NCT01712009. N L NP Randomized 200 202 198 Received prophylaxis 193 198 Completed prophylaxis 150 174 Received PEG 196 200 191 Completed PEG 166 178 155 Pts with all-grade bone pain from AE reporting Cycle 1 40.3% 42.5% 46.6% Across all cycles 59.2% 61.0% 63.4% Pts with grade 3/4 bone pain from AE reporting Cycle 1 3.1% 4.5% 4.7% Across all cycles 4.1% 4.5% 5.8% Mean (SE) patient-reported bone pain (scale 0–10) Cycle 1 1.8 (0.2) 1.7 (0.1) 2.2 (0.2) Across all cycles 1.5 (0.1) 1.5 (0.1) 1.9 (0.1) Mean (SE) maximum patient-reported bone pain (scale 0–10) Cycle 1 3.3 (0.2) 3.0 (0.2) 3.9 (0.2) Across all cycles 4.2 (0.2) 4.1 (0.2) 4.7 (0.2) Treatment-related AEs 15.5% 3.5% Gastrointestinal disorders 10.9% 0.5% Treatment-related serious AEs 0.5% 0.0%