tbuckley/cabot-search huggingface dataset:
AB0591 Efficacy and safety profile of intravenous cyclophosphamide treatment in elderly patients with systemic vasculitis
Authors: S Shimoyama, T Kurita, S Fukaya, M Kanda
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Intravenous cyclophosphamide is mainstay of remission induction and dose reduction of glucocorticoid in patients with systemic vasculitis. However, little evidence has yet shown the safety profile of intravenous cyclophosphamide, especially in elderly patients. <h3>Objectives</h3> To evaluate efficacy and safety of patients diagnosed as systemic vasculitis and treated with intravenous cyclophosphamide. <h3>Methods</h3> This retrospective study comprised the patients with active systemic vasculitis who were admitted to Kitami Red Cross Hospital and Obihiro-Kosei General Hospital from April 2009 to March 2016. These patients were treated with intravenous cyclophosphamide plus conventional therapy (IVCY group) or only with conventional therapy (glucocorticoid/azathioprine/tacrolimus and methotrexate) (conventional therapy group). The patients treated with oral cyclophosphamide or rituximab were excluded. Primary endpoint was defined as death or serious infections. Prognostic factors in IVCY group were analyzed by multivariate Cox regression methods. <h3>Results</h3> This study comprised 90 patients with active systemic vasculitis (61 microscopic polyangiitis, 9 eosinophilic granulomatosis with polyangiitis, 10 granulomatosis with polyangiitis, and 10 polyarteritis nodosa). Fifty-one patients were over 70-year-old (26 patients in IVCY group). The mean observation period was 30.1 months. IVCY group had a trend for higher event-free survival rate as compared with conventional therapy group (p=0.19). IVCY group had significantly higher cumulative survival rate as well (p=0.04). Age (HR=1.07, 95% CI 1.01–1.14, p=0.03), five factor score (FFS, HR=3.39, 95% CI 1.36–8.44, p=0.01) and glucocorticoid dose at 24 weeks (GC24, HR=1.14, 95% CI 1.05–1.22, p=0.001) were identified as risk factors for events. In patients over 70-year-old, IVCY group had a trend for higher cumulative survival rate as well (p=0.07, Figure1). FFS (HR=3.30, 95% CI 1.19–9.15, p=0.02) and GC24 (HR=1.10, 95% CI 1.02–1.20, p=0.01) were identified as risk factors for events. <h3>Conclusions</h3> Intravenous cyclophosphamide treatment had acceptable safety profile even in elderly patients. <h3>Disclosure of Interest</h3> None declared
Beginning and End
Authors: Carol Snyder Halberstadt
Journal: JAMA (2017)

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Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis
Authors: Kenneth G. Saag, Jeffrey Petersen, Maria Luisa Brandi, Andrew C. Karaplis, Mattias Lorentzon, Thierry Thomas, Judy Maddox, Michelle Fan, Paul D. Meisner, Andreas Grauer
Journal: New England Journal of Medicine (2017)

Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).
In acute ischemic stroke, adding early endovascular treatment to usual care improved functional outcomes at 2 y
Authors: Gregory Jacquin, Alexandre Poppe
Journal: Annals of Internal Medicine (2017)

Source Citation van den Berg LA, Dijkgraaf MG, Berkhemer OA, et al; MR CLEAN Investigators. Two-year outcome after endovascular treatment for acute ischemic stroke. N Engl J Med. 2017;376:1341-9. 28379802
Correlation of VEGFR2 expression in tumor tissue with longer progression-free survival in patients with neuroendocrine tumors (NETs) treated with pazopanib.
Authors: Luis Ortega, Victor Reyes, Jaume Capdevila, Daniel E. Castellano, Rocio Garcia-Carbonero, Alex Teule, Ignacio Duran, Jose Fuster, Isabel Sevilla, Pilar Escudero, Javier Sastre, Jesús García-Donas, Teresa Alonso, Enrique Grande
Journal: Journal of Clinical Oncology (2014)

e15154 Background: Pazopanib is a multitargeted tyrosine kinase inhibitor that has shown activity in heavily pretreated gastroenteropancreatic NETs. Biomarker analyses showed that plasma levels of VEGFR2 are modified by treatment and predict for longer progression-free survival (PFS) (Casanovas, et al ESMO 2013). Here we present the correlation of the expression of VEGF, VEGFR1, VEGFR2 and HIF1 on tumor tissue samples with patient clinical outcome. Methods: Protein expression of VEGF, VEGFR1, VEGFR2 and HIF1 was assesed by immunohistochemistry (Anti human VEGF (DakoCytomation); AntiVEGF Receptor 1 and 2 (abcam) and Anti HIF-1 alpha (abcam)) and scored semiquantitatively as negative, or positive (1+ or 2+). Analyses were done for clinical benefit (CB=stable disease plus partial response), PFS and overall survival (OS). Cox models were adjusted by age and duration of treatment. Results: Twenty-three samples were available for histological analysis: 69.6% expressed VEGFR2 (52.2% 1+, 17.4% 2+). At the study close date, 17 (73.9%) patients had progressed and 7 (30.4%) were deceased. Patients showing some degree of VEGFR2 expression presented longer PFS (median of 12.18 vs. 11.56 months; HR 0.95). Although not statistically significant, the impact on OS seemed to be also protective (HR 0.41, 95% CI 0.05-3.16, p=0.39). CB was achieved in 93.8% of the patients expressing VEGFR2 vs. 85.7% in non-expressing tumors. Expression of VEGF, VEGFR1 and HIF1 was present in 43.5%, 34.8% and 34.8% of the patients respectively. The expressions of these biomarkers were not associated with any clinical outcome. A pairwise analysis of the four biomarkers did not identify any correlation between them. Conclusions: Tumor expression of VEGFR2 can predict for longer PFS in metastatic NETs treated with Pazopanib. These results, together with previously reported results on soluble VEGFR2 as a biomarker of pazopanib efficacy suggest that this pathway is relevant regarding the efficacy of this drug. Clinical trial information: 2010-020749-28.
SAT0663 Two-step algorithm for early diagnosis of osteoarthritis based on plasma damaged amino acids provides simple and low cost screening test
Authors: N Rabbani, U Ahmed, PJ Thornalley
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Currently, magnetic resonance imaging techniques have been developed for evaluation of cartilage damage in early-stage osteoarthritis (eOA). These imaging techniques have approximately 70% sensitivity and 90% specificity compared to reference diagnosis by arthroscopy. They require expensive instrumentation, time and facilities. In searching for biomarkers for clinical diagnosis we found that the proteolysis of damaged (oxidised, glycated and nitrated) proteins gives a unique pattern in the plasma of arthritic patients with the severity of the disease – trace level oxidised, glycated and nitrated amino acids. In this study we developed a two-step algorithm using these analytes as features. <h3>Objectives</h3> The objective was to distinguish between the following four groups: healthy control, eOA, early stage rheumatoid arthritis (eRA) and other inflammatory joint disease (non-RA). <h3>Methods</h3> Four algorithm types were tested for performance using random forests, multiclass logistic regression, multi-class sparse logistic regression and support vector machines. In all cases, the diagnostic algorithms were trained on the training data set, before being used to predict the disease class for each sample in the test data set. A two-stage approach was taken: (i) to distinguish between disease and healthy control; and (ii) to distinguish between eOA, eRA and non-RA. The area under the curve of the receiver operating characteristic plot (AUROC) statistic was used as measure of performance <h3>Results</h3> Random forest was the best-performing method. Application of two algorithms consecutively gave the best diagnostic outcome. The AUROC (sensitivity/specificity) values for disease/health were: eOA, 0.99 (0.92/0.91); eRA, 0.96 (0.89/0.90) and non-RA, 0.77 (0.73/0.72) for the training set and test set validations. A random outcome is 0.50. For typing arthritis, eOA, eRA and non-RA, AUROC values were in the range 0.68–0.98, 0.77–0.93 and 0.62–0.91 for training set and test set cross-validations and test set validation, respectively. A random outcome is 0.33. <h3>Conclusions</h3> A two-step algorithm approach based on trace level damaged amino acids gave better diagnostic performance that MRI for detecting and typing eOA. It is low cost and suitable for rollout as a clinical screening test. <h3>References</h3> Menashe, L., Hirko, K., Losina, E., Kloppenburg, M., Zhang, W., Li, L. and Hunter, D. J. (2012) The diagnostic performance of MRI in osteoarthritis: a systematic review and meta-analysis. Osteoarthritis and Cartilage. 20, 13–21. Ahmed, U., Anwar, A., Savage, R.S., Thornalley, P.J. and Rabbani, N. (2016) Application of protein glycation, oxidation and nitration for early-stage diagnosis and severity of osteoarthritis and other arthritic disease. Arthritis Research &amp; Therapy 18:250. <h3>Disclosure of Interest</h3> None declared
Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval
Authors: Vinay Prasad, Sham Mailankody
Journal: JAMA Internal Medicine (2017)

A common justification for high cancer drug prices is the sizable research and development (R&D) outlay necessary to bring a drug to the US market. A recent estimate of R&D spending is $2.7 billion (2017 US dollars). However, this analysis lacks transparency and independent replication.To provide a contemporary estimate of R&D spending to develop cancer drugs.Analysis of US Securities and Exchange Commission filings for drug companies with no drugs on the US market that received approval by the US Food and Drug Administration for a cancer drug from January 1, 2006, through December 31, 2015. Cumulative R&D spending was estimated from initiation of drug development activity to date of approval. Earnings were also identified from the time of approval to the present. The study was conducted from December 10, 2016, to March 2, 2017.Median R&D spending on cancer drug development.Ten companies and drugs were included in this analysis. The 10 companies had a median time to develop a drug of 7.3 years (range, 5.8-15.2 years). Five drugs (50%) received accelerated approval from the US Food and Drug Administration, and 5 (50%) received regular approval. The median cost of drug development was $648.0 million (range, $157.3 million to $1950.8 million). The median cost was $757.4 million (range, $203.6 million to $2601.7 million) for a 7% per annum cost of capital (or opportunity costs) and $793.6 million (range, $219.1 million to $2827.1 million) for a 9% opportunity costs. With a median of 4.0 years (range, 0.8-8.8 years) since approval, the total revenue from sales of these 10 drugs since approval was $67.0 billion compared with total R&D spending of $7.2 billion ($9.1 billion, including 7% opportunity costs).The cost to develop a cancer drug is $648.0 million, a figure significantly lower than prior estimates. The revenue since approval is substantial (median, $1658.4 million; range, $204.1 million to $22 275.0 million). This analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing.
ImmunoPET of Malignant and Normal B Cells with 89Zr- and 124I-Labeled Obinutuzumab Antibody Fragments Reveals Differential CD20 Internalization <i>In Vivo</i>
Authors: Kirstin A. Zettlitz, Richard Tavaré, Scott M. Knowles, Kristopher K. Steward, John M. Timmerman, Anna M. Wu
Journal: Clinical Cancer Research (2017)

Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20.Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89Zr) versus non-residualizing (124I) radionuclides by region of interest analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to assess antigen modulation in vivoResults:124I-GAcDb and 124I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers. ImmunoPET imaging of huCD20TM showed specific uptake in lymphoid tissues. The use of the radiometal 89Zr as alternative label for GAcDb and GAcMb yielded greater target-specific uptake and retention compared with 124I-labeled tracers. Pairwise comparison of 89Zr- and 124I-labeled GAcDb and GAcMb allowed assessment of in vivo internalization of CD20/antibody complexes and revealed that CD20 internalization differs between malignant and endogenous B cells.Conclusions: These obinutuzumab-based PET tracers have the ability to noninvasively and quantitatively monitor CD20-expression and have revealed insights into CD20 internalization upon antibody binding in vivo Because they are based on a humanized mAb they have the potential for direct clinical translation and could improve patient selection for targeted therapy, dosimetry prior to radioimmunotherapy, and prediction of response to therapy. Clin Cancer Res; 23(23); 7242-52. ©2017 AACR.
FRI0414 Can echocardiography replace follow-up cardiac catheterization in re-evaluation of pulmonary arterial hypertension? a longitudinal single-center study of 30 connective tissue disease patients
Authors: V-K Bournia, I Tsangaris, L Rallidis, D Konstantonis, A Anthi, S Orfanos, S Panopoulos, PP Sfikakis
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Transthoracic echocardiography (TTE) is well validated for initial assessment of connective tissue disease patients with suspected pulmonary arterial hypertension (PAH). However, in patients with PAH confirmed by the gold-standard method of right heart catheterization (RHC) the role of TTE in their follow-up is less known. <h3>Objectives</h3> To test the hypothesis that TTE can replace follow-up RHC in connective tissue disease-associated PAH. <h3>Methods</h3> This retrospective study included 30 consecutive patients with systemic sclerosis (n=24) and mixed connective tissue disease (n=6) (mean age±SD: 60±12 years, 87% women), in whom PAH was suggested by TTE and further confirmed by a baseline RHC [pulmonary artery systolic pressure (PASP): 56.8±19.1, range 25–90mmHg; pulmonary vascular resistance (PVR): 5.9±3.8, range 0.7–14.5 Wood units; cardiac output: 4.4±1.3, range 2–7.8 L/min). All 30 patients underwent a second RHC and TTE at follow-up, after 11±6 (range 4–29) months. Ten patients had a 3rd follow-up RHC and TTE 22±7 (range 15–37) months from baseline, thus producing in all 50 pairs of baseline and follow-up measurements. By considering follow-up RHC as the gold-standard, we examined whether clinically meaningful hemodynamic changes (i.e.&gt;15% change from baseline) in either RHC-derived PASP or PVR could be predicted by the corresponding changes from baseline in follow-up TTE. RHC and TTE were always performed, each, by the same examiner. <h3>Results</h3> In 68% of comparisons between baseline and follow-up, the latter TTE measurements could safely replace RHC in terms of PASP estimation. Using Mc Nemars test we confirmed that the two methods did not differ significantly (Table 1). When in addition to changes in PASP, PVR changes were also considered, follow-up TTE could again safely replace the second RHC in 70% patient retests (Table 2). Of note, baseline hemodynamic values or TTE measurements did not differ between patients in whom TTE could replace RHC and those in whom the results of the two methods at follow-up were divergent. <h3>Conclusions</h3> In a study where operator-dependent methodological errors are limited we found that the majority of connective tissue disease patients with PAH can be safely monitored in the long-term by TTE. Further studies to help identify those patients at need for follow-up RHC are warranted. <h3>Disclosure of Interest</h3> None declared
Effect of Early Pitavastatin Therapy on Coronary Fibrous-Cap Thickness Assessed by Optical Coherence Tomography in Patients With Acute Coronary Syndrome
Authors: Tsuyoshi Nishiguchi, Takashi Kubo, Takashi Tanimoto, Yasushi Ino, Yoshiki Matsuo, Takashi Yamano, Kosei Terada, Hiroki Emori, Yosuke Katayama, Akira Taruya, Yuichi Ozaki, Yasutsugu Shiono, Kunihiro Shimamura, Takeyoshi Kameyama, Hironori Kitabata, Tomoyuki Yamaguchi, Atsushi Tanaka, Takeshi Hozumi, Takashi Akasaka
Journal: JACC. Cardiovascular imaging (2017)
AB0704 Hip arthroplasty in patients with ankylosing spondylitis - clinical and functional efficiency
Authors: S Lapshina, I Akhtyamov, I Gilmutdinov, L Myasoutova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To evaluate the results of the hip joints replacement in patients with SpA under the dynamic supervision of a rheumatologist and orthopedic within the first year after the operation. <h3>Methods</h3> As part of special program for rheumatology patients hip endoprosthesis was done in 12 patients (mean age - 44,2±15,3 years) with SpA, 8 of them with ankylosing spondylitis (AS) and 4 with psoriatic arthritis (PsA). Duration of the disease - 13,3±7,9 years, positive for HLA B27 in 9 (75%) patients. High activity for ASDAS was at 58.3% of the patients. Took NSAIDs at the time of the operation - 11 (91.6%) patients, sulfasalazine 5 (41.6%), methotrexate- 2 (16.7%). 1 (8.3%) patient received etanercept,1 (8.3%) patient - infliximab. Dynamic observation of rheumatologist and orthopedic was carried out before, just after surgery, after 6 and 12 months, with the assessment of VAS, BASDAI, ASDAS, BASFI. <h3>Results</h3> The reduction of pain intensity on the VAS was observed in the first month after the surgery (47,3±18,6 mm), initially it was 74,0±24,1 mm, 42.5±9 after 6 months (p&lt;0.05), after 12 months - up to 22,5±9,9 mm (p&lt;0.05). ASDAS significantly (p&lt;0.05) reduced from 2,94±2,01 to 1,68±1,35 - in 6 months and 1,26±0,88 - 12 months after operation; BASDAI: from 6,24±3,91 to 2,75±2,20 - 6 months, 2,65±1,53 at 1 year follow-up. BASFI index before surgery - 5,48±3,29, 6 months - 2,78±2,31, 1 year - 2,32±1,60 points. No complications after surgery were registered. <h3>Conclusions</h3> Hip joints endoprosthesis in patients with SpA is effective not only in improving functional ability and pain relief, but also a reduction of disease activity. Dynamic rheumatologist observation in perioperative period leads to positive dynamics in relation to the activity of SpA and quality of life of patients during the first year after surgery <h3>Disclosure of Interest</h3> None declared