tbuckley/cabot-search huggingface dataset:
Phase III randomized trial comparing weekly versus three-weekly (W3W) cisplatin in patients receiving chemoradiation for locally advanced head and neck cancer.
Authors: Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Jaiprakash Agarwal, Sarbani Ghosh Laskar, Ashwini Narsingrao Budrukkar, Vedang Murthy, Tejpal Gupta, Anil D'Cruz, P. S. Pai, Pankaj Chaturvedi, Devendra Chaukar, Nikhil Pande, Arun Chandrasekharan, Vikas Talreja, Dilip Vallathol, Aparna Manjrekar, Vijayalakshmi Mathrudev, Kamesh Maske, Kumar Prabhash
Journal: Journal of Clinical Oncology (2017)

6007 Background: Chemoradiation (CRT) with cisplatin 100mg/m 2 given 3-weekly is the standard of care in locally advanced head and neck squamous cell cancer (HNSCC). Substituting low dose weekly cisplatin has pharmacological rationale due to lower toxicity and enhanced radiosensitization but has never been compared to 3-weekly cisplatin. Methods: Phase III non-inferiority trial (CTRI/2012/10/003062) in patients with Stage III or IV (non-metastatic) HNSCC planned for radical CRT. Pts were stratified for T-category, N-category and intent of therapy (adjuvant versus definitive) and centrally randomized 1:1 to cisplatin 30mg/m 2 weekly or 100mg/m 2 3-weekly concurrently with radiotherapy. Primary endpoint was locoregional control (LRC); secondary endpoints included toxicity, compliance, response, progression-free survival and overall survival. The upper boundary of non-inferiority margin was set at 15%, assuming LRC of 60% with power 80% and alpha 0.05. Results: 300 pts were randomized,150 to each arm; median age 44 years (range: 25-67), males 89%; 71% were smokeless tobacco users. 61% were T4, 71% &gt; N2. 93% pts received CRT as adjuvant therapy for high-risk disease; indication was perinodal extension in 84%, close/ positive margins 8%. Median total treatment time was 86 days (IQR: 79-95). Median RT dose was 60 Gy (IQR 60-60 Gy) using shrinking field technique. In the weekly arm, 133 pts (88.7%) received &gt; 6 cycles; 14 (9%) required dose reduction, median cumulative cisplatin dose 210 mg/m 2 (IQR 180-210). In the 3-weekly arm, 143 pts (95%) received &gt; 2 cycles, median cumulative cisplatin dose 300 mg/m 2 (IQR 200-300); 12 (8%) required dose reduction. At a median follow up of 20 months (range: 1-49), locoregional relapses (LRR) occurred in 42.2% pts in the weekly arm and 29.6% pts in the 3-weekly arm, leading to an absolute difference in LRR of 12.7% (95%CI:1.89-23.41), p=0.035 by Gray’s test, HR-1.58 (95%CI:1.02-2.46). Acute &gt; grade 3 toxicity occurred in 85.3% pts in 3-weekly arm and 70.7% pts in weekly arm, p=0.002; 30.7% pts in the 3-weekly arm and 14% patients in the weekly arm required hospitalization for management of toxicity, p=0.001. Conclusions: 3-weekly cisplatin leads to 42% relative reduction in locoregional recurrence; it is superior to weekly cisplatin and should be the preferred regimen in CRT for HNSCC. Clinical trial information: CTRI/2012/10/003062.
FRI0075 Rheumatoid arthritis patients receiving glucocorticoid exhibits significant bone quality abnormalities, leading to severe bone fragility regardless of bisphosphonate treatment
Authors: T Shimizu, M Takahata, H Hamano, M Ota, S Hiratsuka, N Iwasaki
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) receiving glucocorticoids develop particularly severe bone fragility accompanied with high risk factors for fragility fractures<sup>1,2</sup>. Although bisphosphonate is recommended for treatment of osteoporosis related RA and glucocorticoid-induced-osteoporosis<sup>3</sup>, there are more frequently fractures than expected from bone mineral density based prediction even after used bisphosphonate. <h3>Objectives</h3> To clarify the pathological mechanisms of bone fragility of these RA patients, we investigated bone biopsy samples obtained from RA and normal postmenopausal patients. <h3>Methods</h3> We examined 10 female postmenopausal RA patients receiving glucocorticoid and bisphosphonate therapy (RA group) and 10 age-matched female patients with postmenopausal osteoporosis (Ctl group) selected from patients who required autologous iliac bone grafts. Analyses of clinical data, bone mineral density, serum metabolic markers, bone quality and material mechanical property of biopsy sample were performed. <h3>Results</h3> Although bone mineral density didn9t show significant differences, RA group had significantly higher score of fracture risk assessment tool (FRAX), number and severity of existing vertebral fractures. RA group exhibited significant bone quality abnormalities including deterioration of the bone microstructure, decreased calcification of the bone matrix, increased osteocyte atrophy and empty lacunae (Figure), and an impairment bone material strength properties. <h3>Conclusions</h3> Our findings showed that RA patients receiving glucocorticoid treatment have severe bone fragility regardless of increased bone quantity by using bisphosphonate. The functional deteriorations of the osteocyte system and the abnormalities of bone quality might induce bone fragility fracture. Therefore, management of osteoporosis associated with RA should be targeted about bone quality as well as bone quantity. <h3>References</h3> Kanis JA et al. J Bone Miner Res 2004. Takaha M et al. Arthritis Rheum 2012. Grossman, J.M. et al. Arthritis Care Res 2010. <h3>Acknowledgements</h3> This project was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan 25462357 (M. Takahata). <h3>Disclosure of Interest</h3> None declared
B cell–derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity
Authors: Tanvi Arkatkar, Samuel W. Du, Holly M. Jacobs, Elizabeth M. Dam, Baidong Hou, Jane H. Buckner, David J. Rawlings, Shaun W. Jackson
Journal: The Journal of Experimental Medicine (2017)

Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral autoimmunity, whether B cell-derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell-derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from systemic autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-γ, consistent with the critical roles for B cell-intrinsic IFN-γ receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive autoimmunity via local IL-6 production required for TFH differentiation and autoimmune GC formation.
循環器病の診断と治療に関するガイドライン(2004-2005年度合同研究班報告)大動脈瘤・大動脈解離診療ガイドライン(2006年改訂版)
Authors: 高本眞一, 石丸新, 上田裕一, 大北裕, 荻野均, 数井暉久, 加藤雅明, 栗林幸夫, 田林晄一, 中島豊, 松尾汎, 宮田哲郎, 吉田清, 青鹿佳和, 圷宏一, 阿部知伸, 石塚尚子, 大平篤志, 加地修一郎, 北村哲也, 齋木佳克, 柴田講, 下野高嗣, 中野赳, 縄田寛, 新沼廣幸, 西上和宏, 林宏光, 師田哲郎, 吉岡邦浩, 鷲山直己, 安藤太三, 伊藤翼, 北村惣一郎, 末田泰二郎, 本田喬, 安田慶秀
Journal: Circulation (2006)
Enrollment into molecular selection trials and impact on patient disposition.
Authors: R Donald Harvey, Conor Ernst Steuer, Emma C Judson, Colleen Margaret Lewis, Hannah H Collins, Nabil F. Saba, Bassel F. El-Rayes, Walter John Curran, Suresh S. Ramalingam, Rebecca D. Pentz, Taofeek Kunle Owonikoko
Journal: Journal of Clinical Oncology (2017)

e14035 Background: Optimal use of molecularly targeted therapies is achieved by pairing agents with driver mutations present in tumor tissue. Enrollment on clinical trials designed to demonstrate this objective requires obtaining informed consent prior to molecular analysis, with potential delays in tissue acquisition, testing results, and treatment initiation. We reviewed our experience and patient disposition with studies where assignment to treatment required mutation data. Methods: We identified trials requiring consent prior to tissue mutational analysis. Review included time intervals between landmark events starting with trial presentation to patient, consent, tissue shipment, mutation analysis results, and if and when treatment was initiated. Demographic data, change in ECOG PS, and subsequent therapy were also collected. Patients were included in the analysis if they signed consent. Results: Experience with 68 patients consented across 4 molecular selection trials was reviewed. Median age: 60 years (32-87); 56% female; self-identified race White (72%), African-American (24%), Asian (4%). Most common cancers were lung (35%), colorectal (18%), parotid (7%) and sarcoma (7%). Nineteen patients required new biopsies; 15 patients (22%) discontinued participation prior to molecular results being available. Common reasons for discontinuation included insufficient archival tissue (5), lost to follow up, initiation of other treatment, and death (2 each). In 53 patients who continued, overall median time from consent to test results received was 41 days (12-149); with median time from consent to obtaining tissue of 22 days (0-121), and tissue sent to results received was 13 days (1-77). In those with advanced disease (n = 36), PS worsening occurred in 28%. Three patients matched to therapy; 1 received more than 1 cycle. In those not matching (n = 50), 46% received approved therapies, 22% were lost to follow-up, 18% enrolled on another trial and 14% died. Conclusions: Molecular selection of patients for clinical trials requires additional time and resources, and many patients do not have driver mutations. Long time intervals between decision points can delay therapies and impair the ability to explore alternative treatment.
FRI0735-HPR Analysis of left ventricular function with echocardiogram in patients with psoriatic arthritis and not diagnosed cardiovascular disease
Authors: P Egea-Serrano, AC Haro-Martínez, A Vidal, D Palma-Sánchez
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> It is known that some rheumatologic disorders may affect the cardiovascular system. In the last years, psoriatic arthritis (PsA) has been pointed out as one of those. <h3>Objectives</h3> The aim of this study was to analyze if there was any subclinical dysfunction sign in patients with PsA of whom no cardiovascular disease had been diagnosed. <h3>Methods</h3> Forty three patients with PsA were studied. A comprehensive echocardiogram was performed. Variables recorded for each patient were: left ventricular (LV) dimensions, LV and right ventricular (RV) systolic function, valve morphology and function, LV diastolic function assessment, and longitudinal strain (LS) assessment with speckle tracking imaging. Information on age, sex, cardiovascular risk factors (hypertension, diabetes, dyslipemia, renal disease and smoking), and evolution time of PsA was also recorded. An electrocardiogram was also carried out for each patient. <h3>Results</h3> There were 23 men and 20 women. The mean age was 52±12 years old. The PsA mean evolution time was 6.8±5.3 years. Most of patients had at least one cardiovascular risk factor. All patients were in synusal rhythm. The LV end-diastolic diameter and ejection fraction, left atrium, and RV function were within normal limits. Men had overall a thicker interventricular septum (12±1.7 mm) when compared to women (9.7±1.6mm). 86% patients had a normal mitral valve function, as so 91% with aortic valve. None of them had findings suggesting pulmonary hypertension, or pericardial effusion. The diastolic function assessment in the general population revealed normal average of septal and lateral A9 and S waves peak velocities, and E/E9 ratio. Men had lower septal E9 and S waves values and higher septal A9 wave velocity. Nearly 50% of patients had a low septal E9 or lateral E9 wave peak velocity. 13 patients (30%) had impaired both septal E9 and lateral E9 waves, who were older and mainly men. The strain analysis showed an average of global LS - 17.9%±3%, two-chambers general LS -17.2%±5%, three-chambers general LS -19%±5.2%, and four-chambers general LS -17.3%±3.5%; without any significant difference between sex. 26 patients (60.5%) had global LS above normal limits; these were younger and with less PsA evolution time. Longitudinal strain values tended to be less negative at the basal level. <h3>Conclusions</h3> Half of the patients with PsA were found to have some feature of diastolic dysfunction and more than the half of them had a slightly impaired global longitudinal strain value. Further studies could be of value to determine whether these findings would have a specific impact on the follow-up in this kind of patients. <h3>Disclosure of Interest</h3> None declared
AB0326 Influence of nonsteroidal anti-inflammatory drugs on arterial stiffness in patients with rheumatic diseases
Authors: JN Kim, J-Y Choe, S-K Kim, S-H Park, H Lee, CU Lee, J-W Kim
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The association with adverse cardiovascular (CV) events and NSAIDs has been the topic of much debate. <h3>Objectives</h3> The aim of the present study was to investigate the effects of continuing NSAIDs therapy on predictable parameters for CV events. <h3>Methods</h3> We enrolled 155 patients with variable rheumatic diseases (95 rheumatoid arthritis, 49 systemic lupus erythematosus, 3 behçet9s disease, 3 gout, 5others.) who were free from established CV diseases and had taken cardiovascular function tests from June 2015 to June 2016. They were divided into two groups depending on whether or not to have taken NSAIDs therapy for at least 5 years: NSAIDs taking group (91 patients) vs. non NSAIDs taking group (64 patients). For evaluating heart function, transthoracic echocardiography was used. Arterial stiffness was assessed using brachial-ankle pulse wave analysis. <h3>Results</h3> There were no significant differences in blood pressure, serum creatinine, serum hemoglobin, total cholesterol, erythrocyte sediment rate, C-reactive protein, disease duration, age, and smoking history between the groups. The NSAIDs taking group had a higher median (95% Cl) baPWV (brachial-ankle pulse wave velocity) and median (95% Cl) mean pulmonary artery pressure (mPAP) than non-NSAIDs taking group: baPWV 13.72 (12.77–15.62) vs. 15.29 (13.93–17.63) m/s, p=0.005; mPAP 26.5 (22.8–30.5) vs. 30.5 (27.3–32.3) mmHg, p=0.011. But baPWV and mPAP were not significantly different between selective cyclooxygenase-2 inhibitor (22 patients) and nonselective NSAIDs (69patients): baPWV 15.33 (13.98–17.63) vs. 14.83 (13.82–17.39) m/s, p=0.191; mPAP 29.0 (24.5–34.5) vs. 30.0 (26.0–33.0) mmHg, p=0.960. <h3>Conclusions</h3> Our study suggests that continuing NSAIDs therapy is associated with increased arterial stiffness in patients with rheumatic diseases, independently noted to increase the incidence of cardiovascular disease. <h3>Disclosure of Interest</h3> None declared
SAT0477 The comparison of ultrasound synovitis and enthesitis findings and clinical findings in patients with psoriatic arthritis and skin psoriasis
Authors: T Okano, K Inui, Y Sugioka, K Mamoto, H Yoshimura, T Koike, H Nakamura
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Conventionally, the assessment of affected joint count in patients with psoriatic arthritis (PsA) was relied for the detection of swelling and tenderness in the joints and enthesis by clinical physical assessment. To date, the modern imaging tool such as ultrasound (US) can detect inflammation in the joint and enthesis more sensitively than clinical assessment. <h3>Objectives</h3> The aim of this study was to research the prevalence of US syovitis and enthesitis findings in patients with PsA and psoriasis (PsO) comparing with clinical assessment. <h3>Methods</h3> Total 100 patients, 54 patients with PsA and 46 patients with PsO, were consecutively included. HI VISION Ascendus (HitachiAloka Medical, Tokyo, Japan) was used with a 18-MHz linear array transducer. US examination was performed in MCP, PIP, DIP and wrist joints in both hand. Grayscale (GS) and power Doppler (PD) US were scored on a 0–3 semiquantitative scale for each joint. Moreover, the US assessment of enthesis was performed. Lateral epicondyle, triceps enthesis, the proximal and distal patella tendon enthesis, Achilles tendon and fascia plantaris tendon enthesis was scanned in both GS and PD assessment. Abnormal findings of enthesis was defined structure thickness, bursitis erosion, calcification and power Doppler signal. <h3>Results</h3> US synovitis was found in 81.5% (n=44) and 60.9% (n=28) by GS, 66.7% (n=36) and 45.7% (n=21) by PD assessment, respectively in patients with PsA and PsO. Active synovitis (GS grade ≧ 2 and/or PD grade ≧ 1) was found 68.5% (n=37) in PsA and 45.7% (n=21) in PsO. US synovitis was more frequently found than clinical assessment. The most common sites of inflammatory synovitis were the wrist. US enthesopathy was found in 87.0% (n=47) in patients with PsA 56.5% (n=26) in patients with PsO. US enthesitis was also more frequently found than clinical assessment. The most common sites of enthesopathy were the enthesis in lateral epicondyle, quadriceps and Achilles tendon. <h3>Conclusions</h3> Our results showed that US was able to detect a high prevalence of inflammatory synovitis in peripheral joints and enthesis in patients with PsA. Moreover, subclinical inflammatory findings were also found in patients with PsO by US. US examination is useful to detect the inflammatory condition in patients with PsA and PsO than clinical examination. <h3>Acknowledgements</h3> We wish to thank Setsuko Takeda, Ayumi Hashimoto and Emi Yamashita for their special efforts as a sonographer and collecting data. <h3>Disclosure of Interest</h3> None declared
Non-invasive diagnosis of hepatocellular carcinoma revisited
Authors: Cora Mueller, Nina Waldburger, Ulrike Stampfl, Hans-Ulrich Kauczor, Peter Schirmacher, Christof Matthias Sommer, Thomas Longerich
Journal: Gut (2017)

We read with interest the recent work by Ho et al demonstrating mutational hyperactivation of mammalian target of rapamycin signalling in a subgroup of hepatocellular carcinoma (HCC).1 As Berasain and Lechel concluded that the prospect of a positive therapeutic response may outweigh the risk associated with the HCC biopsy procedure2 and histology is essential for confirming a diagnosis of intrahepatic cholangiocarcinoma (ICC),3 we revisited the performance of non-invasive HCC diagnosis as recommended by current guidelines (eg, American Association for the Study of Liver Diseases (AASLD)) in clinical practice.4 

We retrospectively analysed all patients (n=182) in which a CT-guided liver biopsy was performed at a tertiary referral centre within a 9-year period due to the clinical differential diagnosis of HCC. After quality control, a total of 94 biopsies (figure 1A, see online supplementary table 1) could be evaluated. HCC development was associated with the presence of cirrhosis (n=51/65, p<0.001), which was also found in 27% (3/11) of ICC and 33% (1/3) of combined hepatocellular–cholangiocarcinoma (HCC–CC) patients. The number of false-positive non-invasive HCC diagnosis was higher in patients without cirrhosis (n=13/19; table …
AB0167 Calcium influx kinetics and the characteristics of potassium channels in peripheral t lymphocytes in systemic sclerosis
Authors: N Legány, G Toldi, I Ocsovszki, L Kovács, A Balog
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by microvascular injury, fibrosis and autoimmunity that affects the skin and internal organs. The short-term activation of peripheral blood T lymphocytes plays a crucial role in initiating and maintaining the chronic inflammation. The transient increase of the cytoplasmic free calcium level plays a key role in the process of lymphocyte activation. Kv1.3 and IKCa1 potassium channels are important regulators of the maintenance of calcium influx during lymphocyte activation. The influx of calcium is maintained by the function of potassium channels that conserve the electrochemical potential gradient via the efflux of potassium from the cytoplasm. Recent reports raised the notion that the inhibition of lymphocyte potassium channels, especially that of the Kv1.3 channel would be an straightforward solution for specific immunosuppression in autoimmune disorders. Furthermore, our previous studies described an alteration of the short-term activation of peripheral lymphocytes in rheumatoid arthritis and primary Sjögren9s syndrome (pSS), and the overexpression of Kv1.3 channels in pSS. <h3>Objectives</h3> Therefore, in this study we aimed to characterize the effects of lymphocyte potassium channel inhibition on short-term peripheral blood T lymphocyte activation in major lymphocyte subsets in SSc. <h3>Methods</h3> We enrolled 12 healthy individuals and 16 SSc patients. We evaluated calcium influx kinetics following activation in CD4, Th1, Th2 and CD8 cells applying a novel kinetic flow cytometry approach. We assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 potassium channels. We also assessed the Kv1.3 expression on lymphocytes. <h3>Results</h3> We observed increased parameters of calcium influx in CD8+ lymphocytes9 as compared with Th1 cells in SSc. However, the activation of CD8+ cells was lower in SSc compared to healthy controls. Moreover, activation of Th1 lymphocytes was slower in SSc than in healthy controls. The inhibition of IKCa1 potassium channel decreased the activation of CD8+ lymphocytes in healthy controls and the activation of Th1 cells in SSc. The inhibition of Kv1.3 channel modified the dynamics of activation of Th1 and Th2 lymphocytes in SSc. <h3>Conclusions</h3> The altered function of CD8+ cells and the specific inhibition of potassium channels seem to be a consequence of altered calcium influx kinetics in SSc, distinguishing it both from healthy controls and other autoimmune diseases. <h3>Acknowledgements</h3> Attila Balog and Gergely Toldi were supported by the János Bolyai Scholarship. Gergely Toldi is an International Society for the Advanecement of Cytometry (ISAC) Scholar. <h3>Disclosure of Interest</h3> None declared