tbuckley/cabot-search huggingface dataset:
High-Attenuation Areas on Chest Computed Tomography and Clinical Respiratory Outcomes in Community-Dwelling Adults
Authors: Anna J. Podolanczuk, Elizabeth C. Oelsner, R. Graham Barr, Elana J. Bernstein, Eric A. Hoffman, Imaani J. Easthausen, Karen Hinckley Stukovsky, Arindam RoyChoudhury, Erin D. Michos, Ganesh Raghu, Steven M. Kawut, David J. Lederer
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Areas of increased lung attenuation visualized by computed tomography are associated with all-cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD).Objectives: To determine whether high-attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population.Methods: We performed a cohort study of 6,808 adults aged 45–84 years sampled from six communities in the United States. High-attenuation areas were defined as the percentage of imaged lung volume with attenuation values between −600 and −250 Hounsfield units. An adjudication panel determined ILD hospitalization and death.Measurements and Main Results: After adjudication, 52 participants had a diagnosis of ILD during 75,232 person-years (median, 12.2 yr) of follow-up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person-years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person-years). High-attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1-SD increment in high-attenuation areas; 95% confidence interval, 1.9–3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High-attenuation areas were also associated with an increased rate of ILD-specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7–3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers.Conclusions: Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high-attenuation areas by screening and diagnostic computed tomography may be warranted in at-risk adults.
Automatic<i>versus</i>manual oxygen administration in the emergency department
Authors: Erwan L'Her, Patricia Dias, Maelenn Gouillou, Anne Riou, Luc Souquiere, Nicolas Paleiron, Patrick Archambault, Pierre-Alexandre Bouchard, François Lellouche
Journal: European Respiratory Journal (2017)

Oxygen is commonly administered in hospitals, with poor adherence to treatment recommendations. We conducted a multicentre randomised controlled study in patients admitted to the emergency department requiring O 2 ≥3 L·min −1 . Patients were randomised to automated closed-loop or manual O 2 titration during 3 h. Patients were stratified according to arterial carbon dioxide tension ( P aCO 2 ) (hypoxaemic P aCO 2 ≤45 mmHg; or hypercapnic P aCO 2 &gt;45–≤55 mmHg) and study centre. Arterial oxygen saturation measured by pulse oximetry ( S pO 2 ) goals were 92–96% for hypoxaemic, or 88–92% for hypercapnic patients. Primary outcome was % time within S pO 2 target. Secondary endpoints were hypoxaemia and hyperoxia prevalence, O 2 weaning, O 2 duration and hospital length of stay. 187 patients were randomised (93 automated, 94 manual) and baseline characteristics were similar between the groups. Time within the S pO 2 target was higher under automated titration (81±21% versus 51±30%, p&lt;0.001). Time with hypoxaemia (3±9% versus 5±12%, p=0.04) and hyperoxia under O 2 (4±9% versus 22±30%, p&lt;0.001) were lower with automated titration. O 2 could be weaned at the end of the study in 14.1% versus 4.3% patients in the automated and manual titration group, respectively (p&lt;0.001). O 2 duration during the hospital stay was significantly reduced (5.6±5.4 versus 7.1±6.3 days, p=0.002). Automated O 2 titration in the emergency department improved oxygenation parameters and adherence to guidelines, with potential clinical benefits.
Bevacizumab combined with first-line chemotherapy in elderly patients (≥75 years old) with metastatic colorectal cancer: Final results of the noninterventional CASSIOPEE study.
Authors: Eric Francois, Denis Michel Smith, Sophie Gourgou, Sophie Gandon, Florence Rollot, Laurent Mineur
Journal: Journal of Clinical Oncology (2017)

3547 Background: Approximately half of the patients (pts) with metastatic colorectal cancer (mCRC) are elderly (≥65 years). Although few elderly pts are included in clinical studies, results in mCRC have shown similar treatment benefits in terms of progression-free survival and overall survival in young and elderly pts. This study was conducted in pts ≥75 years-old with mCRC treated in real life 1st line bevacizumab + chemotherapy in order to improve the knowledge on this population and to contribute in optimizing treatment strategy. Methods: CASSIOPEE is a prospective, multicenter, non-interventional study evaluating 1 st line combination of bev + chemotherapy over 24 months in pts aged ≥75 years with mCRC. The primary endpoint was to describe progression-free survival (PFS). Secondary endpoints included the description of pts characteristics, overall survival, bev and chemotherapy regimen, safety and autonomy criteria (Lawton Instrumental Activities of Daily Living Scale; Balducci score). Results: A total of 402 pts were included between March 2012 and July 2016. In the efficacy population (n = 358), 52% were men, mean age 81 (±4); 54% were≥ 80 years old and 19% were ECOG ≥2; 80% had primary tumor located in the colon; main metastatic sites: liver (66%) and lung (30%). Bev was mainly combined with Folfox (36%) and Folfiri (29%). Median PFS was 9.1 months [8.3;10.2] in the efficacy population and 9.3 months for pts aged &lt; 80, 9.5 months for pts aged ≥ 80 or ≤ 85 and 8.3 months for pts aged &gt; 85. The PFS rate at 24 months was 11.8%. Median OS was 19.0 months [16.5;21.5] in the efficacy population and 20.6 months for pts aged &lt; 80, 17.8 months for pts aged ≥ 80 or ≤ 85 and 13.0 months for pts aged &gt; 85. The OS rate at 24 months was 42.0%. Autonomy and ECOG status remained stable from baseline to 24 months. In the safety population (n = 383), grade ≥ 3 adverse events occurred in 40% pts including 10% pts with bev related AEs. Overall, 4% pts died of an AE and 0.5% were bev related. Conclusions: These results suggest that mCRC patients aged ≥75 years-old, can benefit from 1st line bev plus chemotherapy in daily practice in this population. The safety profile is acceptable. Clinical trial information: NCT01555762.
Effects of abiraterone (ABI) and enzalutamide (ENZA) on cognitive impairment and depressive symptoms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sunil Parimi, Bernhard J. Eigl, Katherine Sunderland, Muhammad Zulfiqar, Daygen L. Finch, Conrad D. Oja, Joanna Vergidis, Leanne Chung-Yan Seto, Arun Azad, Martin Gleave, Kim N. Chi
Journal: Journal of Clinical Oncology (2016)

5059 Background: Cognitive and mood effects of ABI and ENZA are not well described. An ongoing randomized phase II trial evaluating sequencing of ABI and ENZA in treatment-naïve pts with mCRPC (ClinicalTrials.gov: NCT02125357) also includes Montreal Cognitive Association (MoCA) testing for cognitive impairment and Patient Health Questionnaire (PHQ-9) for depression symptoms administered to all pts. Methods: MoCA was performed at baseline and Day 1 Cycle 4; PHQ-9 at baseline and each cycle. The proportion of pts experiencing a worsening of cognitive impairment by MoCA category (normal = 27-30, mild = 18-26, moderate 10-17, severe, < 10), and proportion of patients experiencing a worsening in depression severity level by PHQ-9 (none = 0-4, mild = 5-9, moderate = 10-19, severe = 20-27) was determined. Results: 60 pts with a minimum follow-up of 3 months were evaluated: 27 and 33 were randomized toABI and ENZA, respectively. 10 were non-evaluable for MoCA and 7 for PHQ9 data. At baseline, median score for MoCA was 25 (range 13-30) and 3 for PHQ-9 (range 0-20). Similar proportions of pts in the ABI and ENZA arms had some baseline impairment in PHQ9 (33.3%, 31.3%) and MoCA scores (76.9%, 74.2%). Change from baseline to Cycle 4 in MoCA and PHQ-9 severity levels are shown in the Table. There was a trend for a greater proportion of pts treated with ENZA as compared to ABI to have a worsening cognitive impairment score (p = 0.20). Significantly more pts in the ENZA arm had a worsening depression severity score (P = 0.03). A greater number of ENZA pts reported worsening on PHQ-9 questions related to energy, appetite, and psychomotor symptoms. Conclusions: In this preliminary analysis, there were more pts with a worsening severity of reported depression symptoms and a trend towards an increase in cognitive impairment with ENZA as compared to ABI. These data help to characterize and define the incidence of these symptoms. Table: Change in cognitive impairment and depression severity Clinical trial information: NCT02125357. Change in MoCA Level Change in PHQ-9 Level Improvement or No Change (% of Pts) Worsening (% of Pts) Improvement or No Change (% of Pts) Worsening (% of Pts) ENZA 81 19 75 25 ABI 95 5 96 4
Dose escalation of POL6326 in combination with eribulin in HER2-negative relapsed metastatic breast cancer (mBCa) patients (pts).
Authors: Sonia Pernas Simon, Javier Cortes, Foluso Olabisi Ademuyiwa, Sara Lopez-Tarruella, Luis Manso, Peter Kaufman, Leon W. Hooftman, Barbara Romagnoli, Jose Alejandro Perez-Fidalgo, Timothy J. Pluard, Katherine N. Weilbaecher, Patricia Gomez Pardo
Journal: Journal of Clinical Oncology (2016)

2548 Background: POL6326 is a cyclic peptide and a potent, selective antagonist of the chemokine receptor CXCR4. Evidence suggests that CXCR4 inhibition interferes with the tumor-protective microenvironment and therefore sensitizes tumor cells to chemotherapy. Consequently, POL6326 may enhance the effects of cytoreductive therapy and is being developed as adjunctive cancer treatment. Methods: This open label dose escalation study was conducted in pts with relapsed mBC and with positive CXCR4 expression at tumor site to establish the Maximum Tolerated Dose (MTD) of the combination of POL6326 and eribulin. MTD was defined as the highest dose at which DLT occurs in no more than 1 of 6 pts. Cohorts received eribulin on days 2 and 9, flanked by POL6326 on days 1-3, and 8-10 of 21-day cycles. Pts were treated until disease progression or DLT. Results: 24 pts (median age 53 [38-74]; ECOG PS 1) wereenrolled in 8 cohorts. Eribulin mesilate was administered at 1.4 mg/m2 apart from two cohorts receiving 1.1 mg/m2. POL6326 was escalated from 0.5 to 3.5 mg/kg. MTD of the combination has not been achieved yet. The most commonly reported (Gr 3-4) adverse events were neutropenia (9/24 pts) and leucopenia (3/24 pts); 3/24 pts developed neutropenic fever and 1 patient on 1.4 mg/m2eribulin and 1.0 mg/kg POL6326 died from sepsis. 9/24 pts experienced (Gr 1-2) histaminergic reactions related to POL6326 that were manageable with anti-histamines. Increases of Cmax and AUC were linear among POL6326 doses 0.5-3.5 mg/kg. Eribulin pharmacokinetics were in line with published values with no indication of PK interaction with POL6326. The median duration of treatment was 4 cycles [1-8] and 4 pts achieved a partial tumour response, all on the higher dose of eribulin. Conclusions: POL6326 in doses of 0.5-3.5 mg/kg can be combined safely with eribulin 1.1-1.4 mg/m2 in pts with pretreated mBC. Incidence of neutropenia thus far has been similar to eribulin monotherapy. The combination with POL6326 may enhance cytoreductive potential of eribulin, and this treatment approach therefore warrants efficacy studies in mBC. Clinical trial information: NCT01837095.
The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment
Authors: Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S. Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E. Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J. Dovedi, Paul D. Smith, Ross Stewart, Robert W. Wilkinson
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME). <h3>Methods</h3> In mice, the effects of MEK inhibition, via selumetinib, and anti-CTLA-4 on immune responses to keyhole limpet haemocyanin (KLH) immunization were monitored using ex vivo functional assays with splenocytes. In a KRAS-mutant CT26 mouse colorectal cancer model, the impact on the tumor microenvironment (TME) and the spleen were evaluated by flow cytometry. The TME was further examined by gene expression and immunohistochemical analyses. The combination and sequencing of selumetinib and anti-CTLA-4 were also evaluated in efficacy studies using the CT26 mouse syngeneic model. <h3>Results</h3> Anti-CTLA-4 enhanced the generation of KLH specific immunity following KLH immunization in vivo; selumetinib was found to reduce, but did not prevent, this enhancement of immune response by anti-CTLA-4 in vivo. In the CT26 mouse model, anti-CTLA-4 treatment led to higher expression levels of the immunosuppressive mediators, Cox-2 and Arg1 in the TME. Combination of anti-CTLA-4 with selumetinib negated this up-regulation of Cox-2 and Arg1, reduced the frequency of CD11<sup>+</sup> Ly6G<sup>+</sup> myeloid cells, and led to the accumulation of differentiating monocytes at the Ly6C<sup>+</sup> MHC<sup>+</sup> intermediate state in the tumor. We also report that MEK inhibition had limited impact on anti-CTLA-4-mediated increases in T-cell infiltration and T-cell activation in CT26 tumors. Finally, we show that pre-treatment, but not concurrent treatment, with selumetinib enhanced the anti-tumor activity of anti-CTLA-4 in the CT26 model. <h3>Conclusion</h3> These data provide evidence that MEK inhibition can lead to changes in myeloid cells and immunosuppressive factors in the tumor, thus potentially conditioning the TME to facilitate improved response to anti-CTLA-4 treatment. In summary, the use of MEK inhibitors to alter the TME as an approach to enhance the activities of immune checkpoint inhibitors warrants further investigation in clinical trials.
Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease
Authors: Odilia B. J. Corneth, Gwenny M. P. Verstappen, Sandra M. J. Paulissen, Marjolein J. W. de Bruijn, Jasper Rip, Melanie Lukkes, Jan Piet van Hamburg, Erik Lubberts, Hendrika Bootsma, Frans G. M. Kroese, Rudi W. Hendriks
Journal: Arthritis & Rheumatology (2017)

Objective Bruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacologic BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity; conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We undertook this study to investigate BTK expression and activity in human B cells in the context of autoimmune disease. Methods Using intracellular flow cytometry, we quantified BTK expression and phosphorylation in subsets of peripheral blood B cells from 30 patients with rheumatoid arthritis (RA), 26 patients with primary Sjögren's syndrome (SS), and matched healthy controls. Results In circulating B cells, BTK protein expression levels correlated with BTK phosphorylation. BTK expression was up‐regulated upon BCR stimulation in vitro and was significantly higher in CD27+ memory B cells than in CD27−IgD+ naive B cells. Importantly, BTK protein and phospho‐BTK were significantly increased in B cells from anti–citrullinated protein antibody (ACPA)–positive RA patients but not in B cells from ACPA‐negative RA patients. BTK was increased both in naive B cells and in memory B cells and correlated with frequencies of circulating CCR6+ Th17 cells. Likewise, BTK protein was increased in B cells from a major fraction of patients with primary SS and correlated with serum rheumatoid factor levels and parotid gland T cell infiltration. Interestingly, targeting T cell activation in patients with primary SS using the CTLA‐4Ig fusion protein abatacept restored BTK protein expression in B cells to normal levels. Conclusion These data indicate that autoimmune disease in humans is characterized by enhanced BTK activity, which is linked not only to autoantibody formation but also to T cell activity.
The United Kingdom Sets Limits on Experimental Treatments
Authors: Robert D. Truog
Journal: JAMA (2017)

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Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome
Authors: N. Alonso, J. Cañueto, S. Ciria, E. Bueno, I. Palacios‐Alvarez, M. Alegre, C. Badenas, A. Barreiro, L. Pena, C. Maldonado, M.V. Nespeira‐Jato, C. Peña‐Penabad, A. Azon, M. Gavrilova, I. Ferrer, O. Sanmartin, L. Robles, A. Hernandez‐Martin, M. Urioste, S. Puig, L. Puig, R. Gonzalez‐Sarmiento
Journal: British Journal of Dermatology (2017)

Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon–intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype–phenotype correlation, as seen in relatives carrying similar mutations. This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.
Re: Sumanta K. Pal, Guru Sonpavde, Neeraj Agarwal, et al. Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma. Eur Urol 2017;72:557–64
Authors: Ye Lei, Jens Mundhenk, Christian Schwentner
Journal: European Urology (2017)
A CASE-CONTROL STUDY INVESTIGATING THE RELATIONSHIP BETWEEN 3-T MRI FINDINGS, BONY MORPHOLOGY, AND HIP PAIN AND FUNCTION IN PROFESSIONAL BALLET DANCERS AND NON-DANCING ATHLETES
Authors: Susan Mayes, Peter Smith, April-Rose Ferris, Jill Cook
Journal: British Journal of Sports Medicine (2017)

Background Ballet loads the hip joint in extreme ranges of movement (ROM). Abnormal bony morphology and joint laxity may enable this movement, but predispose dancers to hip injury. Objective To compare hip injury and bony morphology between ballet dancers and non-dancing athletes, and to investigate relationships between these factors and clinical features. Design Blinded, case-control study. Participants 49 professional ballet dancers and 49 age- and sex-matched non-dancing athletes. Setting Professional ballet company and sporting clubs. Assessment of Risk Factors Lateral centre edge angles, anterior and superior alpha angles, femoral neck-shaft angles and acetabular version angles measured with 3.0-Tesla magnetic resonance imaging (3-T MRI), ROM and hypermobility testing. Main Outcome Measurements Cartilage, labral, ligamentum teres (LT) lesions and effusion scored on MRI, and HAGOS (Copenhagen Hip and Groin Outcome Score). Results Cartilage defect and labral tear prevalence was similar in dancers and athletes (p&gt;0.05); LT tears were more prevalent in dancers compared to athletes (p=0.001). Dancers had higher neck-shaft angles (p=0.002); lower acetabular version angles (p=0.003); lower superior alpha angles (p&lt;0.001); similar anterior alpha angles (p=0.2); and similar lateral acetabular coverage (p=0.07), compared to athletes. There was no significant association between the morphological parameters and cartilage, labral, LT injury or effusion (p&gt;0.01 for all). All 6 dancers with cam morphology (α angle &gt;50°) measured anteriorly had cartilage defects, and 5 had labral tears; a trend not observed in athletes. Joint effusions were larger in dancers compared to athletes (p=0.009), and the only factor related to lower HAGOS pain and sports/recreation scores in female dancers (p=0.001 for both). Conclusions Professional ballet dancers had a high incidence of LT tear, and hip bony morphology that may allow extreme motion. Dancers with cam morphology had cartilage defects, but joint effusion was the only correlate with symptoms. Longitudinal studies are required to determine the clinical sequelae.
Long term antiretroviral injection proves effective in trial
Authors: Sophie Cousins
Journal: BMJ (2017)

A long acting injection for HIV could transform antiretroviral therapy (ART) for patients who struggle to take a daily pill, a leading doctor has said, after the first study of a fully injectable antiretroviral regimen found it to be effective.

Research presented at the International AIDS Society’s Conference on HIV Science in Paris, France, showed that a four or eight week maintenance ART injection of cabotegravir plus rilpivirine had high rates of virologic response and was well tolerated through 96 weeks.

At the end of a two year trial of 286 people, 94% of patients who had received the eight week injection and 87% of those who had the four week injection had the virus under control, defined as …