tbuckley/cabot-search huggingface dataset:
Cerebral Perfusion and the Risk of Dementia
Authors: Frank J. Wolters, Hazel I. Zonneveld, Albert Hofman, Aad van der Lugt, Peter J. Koudstaal, Meike W. Vernooij, M. Arfan Ikram
Journal: Circulation (2017)

Cerebral hypoperfusion has previously been associated with mild cognitive impairment and dementia in various cross-sectional studies, but whether hypoperfusion precedes neurodegeneration is unknown. We prospectively determined the association of cerebral perfusion with subsequent cognitive decline and development of dementia.Between 2005 and 2012, we measured cerebral blood flow by 2-dimensional phase-contrast magnetic resonance imaging in participants of the population-based Rotterdam Study without dementia. We determined the association of cerebral perfusion (mL/100mL/min) with risk of dementia (until 2015) using a Cox model, adjusting for age, sex, demographics, cardiovascular risk factors, and apolipoprotein E genotype. We repeated analyses for Alzheimer disease and accounting for stroke. We used linear regression to determine change in cognitive performance during 2 consecutive examination rounds in relation to perfusion. Finally, we investigated whether associations were modified by baseline severity of white matter hyperintensities.Of 4759 participants (median age 61.3 years, 55.2% women) with a median follow-up of 6.9 years, 123 participants developed dementia (97 Alzheimer disease). Lower cerebral perfusion was associated with higher risk of dementia (adjusted hazard ratio, 1.31; 95% confidence interval per standard deviation decrease, 1.07-1.61), similar for Alzheimer disease only, and unaltered by accounting for stroke. Risk of dementia with hypoperfusion was higher with increasing severity of white matter hyperintensities (with severe white matter hyperintensities; hazard ratio, 1.54; 95% confidence interval, 1.11-2.14). At cognitive reexamination after on average 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition (global cognition: β=-0.029, P=0.003), which was similar after excluding those with incident dementia, and again most profound in individuals with higher volume of white matter hyperintensities (P value for interaction=0.019).Cerebral hypoperfusion is associated with accelerated cognitive decline and an increased risk of dementia in the general population.
Retrospective-prospective blinded evaluation predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort.
Authors: Anna Sofie Kappel Buhl, Troels Dreier Christensen, Ib Jarle Christensen, Knud Mejer Nelausen, Eva Balslev, Ann S. Knoop, Eva Brix, Else Svensson, Vesna Glavicic, Adam Luczak, Sven Tyge Langkjer, Soeren Linnet, Erik Jakobsen, Jurij Bogovic, Bent Ejlertsen, Annie Rasmussen, Anker Hansen, Steen Knudsen, Dorte Nielsen, Peter Buhl Jensen
Journal: Journal of Clinical Oncology (2017)

1071 Background: Epirubicin remains a cornerstone in the treatment of primary and advanced breast cancer. This study evaluated the predictive effect of a multigene mRNA-based Drug Response Predictor (DRP) in the treatment of advanced breast cancer (ABC). We applied a mathematical method combining in vitro sensitivity with gene expression patterns in tumors. Previously the DRP has been broadly validated 1 , 2 including retrospective validation of epirubicin 3 . Methods: Among 838 consecutive patients from a DBCG cohort 137 patients were treated with epirubicin between May 1997 and November 2016 at one of the participating sites. Patients were examined every 9 to 12 weeks by CT scan and clinical evaluation. After patient informed consent, mRNA was isolated from formalin fixed paraffin embedded tumor tissue from diagnostic biopsies and analyzed using Affymetrix arrays. Blinded predictions of epirubicin efficacy were compared to clinical data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model adjusted for treatment line. Primary endpoint was progression free survival (PFS). Results: Median time to progression was 9.3 months (95% CI: 7.2-13.2). Of the 137 patients, four received epirubicin more than once. Scoring the DRP as a continuous covariate demonstrated that the DRP was significantly associated to PFS (p = 0.02). The estimated hazard ratio was 0.56 (90% CI: 0.35-0.89) comparing two patients with DRP score differing by 50 percentage points. The estimated median time to progression for a patient with a DRP value of 25% was 7 months versus 13 months for a patient with a DRP value of 75%. No interaction with previous adjuvant chemotherapy was observed (p = 0.98). Conclusions: The current study demonstrates a potential clinical value by being able to select patients that benefit from epirubicin against patients predicted not to benefit sparing the last patients unnecessary toxicity. Studies evaluating the predictor in an adjuvant setting will follow. 1 Knudsen et al PLoS ONE 9(2): e87415; 2 Buhl et al PLoS ONE 11(5): e0155123; 3 Wang et al JNCI 105(17): 1284-91
Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research
Authors: Adam T. Hill, Charles S. Haworth, Stefano Aliberti, Alan Barker, Francesco Blasi, Wim Boersma, James D. Chalmers, Anthony De Soyza, Katerina Dimakou, J. Stuart Elborn, Charles Feldman, Patrick Flume, Pieter C. Goeminne, Michael R. Loebinger, Rosario Menendez, Lucy Morgan, Marlene Murris, Eva Polverino, Alexandra Quittner, Felix C. Ringshausen, Gregory Tino, Antoni Torres, Montserrat Vendrell, Tobias Welte, Rob Wilson, Conroy Wong, Anne O'Donnell, Timothy Aksamit
Journal: European Respiratory Journal (2017)

There is a need for a clear definition of exacerbations used in clinical trials in patients with bronchiectasis. An expert conference was convened to develop a consensus definition of an exacerbation for use in clinical research.A systematic review of exacerbation definitions used in clinical trials from January 2000 until December 2015 and involving adults with bronchiectasis was conducted. A Delphi process followed by a round-table meeting involving bronchiectasis experts was organised to reach a consensus definition. These experts came from Europe (representing the European Multicentre Bronchiectasis Research Collaboration), North America (representing the US Bronchiectasis Research Registry/COPD Foundation), Australasia and South Africa.The definition was unanimously approved by the working group as: a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required.The working group proposes the use of this consensus-based definition for bronchiectasis exacerbation in future clinical research involving adults with bronchiectasis.
Mechanisms of exercise‐induced bronchoconstriction in athletes: Current perspectives and future challenges
Authors: M. Couto, M. Kurowski, A. Moreira, D. M. A. Bullens, K.‐H. Carlsen, L. Delgado, M. L. Kowalski, S. F. Seys
Journal: Allergy (2017)

Abstract The evidence of exercise‐induced bronchoconstriction ( EIB ) without asthma ( EIB w A ) occurring in athletes led to speculate about different endotypes inducing respiratory symptoms within athletes. Classical postulated mechanisms for bronchial obstruction in this population include the osmotic and the thermal hypotheses. More recently, the presence of epithelial injury and inflammation in the airways of athletes was demonstrated. In addition, neuronal activation has been suggested as a potential modulator of bronchoconstriction. Investigation of these emerging mechanisms is of major importance as EIB is a significant problem for both recreational and competitive athletes and is the most common chronic condition among Olympic athletes, with obvious implications for their competing performance, health and quality of life. Hereby, we summarize the latest achievements in this area and identify the current gaps of knowledge so that future research heads toward better defining the etiologic factors and mechanisms involved in development of EIB in elite athletes as well as essential aspects to ultimately propose preventive and therapeutic measures.
Long-term follow up (FU) of patients with durable complete response (DCR) after chemotherapy (CT) and HER2-targeting systemic therapy (HER2-Tx) for HER2+ metastatic breast cancer (MBC).
Authors: Giuseppe Gullo, Annamaria De Giorgi, Cecily Quinn, Jo Ballot, Lisa Hammond, John Crown
Journal: Journal of Clinical Oncology (2014)

641 Background: CT-induced DCR of MBC is reported only anecdotally. The addition of HER2-Tx to conventional CT results in increased response rates and prolonged survival for pts with HER2+ MBC. We previously reported that a minority of pts with HER2+ MBC can achieve prolonged CR but their long-term outcome remains unclear. Methods: We conducted a systematic retrospective review of all pts with HER2+ MBC treated at our Institution with any CT+HER2-Tx and identified DCR. DCR was defined as a complete response according to RECIST 1.1 criteria lasting >36 months. Results: Between January 2000 and December 2010 168 consecutive pts with HER2+ MBC were commenced on CT+HER2-Tx. We identified 17 pts (10%) who met criteria for DCR. Their characteristics are: median age: 53yrs (range 30-65), oestrogen receptors (ER): neg 53%/pos 47%, sites of distant metastases: visceral 47%/lymph nodes only 35%/bone and soft tissues 12%, unknown 6%. All pts received trastuzumab (T). Chemotherapy regimens were: docetaxel+carboplatin 64%/docetaxel+lapatinib 18%/single agent taxane 6%/capecitabine 6%/unknown 6%. Metastatic disease was biopsy-proven in 9/17 pts (53%). All pts received maintenance HER2-Tx after completion of CT. Median FU is 6.5 yrs (range 3.4-13.6). Median duration of HER2-Tx is 61 months (41-127+). Two pts (12%) had MBC relapse while on maintenance T, 1 pt had a second HER2+ primary BC and underwent curative surgery. At database cut-off date (1/2/2014) 15 pts (88%) are alive and disease-free. Their characteristics are: all 1st-line therapy, ER neg 53%, single site of distant metastases 73% (lymph nodes 40%, liver 33%). Conclusions: To our knowledge this is the largest series analyzing long-term outcome of HER2+ MBC pts with DCR after CT+HER2-Tx. Our mature results show that a subgroup of pts can achieve a very prolonged CR thus prompting speculations that they have been cured from HER2+ MBC. These pts are usually treated in the 1st-line setting, have more frequently ER-negative disease and limited metastatic disease. Prolonged HER2-Tx could play a role in maintaining DCR. We are currently investigating the molecular profile of this subset of pts.
Physician-assisted suicide and euthanasia in Washington State. Patient requests and physician responses
Authors: A. L. Back
Journal: JAMA (1996)

Objectives.-To estimate how often physicians receive requests for physician-assisted suicide and euthanasia and to describe a case series of patient requests for physician-assisted suicide and euthanasia, including physician responses to these requests. Design.-A mailed, anonymous two-part questionnaire. Participants.-A total of 828 physicians returned questionnaires sent to 1453 potential respondents, for a response rate of 57%. Questionnaires were mailed to a random sample (25%) of primary care physicians and all physicians in selected medical subspecialties in Washington State. Main Outcome Measures.-The frequency of explicit patient requests for physician-assisted suicide and euthanasia reported by physicians and individual case descriptions of patient characteristics, physician perceptions of patient concerns, and physician responses to patient requests. Results.-In the past year, 12% of responding physicians received one or more explicit requests for physician-assisted suicide, and 4% received one or more requests for euthanasia. These physicians provided 207 case descriptions. The diagnoses most often associated with requests were cancer, neurological disease, and the acquired immunodeficiency syndrome (AIDS). The patient concerns most often perceived by physicians were worries about loss of control, being a burden, being dependent on others for personal care, and loss of dignity. Physicians provided assistance more often to patients with physical symptoms. Physicians infrequently sought advice from colleagues. Of 156 patients who requested physician-assisted suicide, 38 (24%) received prescriptions, and 21 of these died as a result. Of 58 patients who requested euthanasia, 14 (24%) received parenteral medication and died. Conclusions.-Patient requests for physician-assisted suicide and euthanasia are not rare. As perceived by physicians, the most common patient concerns at the time these requests are made are nonphysical. Physicians occasionally provide these practices, even though they are currently illegal in Washington State. Physicians do not consult colleagues often about these requests. These findings raise the question of how to ensure quality in the evaluation of patient requests for physician-assisted death.
Neurology of John Hunter's Last Illness
Authors: R. Brain
Journal: BMJ (1952)

John Hunter's angina has often been described, but less attention has been paid to the neurological symptoms of his last illness.These were unusual enough to be intrinsically interesting, and they derive an added interest from the fact that the account of them given by Home (1794), John Hunter's brother-in-law, was clearly de- rived from Hunter himself and includes his own attempt to interpret them.
Quality of life predicts overall survival in women with platinum-resistant ovarian cancer: an AURELIA substudy
Authors: F.T. Roncolato, E. Gibbs, C.K. Lee, R. Asher, L.C. Davies, V.J. Gebski, M. Friedlander, F. Hilpert, L. Wenzel, M.R. Stockler, M. King, E. Pujade-Lauraine
Journal: Annals of Oncology (2017)

Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic.Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic.In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively.Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making.NCT00976911.
Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer: Phase 1b clinical trial.
Authors: Laura Spring, Shom Goel, Dejan Juric, Steven J. Isakoff, Stephanie Haddad, Karleen R. Habin, Ian E. Krop, Beverly Moy, Sara M. Tolaney, Aditya Bardia
Journal: Journal of Clinical Oncology (2017)

TPS1106 Background: Despite the availability of multiple effective therapies, most patients with metastatic HER2-positive breast cancer will experience disease progression and death. While traditionally the focus has been targeting the HER receptor family itself, combinations involving targets downstream of the HER2 pathway, particularly CDK 4/6, could potentially enhance therapeutic efficacy. In pre-clinical models of acquired resistance to HER2-targeted therapies, inhibition of CDK4/6 has been shown to result in tumor inhibition. Trial Design: This phase Ib, single arm, open-label clinical trialis investigating the combination of Trastuzumab emtansine (T-DM1) and the CDK4/6 inhibitor, ribociclib (LEE011). Eligible patients include patients age ≥ 18 years with HER2-positive metastatic breast cancer. Prior treatment with at least one regimen containing trastuzumab and a taxane is required. Ribociclib is given orally for two weeks of a 21-day cycle (days 8-21), with T-DM1 given at standard dose every 3 weeks on day 1. Trial Objectives: 1. To estimate the MTD and/or RP2D of ribociclib in combination with T-DM1. 2. To assess the safety and tolerability of ribociclib in combination with T-DM1. 3. To explore the clinical activity of T-DM1 and ribociclib in HER2-positive metastatic breast cancer. 4. To assess potential biomarkers of response to ribociclib in combination with T-DM1. Statistical Methods: A standard 3+3 dose escalation design is being used to evaluate various doses of ribociclib in combination with T-DM1 to determine the maximum tolerated dose (MTD) and/or recommended phase-2 dose (RP2D). Once MTD/RP2D is determined there will be a dose-expansion cohort (N = l5) to confirm the safety profile and evaluate preliminary evidence of efficacy, including objective response rate (ORR) by RECIST 1.1 and progression-free survival (PFS). Clinical trial information: NCT02657343.
Recent time trends in chemotherapy use and oncologists' chemotherapy recommendations for early-stage, hormone receptor-positive breast cancer.
Authors: Allison W. Kurian, Irina Bondarenko, Reshma Jagsi, Chandler McLeod, Sarah T. Hawley, Ann S. Hamilton, Kevin C. Ward, Steven J. Katz
Journal: Journal of Clinical Oncology (2017)

541 Background: Advances in tumor genomic profiling enable increasingly precise estimates of the benefit of adjuvant chemotherapy in early-stage breast cancer. However, little is known about how chemotherapy use, medical oncologists’ (MO) perspectives and recommendations have changed in recent years, particularly in key clinical subgroups such as node-negative and node-positive. Methods: We surveyed 5,080 women (70% response rate), newly diagnosed with breast cancer in 2013-2015 and accrued through two population-based SEER registries (Georgia and Los Angeles), about their MOs’ chemotherapy recommendations and whether they received chemotherapy. Using patient report, we identified 470 attending MOs and surveyed them (n=310, 66% response) about approaches to chemotherapy recommendation, using node-negative and node-positive case scenarios. We evaluated factors associated with chemotherapy receipt over time using multi-level logistic regression. Results: The analytic sample was 2,926 patients with stages I-II, estrogen receptor-positive, HER2-negative breast cancer. Chemotherapy use declined to 21% from 34% during the study period (2013-2015, p&lt;.001). For node-positive patients, chemotherapy use declined to 64% from 81% and for node-negative/micrometastasis patients to 14% from 27%. Based on patient report, MOs’ recommendations for chemotherapy declined during the study period to 32% from 45% (p&lt;.001). Recommendations reported by MOs were generally guideline-concordant. MOs were much more likely to order tumor genomic profiling when patient preferences were discordant with recommendations [67%, standard error (SE) 3% versus 18% (SE 2%) without discordance], and they adjusted chemotherapy recommendations based on patient preferences and genomic profiling results. Conclusions: For both node-negative/micrometastasis and node-positive patients, chemotherapy receipt and oncologists’ recommendations for chemotherapy declined markedly in recent years. The results of ongoing clinical trials of genomic profiling will be essential to confirm the quality of this approach to breast cancer care. Funded by NCI P01CA163233.
Intraoperative Infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery
Authors: Stacie Deiner, Xiaodong Luo, Hung-Mo Lin, Daniel I. Sessler, Leif Saager, Frederick E. Sieber, Hochang B. Lee, Mary Sano, Christopher Jankowski, Sergio D. Bergese, Keith Candiotti, Joseph H. Flaherty, Harendra Arora, Aryeh Shander, Peter Rock
Journal: JAMA Surgery (2017)

<h3>Importance</h3> Postoperative delirium occurs in 10% to 60% of elderly patients having major surgery and is associated with longer hospital stays, increased hospital costs, and 1-year mortality. Emerging literature suggests that dexmedetomidine sedation in critical care units is associated with reduced incidence of delirium. However, intraoperative use of dexmedetomidine for prevention of delirium has not been well studied. <h3>Objective</h3> To evaluate whether an intraoperative infusion of dexmedetomidine reduces postoperative delirium. <h3>Design, Setting, and Participants</h3> This study was a multicenter, double-blind, randomized, placebo-controlled trial that randomly assigned patients to dexmedetomidine or saline placebo infused during surgery and for 2 hours in the recovery room. Patients were assessed daily for postoperative delirium (primary outcome) and secondarily for postoperative cognitive decline. Participants were elderly (&gt;68 years) patients undergoing major elective noncardiac surgery. The study dates were February 2008 to May 2014. <h3>Interventions</h3> Dexmedetomidine infusion (0.5 µg/kg/h) during surgery and up to 2 hours in the recovery room. <h3>Main Outcomes and Measures</h3> The primary hypothesis tested was that intraoperative dexmedetomidine administration would reduce postoperative delirium. Secondarily, the study examined the correlation between dexmedetomidine use and postoperative cognitive change. <h3>Results</h3> In total, 404 patients were randomized; 390 completed in-hospital delirium assessments (median [interquartile range] age, 74.0 [71.0-78.0] years; 51.3% [200 of 390] female). There was no difference in postoperative delirium between the dexmedetomidine and placebo groups (12.2% [23 of 189] vs 11.4% [23 of 201],<i>P</i> = .94). After adjustment for age and educational level, there was no difference in the postoperative cognitive performance between treatment groups at 3 months and 6 months. Adverse events were comparably distributed in the treatment groups. <h3>Conclusions and Relevance</h3> Intraoperative dexmedetomidine does not prevent postoperative delirium. The reduction in delirium previously demonstrated in numerous surgical intensive care unit studies was not observed, which underscores the importance of timing when administering the drug to prevent delirium. <h3>Trial Registration</h3> clinicaltrials.gov IdentifierNCT00561678