tbuckley/cabot-search huggingface dataset:
Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221)
Authors: Christine B. Ambrosone, Gary R. Zirpoli, Alan D. Hutson, William E. McCann, Susan E. McCann, William E. Barlow, Kara M. Kelly, Rikki Cannioto, Lara E. Sucheston-Campbell, Dawn L. Hershman, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Gabriel N. Hortobagyi, Julie R. Gralow, George T. Budd, Kathy S. Albain
Journal: Journal of Clinical Oncology (2019)

Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes.Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach.There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.
Abstract I09: Tumor-specific T cells reprogram mononuclear phagocytes for destruction of checkpoint blockade-resistant pancreatic cancer
Authors: Stephanie K. Dougan
Journal: Cancer Research (2019)

Abstract Like virally infected cells, tumors can evade CD8 T-cell recognition by downregulation of MHC class I. Loss of MHC class I and IFNg sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. The cellular (c)-IAPs regulate classical and alternative NF-kB signaling, and induction of noncanonical NF-kB signaling using IAP antagonists mimics costimulatory signaling, augmenting antitumor immunity. We now show that induction of noncanonical NF-kB signaling promotes antitumor immunity across a range of orthotopic and spontaneous pancreatic cancer models, and induces T cell-dependent immune responses even in b2m-/- tumors, demonstrating that direct CD8 T-cell recognition of tumor cell expressed MHC class I is not required. Here we show that MHC class I negative tumors can be controlled in a T-cell dependent fashion by repolarized intratumoral phagocytes. In wild-type mice, but not mice incapable of mounting antigen-specific T cell responses, treatment with IAP antagonists increases phagocytosis of tumor cells, as determined by flow cytometry, imaging flow cytometry, and quantitative immunofluorescence. This mechanism of action inspired combination therapy with CD47 blockade, a strategy that induced curative responses in otherwise refractory preclinical models. To our knowledge, this is the first example of antigen specific immunotherapy for tumors that are refractory to checkpoint blockade due to loss of MHC class I or IFNg sensing. Citation Format: Stephanie K. Dougan. Tumor-specific T cells reprogram mononuclear phagocytes for destruction of checkpoint blockade-resistant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I09.
Outcomes Before and After the Recall of a Heart Failure Pacemaker
Authors: Jay Sengupta, Katelyn Storey, Susan Casey, Lena Trager, Melissa Buescher, Mark Horning, Charles Gornick, Raed Abdelhadi, Chuen Tang, Suzanne Brill, Laura Ashbach, Robert G. Hauser
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Timely and complete disclosure of medical device defects is necessary to manage patient care safely and effectively. <h3>Objectives</h3> To determine if the manufacturer's recommendations following the recall of a medical device were timely and complete, the follow-up information and data provided to patients and physicians were adequate for managing patient care, and the actions taken by the US Food and Drug Administration (FDA) regarding the recall were appropriate. <h3>Design, Setting, and Participants</h3> This single-center retrospective case series included 90 of 448 patients who were implanted with a cardiac resynchronization therapy pacemaker at the Minneapolis Heart Institute from May 2003 through January 2011; this pacemaker was recalled in November 2015. In addition, returned product reports submitted by the manufacturer to the FDA via the Manufacturer and User Facility Device Experience (MAUDE) database from January 2008 through December 2018 were analyzed. <h3>Main Outcomes and Measures</h3> Clinical outcomes were serious adverse clinical events that occurred before and after the November 2015 recall notifying physicians and patients that the device's battery could fail unexpectedly because of high internal impedance. Technical outcomes were signs and causes of failure. <h3>Results</h3> Five of 90 patients observed during 2015 experienced syncope when their pacemakers stopped pacing owing to battery or wire connection defects prior to the recall. Of the 90 patients, 37 (41%) were men, and the median (interquartile range) age at implantation was 71.3 (66.1-78.2) years. Analysis of the MAUDE data revealed that battery failures prior to the recall were associated with serious adverse events that included 1 death, 1 cardiac arrest, 5 syncopal attacks, and 6 heart failure exacerbations; 3 additional prerecall syncopal events were caused by wire connection defects. The manufacturer and the FDA were aware of the battery and wire connection defects for 19 months before issuing the recall, yet the wire connection problem was not included in the advisory and physicians were not informed that interrogating the pacemaker could result in loss of pacing. The FDA classified the recall as class II rather than the more critical class I. <h3>Conclusions and Relevance</h3> This case series study of patients implanted with a defective pacemaker found that the pacemaker recall was delayed and that subsequent communications did not include all critical information needed for safe and effective patient care. These findings should prompt reforms in how the medical device industry and the FDA manage future medical device recalls.
Eliminating biasing signals in lung cancer images for prognosis predictions with deep learning
Authors: W. A. C. van Amsterdam, J. J. C. Verhoeff, P. A. de Jong, T. Leiner, M. J. C. Eijkemans
Journal: npj Digital Medicine (2019)

Deep learning has shown remarkable results for image analysis and is expected to aid individual treatment decisions in health care. To achieve this, deep learning methods need to be promoted from the level of mere associations to being able to answer causal questions. We present a scenario with real-world medical images (CT-scans of lung cancers) and simulated outcome data. Through the sampling scheme, the images contain two distinct factors of variation that represent a collider and a prognostic factor. We show that when this collider can be quantified, unbiased individual prognosis predictions are attainable with deep learning. This is achieved by (1) setting a dual task for the network to predict both the outcome and the collider and (2) enforcing independence of the activation distributions of the last layer with ordinary least squares. Our method provides an example of combining deep learning and structural causal models for unbiased individual prognosis predictions.
Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery
Authors: Natalie F. Nidetz, Michael C. McGee, Longping V. Tse, Chengwen Li, Le Cong, Yunxing Li, Weishan Huang
Journal: Pharmacology & Therapeutics (2019)

Adeno-associated viral (AAV) vectors have emerged as the leading gene delivery platform for gene therapy and vaccination. Three AAV-based gene therapy drugs, Glybera, LUXTURNA, and ZOLGENSMA were approved between 2012 and 2019 by the European Medicines Agency and the United States Food and Drug Administration as treatments for genetic diseases hereditary lipoprotein lipase deficiency (LPLD), inherited retinal disease (IRD), and spinal muscular atrophy (SMA), respectively. Despite these therapeutic successes, clinical trials have demonstrated that host anti-viral immune responses can prevent the long-term gene expression of AAV vector-encoded genes. Therefore, it is critical that we understand the complex relationship between AAV vectors and the host immune response. This knowledge could allow for the rational design of optimized gene transfer vectors capable of either subverting host immune responses in the context of gene therapy applications, or stimulating desirable immune responses that generate protective immunity in vaccine applications to AAV vector-encoded antigens. This review provides an overview of our current understanding of the AAV-induced immune response and discusses potential strategies by which these responses can be manipulated to improve AAV vector-mediated gene transfer.
A Multi-Center Phase IIA Trial to Assess the Safety and Efficacy of BL-8040 (a CXCR4 Inhibitor) in Combination with Pembrolizumab and Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma (PDAC)
Authors: M. Hidalgo, V. Semenisty, B. Bockorny, E. Borazanci, D.D. von Hoff, J. Feliu, M. Ponz Sarvise, D. Gutierrez Abad, A. Peled, O. Bohana-Kashtan, Y. Gozlan, E. Sorani, M. Chaney, S. Kadosh, A.V. Vainstein, T. Macarulla
Journal: Annals of Oncology (2019)
The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis
Authors: Michael Cullen, Robert Huddart, Johnathan Joffe, Deborah Gardiner, Lauren Maynard, Paul Hutton, Danish Mazhar, Jonathan Shamash, Matthew Wheater, Jeff White, Aicha Goubar, Nuria Porta, Stephanie Witts, Rebecca Lewis, Emma Hall
Journal: European Urology (2020)

Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. A total of 246 patients with vascular invasion–positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1–3, and cisplatin 50 mg/m2 on days 1–2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. The median follow-up was 49 mo (interquartile range 37–60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3–3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3–4 febrile neutropenia occurred in 6.8% of participants. BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.
Abstract C25: Aspiration liquid biopsy (ALB) of pancreatic cancer (PC)
Authors: Aleksei Kashintsev, Nikolai Kokhanenko, Evgeniy Imyanitov, Vitaliy Proutski, Oleg Granstrem, Lyudmila Solovieva, Konstantin Medvedev, Konstantin Pavelets, Sergey Anisimov
Journal: Cancer Research (2019)

Abstract Introduction: Early detection of PC is the main clue for improving results of treatment. Liquid biopsy (LqB) is the most promising method of detection of disease in a screening context, but selection of biologic material for that is not a resolved problem. Pancreatic juice is the highly specific substance for that aim. However, its collection and analysis are associated with many technical difficulties. Materials and Methods: For pancreatic juice collection we developed a method of ALB using a proprietory pancreatodigestive stent. This stent allows for active aspiration of pancreatic juice. We had recruited 15 patients with verified PC before treatment. Placement of the stent was performed by endoscopy and followed by collecting of pancreatic juice in sterile container at 4o C. After collecting sufficiently large volume of the material, we centrifugated it and made cell-block for cytologic examination. Results: ALB was performed in all 15 cases without any complications. Placement and removal of the stent was atraumatic and without technical problems. However, only in 1 sample out of 15 did we detect atypical cells using standard cytologic examination. Conclusion: We present new methodology for collecting biomaterial potentially useful for the early diagnosis of pancreatic cancer. This method is simple and can be easily replicated. Its application does not require high-quality specialized medical centers and personnel and can be performed in standard gastroenterologic clinics. Collected samples can be easily stored. Furthermore, in addition to cells it allows to obtain the liquid fraction of pancreatic juice that could be used for the detection of tumor DNA. Citation Format: Aleksei Kashintsev, Nikolai Kokhanenko, Evgeniy Imyanitov, Vitaliy Proutski, Oleg Granstrem, Lyudmila Solovieva, Konstantin Medvedev, Konstantin Pavelets, Sergey Anisimov. Aspiration liquid biopsy (ALB) of pancreatic cancer (PC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C25.
Update: Interim Guidance for Health Care Professionals Evaluating and Caring for Patients with Suspected E-cigarette, or Vaping, Product Use–Associated Lung Injury and for Reducing the Risk for Rehospitalization and Death Following Hospital Discharge — United States, December 2019
Authors: Mary E. Evans, Evelyn Twentyman, Eleanor S. Click, Alyson B. Goodman, David N. Weissman, Emily Kiernan, Susan Adkins Hocevar, Christina A. Mikosz, Melissa Danielson, Kayla N. Anderson, Sascha Ellington, Matthew J. Lozier, Lori A. Pollack, Dale A. Rose, Vikram Krishnasamy, Christopher M. Jones, Peter Briss, Brian A. King, Jennifer L. Wiltz, Maleeka J. Glover, Paul C. Melstrom, Katherine R. Shealy, Stacy L. Thorne,, Scott Aberegg, Carolyn S. Calfee, Sean J. Callahan, Annette Esper, Anne Griffiths, Dixie Harris, Don Hayes, Devika R. Rao, Lincoln S. Smith
Journal: MMWR Morbidity and Mortality Weekly Report (2019)
DELTA<sup>2</sup> guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial
Authors: Jonathan A Cook, Steven A Julious, William Sones, Lisa V Hampson, Catherine Hewitt, Jesse A Berlin, Deborah Ashby, Richard Emsley, Dean A Fergusson, Stephen J Walters, Edward C F Wilson, Graeme MacLennan, Nigel Stallard, Joanne C Rothwell, Martin Bland, Louise Brown, Craig R Ramsay, Andrew Cook, David Armstrong, Doug Altman, Luke D Vale
Journal: BMJ (2018)

Randomised controlled trials are considered to be the best method to assess comparative clinical efficacy and effectiveness, and can be a key source of data for estimating cost effectiveness. Central to the design of a randomised controlled trial is an a priori sample size calculation, which ensures that the study has a high probability of achieving its prespecified main objective. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of study participants be recruited, to avoid imposing the burdens of a clinical trial on more patients than necessary. The scientific concern is satisfied and the ethical imperative is further addressed by the specification of a target difference between treatments that is considered realistic or important by one or more key stakeholder groups. The sample size calculation ensures that the trial will have the required statistical power to identify whether a difference of a particular magnitude exists. In this article, the key messages from the DELTA<sup>2</sup> guidance on determining the target difference and sample size calculation for a randomised controlled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.
Comparison of extracellular and hepatobiliary MR contrast agents for the diagnosis of small HCCs
Authors: Anita Paisant, Valérie Vilgrain, Jérémie Riou, Frédéric Oberti, Olivier Sutter, Valérie Laurent, Agnès Rodes, Boris Guiu, Christophe Cassinotto, Hervé Trillaud, Ivan Bricault, Sophie Michalak, Onorina Bruno, Maxime Ronot, Christophe Aubé
Journal: Journal of Hepatology (2019)
LBA3 Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 - part 2 final analysis
Authors: L. Paz-Ares, T.E. Ciuleanu, X. Yu, P. Salman, A. Pluzanski, A. Nagrial, L. Havel, R. Kowalyszyn, C. Audigier-Valette, Y.-L. Wu, H. Borghaei, M.D. Hellmann, J. Brahmer, M. Reck, S. Ramalingam, L. Zhang, P. Bhagavatheeswaran, F.E. Nathan, K.J. O'Byrne
Journal: Annals of Oncology (2019)
Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial
Authors: Thomas Gaisl, Protazy Rejmer, Sira Thiel, Sarah R. Haile, Martin Osswald, Malgorzata Roos, Konrad E. Bloch, John R. Stradling, Malcolm Kohler
Journal: European Respiratory Journal (2019)

Introduction Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA. Material and methods In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score &gt;10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3–4 h). Patients were allocated through minimisation to either subtherapeutic CPAP (“sham CPAP”) or continuation of CPAP (“therapeutic CPAP”). A Bayesian analysis with historical priors calculated the posterior probability of superiority. Results Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6–4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure. Conclusions Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.
In Pursuit of Meaningful Performance Measures for Postacute Care
Authors: Andrea Gilmore-Bykovskyi, Christopher J. Crnich, Amy J. H. Kind
Journal: JAMA Network Open (2019)

Matt P. Malcolm, PhD, OTR/L; Addie Middleton, PhD, DPT; Allen Haas, MS; Kenneth J. Ottenbacher, PhD, OTR; James E. Graham, PhD, DC
Retraction: Retinal Hemorrhage from Blunt Ocular Trauma. N Engl J Med 2019;381:2252.
Authors: Jitender Jinagal, Poonam Dhiman
Journal: New England Journal of Medicine (2019)

To the Editor: We would like to retract the Image in Clinical Medicine entitled “Retinal Hemorrhage from Blunt Ocular Trauma,” which was published in the December 5, 2019, issue of the Journal.1 Th...
A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models
Authors: John O. DaSilva, Katie Yang, Andres E. Perez Bay, Julian Andreev, Peter Ngoi, Erica Pyles, Matthew C. Franklin, Drew Dudgeon, Ashique Rafique, Anthony Dore, Frank J. Delfino, Terra B. Potocky, Robert Babb, Gang Chen, Douglas MacDonald, William C. Olson, Gavin Thurston, Christopher Daly
Journal: Clinical Cancer Research (2019)

Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody with enhanced efficacy.Here, we describe the activity of a biparatopic MET×MET antibody that recognizes two distinct epitopes in the MET Sema domain. We use a combination of in vitro assays and tumor models to characterize the effect of our antibody on MET signaling, MET intracellular trafficking, and the growth of MET-dependent cells/tumors.In MET-driven tumor models, our biparatopic antibody exhibits significantly better activity than either of the parental antibodies or the mixture of the two parental antibodies and outperforms several clinical-stage MET antibodies. Mechanistically, the biparatopic antibody inhibits MET recycling, thereby promoting lysosomal trafficking and degradation of MET. In contrast to the parental antibodies, the biparatopic antibody fails to activate MET-dependent biological responses, consistent with the observation that it recycles inefficiently and induces very transient downstream signaling.Our results provide strong support for the notion that biparatopic antibodies are a promising therapeutic modality, potentially having greater efficacy than that predicted from the properties of the parental antibodies.