tbuckley/cabot-search huggingface dataset:
Validation of the two best models to predict “benign” pathohistology in patients with advanced nonseminomatous germ cell tumors (NSGCT) undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Tim Nestler, Pia Paffenholz, Bettina Baeßler, Martin Hellmich, Andreas Hiester, Alessandro Nini, David Pfister, Peter Albers, Axel Heidenreich
Journal: Journal of Clinical Oncology (2020)

389 Background: The aim of our study is to validate and evaluate the two currently best performing prediction models (Vergouwe and Leao) for final pathohistology in NSGCT patients undergoing PC-RPLND and we introduce a new radiomics approach. Methods: We performed a retrospective analysis including 496 patients who underwent a PC-RPLND between 2008 and 2018 to validate the two prediction models using published formulas and thresholds. ROC were plotted and AUC was calculated. We determined the optimal cut point and used bootstrapping (1,000 replications) to estimate its variability. For radiomics, lymph nodes of 80 patients were identified on CT images, semiautomatically segmented with 93 radiographic features (pyRadiomics package). A linear support vector machine algorithm was applied to analyze reproducible radiomics features. A continuous reduction of features analyzed was performed using Random Forest algorithms and ROC analysis. Results: In our validation cohort, the Vergouwe model had a significantly better AUC compared to Leao model (0.749 [CI 0.706-0.792] vs. 0.689 [0.642-0.736], p=0.004) to predict benign histology. At a threshold of &gt; 70% for the probability of benign disease, the Leao model would have avoided PC-RPLND in 8.6% with benign disease with an error rate of 5.6% for viable tumor. The Vergouwe model would avoid PC-RPLND in 23.4% with benign disease with an error rate of 12.7% for viable tumor/teratoma. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm on the training dataset resulted in an accuracy of 0.96 (93% sensitivity, 100% specificity, 100% PPV), on an independent validation cohort the accuracy was 0.81 (88% sensitivity, 72% specificity, 78% PPV). Conclusions: According to our data, the discriminatory accuracy of both models is not sufficient to safely select patients for surveillance strategy instead of PC-RPLND. The radiomics model is promising but needs prospective validation. Further studies including new biomarkers are needed to optimize the accuracy of potential prediction models.
81P Response to Endocrine and Targeted Therapies in A Large Panel of Patient-Derived Luminal Breast Cancer Xenografts
Authors: P.H. Cottu, F. Assayag, O. Chouchane-Mlik, F. Reyal, P. De Cremoux, D. Gentien, S. Chateau-Joubert, A. Vincent-Salomon, D. Decaudin, E. Marangoni
Journal: Annals of Oncology (2012)
Earlier palliative home care is associated with patient-centred medical resource utilisation and lower costs in the last 30 days before death in COPD: a population-level decedent cohort study
Authors: Charlotte Scheerens, Kristof Faes, Peter Pype, Kim Beernaert, Guy Joos, Eric Derom, Joachim Cohen, Luc Deliens, Kenneth Chambaere
Journal: European Respiratory Journal (2020)

COPD patients often use many medical resources, such as hospital admissions and medical imaging, inappropriately close to death. Palliative home care (PHC) could beneficially affect this. The aim was to study the effect of use and timing of PHC on medical resource use and costs in the last 30 days before death (DBD) for COPD.We performed a retrospective study of all Belgian decedents in 2010-2015 with COPD and a primary cause of death being COPD or cardiovascular diseases. Odds ratios for medical resources were calculated between using and four PHC timing categories (>360, 360-181, 180-91 and 90-31 DBD) versus not using. Confounders were socio-demographic, care intensity and disease severity variables.Of the 58 527 decedents with COPD, 644 (1.1%) patients received PHC earlier than 30 DBD. Using PHC (versus not using) decreased the odds ratio for hospitalisation (0.35), intensive care unit admission (0.16), specialist contacts (0.58), invasive ventilation (0.13), medical imaging including chest radiograph (0.34), sedatives (0.48) and hospital death (0.14). It increased the odds ratio for home care (3.27), general practitioner contact (4.65), palliative care unit admission (2.61), noninvasive ventilation (2.65), gastric tube (2.15), oxygen (2.22) and opioids (4.04) (p<0.001). Mean total healthcare costs were €1569 lower for using PHC. All PHC timing categories showed a benefit in medical resource use and costs. However, we observed the largest benefit in the category PHC 90-31 DBD.Health policy and services should focus on increasing PHC access, while research should further explore early PHC initiation for COPD.
Dual Eigen-modules of <i>Cis</i>-Element Regulation Profiles and Selection of Cognition-Language Eigen-direction along Evolution in Hominidae
Authors: Liang Li, Sheng Zhang, Lei M Li
Journal: Molecular Biology and Evolution (2020)

To understand the genomic basis accounting for the phenotypic differences between human and apes, we compare the matrices consisting of the cis-element frequencies in the proximal regulatory regions of their genomes. One such frequency matrix is represented by a robust singular value decomposition. For each singular value, the negative and positive ends of the sorted motif eigenvector correspond to the dual ends of the sorted gene eigenvector, respectively, comprising a dual eigen-module defined by cis-regulatory element frequencies (CREF). The CREF eigen-modules at levels 1, 2, 3, and 6 are highly conserved across humans, chimpanzees, and orangutans. The key biological processes embedded in the top three CREF eigen-modules are reproduction versus embryogenesis, fetal maturation versus immune system, and stress responses versus mitosis. Although the divergence at the nucleotide level between the chimpanzee and human genome was small, their cis-element frequency matrices crossed a singularity point, at which the fourth and fifth singular values were identical. The CREF eigen-modules corresponding to the fourth and fifth singular values were reorganized along the evolution from apes to human. Interestingly, the fourth sorted gene eigenvector encodes the phenotypes unique to human such as long-term memory, language development, and social behavior. The number of motifs present on Alu elements increases substantially at the fourth level. The motif analysis together with the cases of human-specific Alu insertions suggests that mutations related to Alu elements play a critical role in the evolution of the human-phenotypic gene eigenvector.
Determination of the ability of a novel, long-acting subcutaneous GnRH antagonist, VERU-100, to castrate without a testosterone surge in a rat model.
Authors: Robert H. Getzenberg, Jui-Chen Lin, Andrew Cerro, Christopher A. Rhodes, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2020)

128 Background: Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. LHRH agonists are frequently used for ADT but these agents often result in initial surges in testosterone (T) levels. Although they do not result in initial T surges, current injectable GnRH antagonists are short term (1 month) subcutaneous (sc) depots that require a high volume loading dose followed by monthly maintenance dosing. VERU-100 is a novel GnRH decapeptide antagonist for long term suppression of T to castrate levels and is administered as a low volume sc injection without the requirement of a loading dose. Eight distinct formulations were evaluated in rats in order to select the best formulation, VERU-100. Methods: Male Sprague Dawley rats (n=3 per group) were injected sc through a 21G needle, with approximately 200 μl of each formulation at a dose level of 20 mg/kg. Eight groups consisting of the distinct test formulations were evaluated. Blood samples were drawn at weekly intervals until week 4 and then bi-weekly for pharmacokinetic (PK) (Integrated Analytical Solutions) and testosterone (T) level determinations (Cornell University Animal Health Diagnostic Center). Results: Within approximately 24 hours after administration of the GHRH antagonist formulations, testosterone levels in the rats went from a mean of 7.36 ng/ml to undetectable. The T levels resulting from a single injection of the lead formulation in these studies, VH-030-002, remained undetectable for greater than 26 weeks (6 months) as did the other formulations tested. The corresponding PK analysis demonstrated that the GnRH antagonist levels were detectable for greater than 26 weeks and remained above 1 ng/ml for almost all of the study points. The T levels correlated to the exposure from the formulations, and PKPD was as consistent for GnRH antagonists. Conclusions: VERU-100 is a novel GnRH antagonist formulation that in this rodent study, with a low injection volume, resulted in undetectable T for at least six months. No surge of T is observed after administration. An IND submission is anticipated in early 2020 for the dose finding Phase 2 trial in men with advanced prostate cancer.
Effectiveness of dulaglutide vs liraglutide and exenatide once-weekly. A real-world study and meta-analysis of observational studies
Authors: Mario Luca Morieri, Mauro Rigato, Vera Frison, Natalino Simioni, Michele D'Ambrosio, Federica Tadiotto, Agostino Paccagnella, Annunziata Lapolla, Angelo Avogaro, Gian Paolo Fadini
Journal: Metabolism (2020)
一项在银屑病患者中开展的 tildrakizumab 药物研究
Authors: K. Reich, R.B. Warren, L. Iversen, L. Puig, I. Pau‐Charles, A. Igarashi, M. Ohtsuki, M. Falqués, M. Harmut, S. Rozzo, M.G. Lebwohl, W. Cantrell, A. Blauvelt, D. Thaçi
Journal: British Journal of Dermatology (2020)

银屑病是一种常见的皮肤病,可导致皮肤发红和鳞斑。全世界约 2% 的人患有银屑病。该研究的作者希望了解 tildrakizumab 药物治疗银屑病的效果以及长期使用可能产生的副作用。 为此,他们综合了来自两项临床试验(reSURFACE 1 和 reSURFACE 2)的信息。作者使用银屑病面积与严重性指数 (PASI) 的评分方法,检查三年期间银屑病症状的改善。这种方法可以分级患者银屑病的严重程度,有助于测量任何改善。 在临床试验中,成功的测量标准是达到“PASI 75”或“PASI 90”的患者比例,指从治疗开始将 PASI 评分降低 75% 或 90%。此外,通过达到低的 PASI 评分(例如 PASI 评分小于 3 分或小于 1 分)也可以说明对治疗的良好反应。 作者发现,在第一年中有很高比例的患者获得了 PASI 改善,继续使用 100 或 200 mg tildrakizumab 可很好地维持 PASI 改善,三年后分别有 80% 和 60% 的患者达到了 PASI 75 和 PASI 90。 观察 PASI 评分,三年后分别有 70% 和 50% 的患者 PASI 评分保持低于 3 和低于 1。如果维持治疗,即使最初对 tildrakizumab 反应较差(即没有太大改善)的患者也随着时间的推移而有所改善。先前使用依那西普(用于银屑病的另一种药物)治疗无效的患者,仅接受两剂 tildrakizumab 即可改善银屑病,分别有 80% 和 40% 的患者达到 PASI 75 和 PASI 90。 很少观察到不良反应,也没有报告新的或非预期副作用。最常见的副作用是鼻咽炎,通常称为感冒。重度感染、恶性肿瘤或心血管影响不常见,与安慰剂(一种非活性物质,如“糖丸”)相当,这表明使用 tildrakizumab 不会增加这些事件的风险。 综上所述,在长达三年的时间里,证明 tildrakizumab 是治疗银屑病的一种好方法,安全且副作用很少。 本摘要涉及研究: Tildrakizumab 对中至重度银屑病的长期疗效和安全性: 两项随机 III 期临床试验(reSURFACE 1 和 reSURFACE 2)至第 148 周的汇总分析
Immune globulin subcutaneous, human – klhw 20% solution (Xembify®, IGSC-C 20%) is effective in primary humoral immunodeficiency (PI): results from a prospective, open-label, multicenter, phase 3 study
Authors: John Sleasman, William Lumry, Iftikhar Hussain, H. James Wedner, James Harris, Elsa Mondou, Jiang Lin, Carrie Hames, Montse Querolt, Mark Stein
Journal: Journal of Allergy and Clinical Immunology (2020)
Impact of 68Ga-PSMA-11 PET on the management of biochemically recurrent prostate cancer in a prospective single-arm clinical trial.
Authors: Wolfgang Fendler, Justin Ferdinandus, Jeremie Calais, Matthias Eiber, Robert R. Flavell, Ashley Mishoe, Felix Y Feng, Hao Gia Nguyen, Robert Evan Reiter, Matthew Rettig, Jeannine Gartmann, Raven Smith, Eric Jay Small, Roger Slavik, Peter Carroll, Ken Herrmann, Johannes Czernin, Thomas Hope
Journal: Journal of Clinical Oncology (2020)

292 Background: Prostate-specific membrane antigen ligand positron emission tomography (PSMA PET) induced management changes in up to every second patient in smaller clinical trials. We aim to determine the impact of 68 Ga-PSMA-11 PET/CT on management of biochemically recurrent prostate cancer in a large prospective cohort. Methods: We report management changes following PSMA PET, a secondary endpoint of a prospective multicenter trial in men with prostate cancer biochemical recurrence (NCT02940262 and NCT03353740). Pre-PET, Post-PET and Post-Treatment Questionnaires were sent to referring physicians recording working clinical summaries, intended and implemented therapeutic and diagnostic management. Results: Intended management change occurred in 260/382 (68%) patients. Intended change was considered major in 176/382 (46%) patients. Management pathway aligned with PET findings, i.e. change towards local/focal therapy for locoregional disease (54/126 patients, 44%) and towards systemic therapy or combination approaches for metastatic disease (106/153 patients, 69%). Intended management was implemented in 160/206 (78%) patients. Perceived site of disease was unknown in 259/382 (68%) patients before and 111/382 (29%) patients after PSMA PET. A total of 150 intended diagnostic tests, mostly CT (n=43, 29%) and bone Scans/NaF-PET (n=52, 35%), were prevented by PSMA PET. A total of 73 tests, mostly biopsies (n=44, 60%) requested by the study protocol, were triggered. Conclusions: Disease localization by PSMA PET translated into management changes in more than half of patients with biochemical recurrence of prostate cancer. More than twice as many diagnostic tests were prevented than triggered following PET. Clinical trial information: NCT02940262 and NCT03353740.
Budesonide Oral Suspension Improves Histologic Features In Patients With Eosinophilic Esophagitis: Results From A Phase 3, Randomized, Double-blind, Placebo-Controlled Trial
Authors: Margaret Collins, Ikuo Hirano, David Katzka, Antonella Cianferoni, James Williams, Nirav Desai, Lan Lan, Evan Dellon
Journal: Journal of Allergy and Clinical Immunology (2020)
State-of-the-Art Strategies for Targeting <i>RET</i>-Dependent Cancers
Authors: Vivek Subbiah, Dong Yang, Vamsidhar Velcheti, Alexander Drilon, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2020)

Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non-small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis
Authors: Lukas Ronner, Nikolai Podoltsev, Jason Gotlib, Mark L. Heaney, Andrew T. Kuykendall, Casey O’Connell, Jamile Shammo, Angela G. Fleischman, Robyn M. Scherber, Ruben Mesa, Abdulraheem Yacoub, Cecelia Perkins, Shelby Meckstroth, Lindsey Behlman, Matthew Chiaramonte, Mahta Salehi, Kimia Ziadkhanpour, Hellen Nguyen, Olivia Siwoski, Annie Kwok Hung, Michelle Janania Martinez, Jenny Nguyen, Sagar Patel, Revathi Kollipara, Ami Dave, Megan Randall, Michael Grant, Mitchell Harrison, Paola Fernandez Soto, Douglas Tremblay, Ronald Hoffman, Erin Moshier, John Mascarenhas
Journal: Blood (2020)
Age of Asthma Onset, not Severity, Predicts Environmental Allergy Clusters
Authors: Merritt Fajt, Seyed Mehdi Nouraie, Rachel Wojcik, John Trudeau, Eugene Bleecker, Deborah Meyers, Nizar Jarjour, Loren Denlinger, Mario Castro, Leonard Bacharier, Elliot Israel, Bruce Levy, Wanda Phipatanakul, Anne Fitzpatrick, Serpil Erzurum, Benjamin Gaston, Wendy Moore, Annette Hastie, Sally Wenzel
Journal: Journal of Allergy and Clinical Immunology (2020)
PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible <i>FGFR3</i> alterations.
Authors: Siamak Daneshmand, Petros Grivas, Srikala S. Sridhar, Shilpa Gupta, Joaquim Bellmunt, Guru Sonpavde, Mark T. Fleming, Seth P. Lerner, Yohann Loriot, Hao Wang, Hiywot Takkele, Corina Andresen, Jessica Rearden, Craig Berman, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

TPS5095 Background: Radical surgery ± cisplatin‐based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986 .
Abstract 11110: Lead Less Pacemaker and Deep Brain Stimulator: A Unique Cohabitations
Authors: Najam U Saqib, Muhammad Siddique Pir, Abdul Haseeb, Wilson Young
Journal: Circulation (2019)

Introduction: In advanced Parkinson disease refractory to medical therapy, patients are mostly treated with deep brain stimulators (DBS). DBS helps patients by reducing thalamocortical activity, su...
Results of the ADRRAD Trial of pelvic IMRT plus radium-223 in men with mHSPC metastatic to bone.
Authors: Joe O'Sullivan, Philip Geoffrey Turner, Suneil Jain, Arthur Grey, Sandra Biggart, Alan R. Hounsell, Aidan Cole
Journal: Journal of Clinical Oncology (2020)

136 Background: Radiotherapy to the Prostate in mHSPC improves overall survival (OS) and Progression free survival (PFS) for patients with low-volume-disease[1]. Radium-223 in metastatic castration resistant prostate cancer (mCRPC) improves OS [2]. We conducted a prospective phase 1/2 clinical trial in mHSPC, testing the combination of with LHRHa, concurrent pelvic radiotherapy and radium-223. Methods: Thirty patients were recruited with mHSPC; they had a minimum of 3 bone metastases (majority had &gt; 20 bone mets), nil visceral metastases, PS0-1. Patients were encouraged to receive up front docetaxel. They were treated with ongoing LHRHa, pelvic radiotherapy aiming for 74Gy in 37 fractions to prostate PTV with 60Gy concomitantly delivered to pelvic nodal PTV. Concurrently, patients received radium-223, 55kBq/kg for 6 cycles q28 days; fraction 1 radiotherapy was synchronous with cycle 1 day 1 radium-223. Results: Median age was 63 years and 28 (93%) received at least 4 cycles of docetaxel. One patient received prostate only radiotherapy due to bowel constraints. Three patients had cycle 6 radium-223 omitted. At a median follow-up of 28 months, there have been 415 Adverse events, (3% Grade &gt;3), and 6 serious adverse events (SAEs) ( 2 episodes of UTI, 1 each of cystitis non-infective, cardiac chest pain, pyrexia and AKI). Commonest AEs by number were: leucopenia, neutropenia, and diarrhoea. Ten SSE’s have occurred including 8 courses of palliative radiotherapy for bone pain, 1 course of radiotherapy for impending MSCC and 1 pathological fracture. At median follow up 28.0 months, median biochemical PFS is 17.9 months, median OS not yet reached. Conclusions: This trial shows clear tolerability and promising early efficacy data requiring further exploration in a randomised phase 3 trial. Clinical trial information: 2014-000273-39.
Polymeric Films for the Encapsulation, Storage, and Tunable Release of Therapeutic Microbes
Authors: Kunyu Qiu, Isabella Young, Blaide M. Woodburn, Yirui Huang, Aaron C. Anselmo
Journal: Advanced Healthcare Materials (2020)

Microbe-based therapeutics (MBTs) are an emerging therapeutic modality for treating gastrointestinal infections and inflammatory bowel diseases. Current formulations for oral delivery of MBTs use capsules to achieve safe gastric transit, but oral formulations that control the spatiotemporal concentration of MBTs are yet to be developed, despite well-established connections between all therapeutics and their location, concentration, and distribution at sites of action. The development of a multi-functional polymer-based encapsulation system to formulate MBTs for enhanced storage and delivery through formulation of a model MBT, Lactobacillus casei ATCC393, is reported here. This approach enables the additive inclusion of excipients and polymers to grant specific functions, toward the development of a modular MBT platform. Through addition of established excipients, the formulation provides long-term storage of the encapsulated MBT. By adding higher molecular weight polymers, the release kinetics of the encapsulated MBTs can be modified. The inclusion of a mucoadhesive polymer significantly increases the adhesion force between the formulation and the intestinal tissue. Together, mucoadhesive and sustained release properties can be used to modulate the spatiotemporal concentration of MBTs. The formulation is compatible with standard oral capsules, thus maintaining existing clinical advantages of oral capsules while providing new functions from film encapsulation.