tbuckley/cabot-search huggingface dataset:
Inclisiran: UK to roll out new cholesterol lowering drug from next year
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The UK government is to launch a major clinical trial of the novel cholesterol lowering drug inclisiran later this year and aims to make it available to NHS patients from 2021.

Inclisiran, an investigational treatment taken by injection twice a year, is a cholesterol lowering therapy in the small interfering RNA (siRNA) class. It has not yet been approved by the US Food and Drug Administration or the European Medicines Agency but is expected to be filed for approval later this year as a preventive add-on treatment to statins for patients who already have a cardiovascular disease diagnosis.

Results of a phase III study of inclisiran involving patients who had elevated LDL cholesterol concentrations despite taking the maximum …
P-0117 Second-Line Chemotherapy with S-1 after Cisplatin and Gemcitabine Failure in Patients with Advanced Biliary Tract Cancer
Authors: Shinya Ueda, Hisato Kawakami, Wataru Okamoto, Shinichi Nishina, Toshihiro Kudo, Chihiro Makimura, Hidemi Kiyota, Kaoru Tanaka, Hiroyasu Kaneda, Yasuhito Fujisaka, Masaki Miyazaki, Junji Turutani, Isamu Okamoto, Takayasu Kurata, Kazuhiko Nakagawa
Journal: Annals of Oncology (2012)
Docetaxel Plus Cisplatin as First-Line Chemotherapy in Patients with Recurrent or Metastatic Head and Neck Cancer
Authors: Y. Ohhara, N. Nishimura, E. Nara, K. Nakano, K. Ueda, S. Sakajiri, Y. Mishima, M. Yokoyama, Y. Terui, S. Takahashi, K. Hatake
Journal: Annals of Oncology (2012)
Natural History of Serous Ovarian Carcinoma: High Grade Versus Low Grade and Carcinomas with BRCA Mutations
Authors: S. Ayers, T.T. Tun, N. Mescallado, A. Wright, D.G.R. Evans, A. Clamp, G.C. Jayson, J. Hasan
Journal: Annals of Oncology (2012)
Comparison of Second Line Treatment Outcomes Between Sensitive and Refractory Small Cell Lung Cancer Patients: a Retrospective Analysis
Authors: T. Korkmaz, S. Seber, E. Sari, M. Canhoroz, B. Oven Ustaalioglu, U. Kefeli, O. Balvan, M. Gumus, N. Yasar, S.N. Turhal
Journal: Annals of Oncology (2012)
Mechanism of a long-term controlled drug release system based on simple blended electrospun fibers
Authors: Jiaen Wu, Zixin Zhang, Jin’ge Gu, Weixian Zhou, Xiaoyu Liang, Guoqiang Zhou, Charles C. Han, Shanshan Xu, Ying Liu
Journal: Journal of Controlled Release (2020)

Drug delivery systems based on electrospun fibers have been under development for many years. However, studies of controllable long-term drug release from electrospun membrane systems and the underlying release mechanisms have seldom been reported. In this study, electrospun membrane drug delivery systems consisting of the antibiotic ciprofloxacin hydrochloride and FDA-approved polymers are fabricated. Different second-component polymers are introduced to change the properties of a poly(d,l-lactide-co-glycolide) (PLGA) matrix, thereby altering the drug release behavior. On the basis of observations of morphology, cumulative release profiles, and determinations of release duration, the drug release kinetics and critical characteristics influencing drug release behavior are discussed. It is found that the drug release profiles can be divided into three stages according to the rate of drug release. Stage I is controlled by fiber swelling and diffusion according to Fick's second law. Stage II is controlled by diffusion through a fused membrane structure, which results in very slow drug release. Stage III is controlled by polymer degradation and involves release of the remaining drug. The results of this study of release mechanisms should provide a basis for adjustments of drug release dosage and duration, thereby contributing to the development of drug delivery systems satisfying clinical requirements.
Myocardial Inflammation and Edema in People Living With Human Immunodeficiency Virus
Authors: Katia Menacho, Andreas Seraphim, Sara Ramirez, Liana Falcon, Anish Bhuva, Jorge Alave, Claudia Banda, Fernando Mejia, Daniela Salazar, Astrid Putri, Flavio Mosto, Pedro Gonzales, Veronica Culotta, Julio Menacho, Anna S. Herrey, Ntobeko A.B. Ntusi, J. Malcolm Walker, James C. Moon
Journal: JACC. Cardiovascular imaging (2020)
Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives
Authors: E. Martinelli, D. Ciardiello, G. Martini, T. Troiani, C. Cardone, P.P. Vitiello, N. Normanno, A.M. Rachiglio, E. Maiello, T. Latiano, F. De Vita, F. Ciardiello
Journal: Annals of Oncology (2020)

Highlights•The epidermal growth factor (EGFR) is a therapeutic option for patients with all RAS WT metastatic colorectal cancer (mCRC).•A better knowledge of the mechanism of primary or acquired resistance to EGFR-therapies can improve patient's selection.•Despite disease progression a subset of mCRC are still sensitive to EGFR inhibition.•Rechallenge strategies with anti-EGFR might represent a promising therapeutic option.AbstractEpidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis
Authors: Steven Yeh, Rahul N. Khurana, Milan Shah, Christopher R. Henry, Robert C. Wang, Jennifer M. Kissner, Thomas A. Ciulla, Glenn Noronha
Journal: Ophthalmology (2020)

Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME).Phase 3 masked, randomized trial.One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye.Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week 12.The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week 24.In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 μm versus 18 μm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively).Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.
Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis
Authors: Johannes Laengle, Julijan Kabiljo, Leah Hunter, Jakob Homola, Sophie Prodinger, Gerda Egger, Michael Bergmann
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized. Methods We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach. Results VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells. Conclusions HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.
Mutational Landscape and Patterns of Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia
Authors: Esmé Waanders, Zhaohui Gu, Stephanie M. Dobson, Željko Antić, Jeremy Chase Crawford, Xiaotu Ma, Michael N. Edmonson, Debbie Payne-Turner, Maartje van de Vorst, Marjolijn C.J. Jongmans, Irina McGuire, Xin Zhou, Jian Wang, Lei Shi, Stanley Pounds, Deqing Pei, Cheng Cheng, Guangchun Song, Yiping Fan, Ying Shao, Michael Rusch, Kelly McCastlain, Jiangyan Yu, Ruben van Boxtel, Francis Blokzijl, Ilaria Iacobucci, Kathryn G. Roberts, Ji Wen, Gang Wu, Jing Ma, John Easton, Geoffrey Neale, Scott R. Olsen, Kim E. Nichols, Ching-Hon Pui, Jinghui Zhang, William E. Evans, Mary V. Relling, Jun J. Yang, Paul G. Thomas, John E. Dick, Roland P. Kuiper, Charles G. Mullighan
Journal: Blood Cancer Discovery (2020)

Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of childhood death. Prior studies have shown clonal mutations at relapse often arise from relapse-fated subclones that exist at diagnosis. However, the genomic landscape, evolutionary trajectories and mutational mechanisms driving relapse are incompletely understood. In an analysis of 92 cases of relapsed childhood ALL, incorporating multimodal DNA and RNA sequencing, deep digital mutational tracking and xenografting to formally define clonal structure, we identify 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment.
Association of Powder Use in the Genital Area With Risk of Ovarian Cancer
Authors: Katie M. O’Brien, Shelley S. Tworoger, Holly R. Harris, Garnet L. Anderson, Clarice R. Weinberg, Britton Trabert, Andrew M. Kaunitz, Aimee A. D’Aloisio, Dale P. Sandler, Nicolas Wentzensen
Journal: JAMA (2020)

<h3>Importance</h3> The relationship between use of powder in the genital area and ovarian cancer is not established. Positive associations reported in case-control studies have not been confirmed in cohort studies. <h3>Objective</h3> To estimate the association between use of powder in the genital area and ovarian cancer using prospective observational data. <h3>Design, Setting, and Participants</h3> Data were pooled from 4 large, US-based cohorts: Nurses' Health Study (enrollment 1976; follow-up 1982-2016; n = 81 869), Nurses' Health Study II (enrollment 1989; follow-up 2013-2017; n = 61 261), Sister Study (enrollment 2003-2009; follow-up 2003-2017; n = 40 647), and Women's Health Initiative Observational Study (enrollment 1993-1998; follow-up 1993-2017; n = 73 267). <h3>Exposures</h3> Ever, long-term (≥20 years), and frequent (≥1/week) use of powder in the genital area. <h3>Main Outcomes and Measures</h3> The primary analysis examined the association between ever use of powder in the genital area and self-reported incident ovarian cancer. Covariate-adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models. <h3>Results</h3> The pooled sample included 252 745 women (median age at baseline, 57 years) with 38% self-reporting use of powder in the genital area. Ten percent reported long-term use, and 22% reported frequent use. During a median of 11.2 years of follow-up (3.8 million person-years at risk), 2168 women developed ovarian cancer (58 cases/100 000 person-years). Ovarian cancer incidence was 61 cases/100 000 person-years among ever users and 55 cases/100 000 person-years among never users (estimated risk difference at age 70 years, 0.09% [95% CI, −0.02% to 0.19%]; estimated HR, 1.08 [95% CI, 0.99 to 1.17]). The estimated HR for frequent vs never use was 1.09 (95% CI, 0.97 to 1.23) and for long-term vs never use, the HR was 1.01 (95% CI, 0.82 to 1.25). Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. While the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among women with a patent reproductive tract was 1.13 (95% CI, 1.01 to 1.26), the<i>P</i>value for interaction comparing women with vs without patent reproductive tracts was .15. <h3>Conclusions and Relevance</h3> In this analysis of pooled data from women in 4 US cohorts, there was not a statistically significant association between use of powder in the genital area and incident ovarian cancer. However, the study may have been underpowered to identify a small increase in risk.
Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction
Authors: Gopalkrishna Sreejit, Ahmed Abdel-Latif, Baskaran Athmanathan, Rahul Annabathula, Ashish Dhyani, Sunil K. Noothi, Gregory A. Quaife-Ryan, Annas Al-Sharea, Gerard Pernes, Dragana Dragoljevic, Hind Lal, Kate Schroder, Beatriz Y. Hanaoka, Chander Raman, Maria B. Grant, James E. Hudson, Susan S. Smyth, Enzo R. Porrello, Andrew J. Murphy, Prabhakara R. Nagareddy
Journal: Circulation (2020)

Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
Independent and Combined Effects of Heatwaves and PM2.5 on Preterm Birth in Guangzhou, China: A Survival Analysis
Authors: Qiong Wang, Bing Li, Tarik Benmarhnia, Shakoor Hajat, Meng Ren, Tao Liu, Luke D. Knibbs, Huanhuan Zhang, Junzhe Bao, Yawei Zhang, Qingguo Zhao, Cunrui Huang
Journal: Environmental Health Perspectives (2020)

Background: Both extreme heat and air pollution exposure during pregnancy have been associated with preterm birth; however, their combined effects are unclear. Objectives: Our goal was to estimate the independent and joint effects of heatwaves and fine particulate matter [PM &lt;2.5μm in aerodynamic diameter (PM2.5)], exposure during the final gestational week on preterm birth. Methods: Using birth registry data from Guangzhou, China, we included 215,059 singleton live births in the warm season (1 May–31 October) between January 2015 and July 2017. Daily meteorological variables from 5 monitoring stations and PM2.5 concentrations from 11 sites were used to estimate district-specific exposures. A series of cut off temperature thresholds and durations (2, 3, and 4 consecutive d) were used to define 15 different heatwaves. Cox proportional hazard models were used to estimate the effects of heatwaves and PM2.5 exposures during the final week on preterm birth, and departures from additive joint effects were assessed using the relative excess risk due to interaction (RERI). Results: Numbers of preterm births increased in association with heatwave exposures during the final gestational week. Depending on the heatwave definition used, hazard ratios (HRs) ranged from 1.10 (95% CI: 1.01, 1.20) to 1.92 (1.39, 2.64). Associations were stronger for more intense heatwaves. Combined effects of PM2.5 exposures and heatwaves appeared to be synergistic (RERIs&gt;0) for less extreme heatwaves (i.e., shorter or with relatively low temperature thresholds) but were less than additive (RERIs&lt;0) for more intense heatwaves. Conclusions: Our research strengthens the evidence that exposure to heatwaves during the final gestational week can independently trigger preterm birth. Moderate heatwaves may also act synergistically with PM2.5 exposure to increase risk of preterm birth, which adds new evidence to the current understanding of combined effects of air pollution and meteorological variables on adverse birth outcomes. https://doi.org/10.1289/EHP5117
Next and Venice: Design of two Multicentre, Phase IV, Prospective, Longitudinal Studies Evaluating The Safety Profile of a Biosimilar Filgrastim in Patients Treated with Cytotoxic Chemotherapy
Authors: S. Fruehauf, C. Berthou, S. Lepretre, L. Cals, F. Maloisel, D. Kamioner
Journal: Annals of Oncology (2012)
Reporting of the Medical Licensing Examination
Authors: Thomas R. Schneider
Journal: JAMA (2020)

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A randomized phase II trial comparing continuation maintenance therapy with pemetrexed and switch maintenance therapy with docetaxel after first-line therapy with carboplatin and pemetrexed in patients with advanced nonsquamous non-small cell lung cancer.
Authors: Masato Karayama, Naoki Inui, Shigeki Kuroishi, Koshi Yokomura, MIkio Toyoshima, Toshihiro Shirai, Msafumi Masuda, Takashi Yamada, Kazumasa Yasuda, Takafumi Suda, Kingo Chida
Journal: Journal of Clinical Oncology (2013)

8038 Background: Emerging evidence suggests that maintenance chemotherapy could prolong survival in patients with advanced non-small-cell lung cancer (NSCLC), whereas the optimal treatment strategy remains controversial. Methods: We conducted a randomized phase II study to compare the efficacy and safety of continuation maintenance with pemetrexed (500 mg/m 2 ) and switch maintenance with docetaxel (60 mg/m 2 ) in patients with non-squamous NSCLC who achieved disease control after first-line chemotherapy with four cycles of carboplatin (AUC 6) and pemetrexed (500 mg/m 2 ). Results: Eighty-five patients participated in the study, and 26 and 25 patients were randomized to the pemetrexed and the docetaxel maintenance therapies, respectively. The docetaxel group showed a trend toward longer progression-free survival (median 8.2 months, 95% CI; 3.9-12.2 months) compared with the pemetrexed group (median 4.1 months, 95% CI; 3.0-6.1 months), but not significantly (log-rank p=0.084). Grade 3/4 hematologic toxicity was significantly more frequent in the docetaxel group (80%) than the pemetrexed group (20%, p&lt;0.0001). Conclusions: Continuation maintenance with pemetrexed after induction therapy with carboplatin and pemetrexed may be an efficacious treatment with less toxicity. In contrast, switch maintenance with docetaxel frequently causes severe hematologic toxicity but may be more efficacious. Further studies are warranted to evaluate the risks and benefits of maintenance therapies. Clinical trial information: 000004075.