tbuckley/cabot-search huggingface dataset:
Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients
Authors: Lin Xiao, Dongzhi Cen, Haining Gan, Yan Sun, Nanqi Huang, Hanzhen Xiong, Qiongmei Jin, Liqun Su, Xuejuan Liu, Kejian Wang, Guangrong Yan, Tianfa Dong, Shangbiao Wu, Pengzhi Zhou, Jinshan Zhang, Weixiang Liang, Junlan Ren, Yaoshu Teng, Can Chen, Xue Hu Xu
Journal: Molecular Therapy (2019)

By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Three patients with metastatic colorectal cancer were then treated with local infusion of the CAR-NK cells. Reduction of ascites generation and a marked decrease in number of tumor cells in ascites samples were observed in the first two patients treated with intraperitoneal infusion of low doses of the CAR-NK cells. The third patient with metastatic tumor sites in the liver was treated with ultrasound-guided percutaneous injection, followed by intraperitoneal infusion of the CAR-NK cells. Rapid tumor regression in the liver region was observed with Doppler ultrasound imaging and complete metabolic response in the treated liver lesions was confirmed by positron emission tomography (PET)- computed tomographic (CT) scanning. Our results highlight a promising therapeutic potential of using RNA CAR-modified NK cells to treat metastatic colorectal cancer. By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Three patients with metastatic colorectal cancer were then treated with local infusion of the CAR-NK cells. Reduction of ascites generation and a marked decrease in number of tumor cells in ascites samples were observed in the first two patients treated with intraperitoneal infusion of low doses of the CAR-NK cells. The third patient with metastatic tumor sites in the liver was treated with ultrasound-guided percutaneous injection, followed by intraperitoneal infusion of the CAR-NK cells. Rapid tumor regression in the liver region was observed with Doppler ultrasound imaging and complete metabolic response in the treated liver lesions was confirmed by positron emission tomography (PET)- computed tomographic (CT) scanning. Our results highlight a promising therapeutic potential of using RNA CAR-modified NK cells to treat metastatic colorectal cancer.
Safety, Tolerability, and Management of Toxic Effects of Phosphatidylinositol 3-Kinase Inhibitor Treatment in Patients With Cancer
Authors: Angela Esposito, Giulia Viale, Giuseppe Curigliano
Journal: JAMA Oncology (2019)

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, which regulates multiple cellular processes, including metabolism, proliferation, motility, growth, and survival, is one of the most frequently dysregulated pathways in human cancers. The PI3K/AKT/mTOR cascade can be aberrantly activated by multiple factors, including diverse oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, MTOR, and other critical genes, which can be used as targets for anticancer therapy. Limited single-agent activity, high levels of toxic effects, and a lack of predictive biomarkers for treatment selection have all been major barriers to the clinical development of these compounds. Many adverse effects are uncommon and have poorly understood mechanisms. An understanding of these toxic effects, as well as a better definition of management guidelines, will be important because more PI3K inhibitors are under development and may soon be incorporated into routine practice.A search of PubMed, draft prescribing information of currently approved PI3K inhibitors, European Medical Association and US Food and Drug Administration product information, and expert panel opinion on the management of the prominent toxic effects of this class of agents was conducted on August 29, 2018. This article provides an overview of the main toxic effects of PI3K inhibitors reported in clinical trials and a summary of recommendations for identification and management of treatment-emergent toxic effects, including hypoglycemia, cutaneous reactions, pneumonitis, neuropsychiatric effects, hepatotoxic effects, diarrhea, and colitis. Overall, the clinical development of most PI3K inhibitors has been discontinued owing to insufficient activity, problematic toxic effects, and the absence of biomarkers correlated with clinical activity. Knowledge of the isoforms and their distribution in tissue can help clinicians anticipate toxic effects. Notably, novel, more specific inhibitors for individual isoforms of PI3K showed therapeutic activity with improved toxic effect profiles compared with non-isoform-selective agents.An improved understanding of the complexities of the main toxic-effect mechanisms and their management might open viable paths to advancing PI3K inhibitors from clinical studies to new standard-of-care treatments.
HSR19-082: Epidemiological Findings and Outcomes in Non-Small Cell Lung Cancer Patients with Exon 20 Insertion Mutations: A Meta-Analysis
Authors: Victoria Crossland, Aaron Galaznik, Huamao M. Lin, Dimitrios Tomaras, Shan Ashton Garib, Shuanglian Li, Hui Huang, Anna Forsythe
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Epidermal growth factor receptor (EGFR) mutations are frequently found in non-small cell lung cancer (NSCLC) patients. Various EGFR mutations respond differently to EGFR tyrosine kinase inhibitors (TKIs), and several TKIs have been approved for use on common mutations but none have been approved for EGFR exon 20 insertions, indicating a need for targeted therapy for this subpopulation. A systematic literature review (SLR) and meta-analysis were conducted to synthesize epidemiological and outcome data for the uncommon EGFR exon 20 insertion mutation. Methods: An SLR was performed on August 7, 2018 following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using the Population, Intervention Comparators, Outcomes and Study Design (PICOS) criteria. Studies were identified based on a systematic search using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. Relevant congress abstracts published between 2015–2018 were also identified. Two independent reviewers screened all citations and full-text articles using PICOS-based criteria; any discrepancies were resolved by a third independent reviewer. Data were extracted into a predefined template for meta-analysis and summarized using the PRISMA flow diagram. Results: A total of 61 studies reporting the number of EGFR mutation−positive patients and/or NSCLC patients were identified. A meta-analysis found that 3.7% of EGFR mutation−positive patients and 0.8% of NSCLC patients harbored the EGFR exon 20 insertion, with geographic variations in epidemiology. There were 12, 10, and 12 studies, respectively, that reported overall survival, progression-free survival, and overall response rates in 2 cohorts, patients with EGFR exon 20 insertions and patients without EGFR exon 20 mutations. A Most patient populations in these studies included a mixture of treatment at various lines. A meta-analysis of outcomes across these studies showed that patients with EGFR exon 20 insertions experienced worse outcomes compared with those without the mutation (Table 1). Meta-analyses were weighted based on each study’s relevant population. No economic or quality of life studies were identified. Conclusions: Exon 20 insertion mutations represent an important subgroup of EGFR mutations in patients with NSCLC, and current therapies have limited efficacy. These relatively poor outcomes indicate a need for novel treatment strategies.
Enterovirus D68–Associated Acute Respiratory Illness — New Vaccine Surveillance Network, United States, July–October, 2017 and 2018
Authors: Stephanie A. Kujawski, Claire M. Midgley, Brian Rha, Joana Y. Lively, W. Allan Nix, Aaron T. Curns, Daniel C. Payne, Janet A. Englund, Julie A. Boom, John V. Williams, Geoffrey A. Weinberg, Mary A. Staat, Rangaraj Selvarangan, Natasha B. Halasa, Eileen J. Klein, Leila C. Sahni, Marian G. Michaels, Lynne Shelley, Monica McNeal, Christopher J. Harrison, Laura S. Stewart, Adriana S. Lopez, Janell A. Routh, Manisha Patel, M. Steven Oberste, John T. Watson, Susan I. Gerber
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Based on active, prospective surveillance of acute respiratory illness through the New Vaccine Surveillance Network, EV-D68 was detected in two (0.8%) patients in 2017 and 358 (13.9%) in 2018. Detections in 2018 peaked in September.
QIM19-123: Addressing Opportunities for Improving Care Cadence by Driving Interdepartmental Collaboration
Authors: Kimberly Byrwa-Neff, Wendi Waugh, Rhondalyn Bomkamp
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Southern Ohio Medical Center (SOMC) is a community hospital in Portsmouth, Ohio. Review of data pertaining to breast care delivery demonstrated opportunities for improvement. Analysis of the cadence of care processes across departments demonstrated delays in care and outmigration potential. One quality study demonstrated 10% of patients did NOT select SOMC for surgical intervention post biopsy. Method: SOMC reached out to industry for solutions and suggestions to better coordinate care and address barriers within the breast program. A team of clinical, process excellence specialists from Leica Biosystems conducted telephonic interviews and on-site assessments relative to internal processes and methods for care delivery. The SOMC Breast Health Leadership Team (BHLT) in concert with the Leica Biosystems Process Excellence Team identified the following barriers and opportunities: Barriers were (1) Lack of timely data to drive breast care coordination and prioritization; (2) Inefficiencies in patient scheduling; (3) Lack of common goal deployment across departments; and (4) Limitations of resources. Opportunities were to (1) Improve coordination, (2) improve quality and safety of care provided, (3) increase market share, and (4) increase patient loyalty. Results: The SOMC BHLT purposefully initiated interdepartmental communications and emphasized the importance of interdepartmental task interdependence. Data reviewed and collected during the on-site observational analysis provided baselines for opportunities for improvement in care delivery and pointed out where delays and risks for patient safety existed. Patients requiring additional imaging evaluation and/or comparison to prior mammograms (BI-RADS 0) experienced improvement when changes were implemented relative to scheduling; days from screening to diagnostic mammogram in 2017 was 21.8 days versus 6.5 days in 2018. Patients with BI-RADS 4 or 5 experienced improved timelines from diagnostic mammogram to biopsy, 4.5 days in 2017 to 2.5 days in 2018. Finally, 34% of patients received their biopsy within 24 hours in the fourth quarter in 2017 while 76% of the patients received a biopsy within 24 hours in the most recent quarter (July–September 2018). Conclusion: Working together, industry can provide expertise and guidance not always available in community hospital settings to help: identify barriers and opportunities, drive interdepartmental care optimization, reduce opportunity for outmigration, mitigate risks, and strive to improve quality.
The Long-Term Adverse Event Profile of Oral Eliglustat for the Treatment of Gaucher Disease Type 1: Pooled Analysis of Data from 393 Patients in 4 Completed Trials
Authors: M. Judith Peterschmitt, Selena Freisens, Audrey W Hou, Lisa Underhill, Meredith C. Foster, Sebastiaan J.M. Gaemers
Journal: Blood (2018)
Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis
Authors: Isabell S von Loga, Aadil El-Turabi, Luke Jostins, Jadwiga Miotla-Zarebska, Jennifer Mackay-Alderson, Andris Zeltins, Ida Parisi, Martin F Bachmann, Tonia L Vincent
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Nerve growth factor (NGF) has emerged as a key driver of pain in osteoarthritis (OA) and antibodies to NGF are potent analgesics in human disease. Here, we validate a novel vaccine strategy to generate anti-NGF antibodies for reversal of pain behaviour in a surgical model of OA. Methods Virus-like particles were derived from the cucumber mosaic virus (CuMV) and coupled to expressed recombinant NGF to create the vaccine. 10-week-old male mice underwent partial meniscectomy to induce OA or sham-surgery. Spontaneous pain behaviour was measured by Linton incapacitance and OA severity was quantified using OARSI histological scoring. Mice (experimental and a sentinel cohort) were inoculated with CuMVtt NGF (Vax) or CuMVtt ctrl (Mock) either before surgery or once pain was established. Efficacy of anti-NGF from the plasma of sentinel vaccinated mice was measured in vitro using a neurite outgrowth assay in PC12 cells. Results Anti-NGF titres were readily detectable in the vaccinated but not mock vaccinated mice. Regular boosting with fresh vaccine was required to maintain anti-NGF titres as measured in the sentinel cohort. Both prophylactic and therapeutic vaccination demonstrated a reversal of pain behaviour by incapacitance testing, and a meta-analysis of the two studies showing analgesia at peak anti-NGF titres was highly statistically significant. Serum anti-NGF was able to inhibit neurite outgrowth equivalent to around 150 ug/mL of recombinant monoclonal antibody. Conclusions This study demonstrates therapeutic efficacy of a novel NGF vaccine strategy that reversibly alleviates spontaneous pain behaviour in surgically induced murine OA.
Spinal surgeon loses appeal in case of woman left disabled after heparin injection
Authors: Clare Dyer
Journal: BMJ (2019)

A consultant neurosurgeon was negligent in giving a patient antithrombotic treatment only three hours after spinal surgery, the Court of Appeal has ruled.1

Three senior judges unanimously dismissed Christos Tolias’s appeal against a High Court decision that he had been negligent in 2013 in administering low molecular weight heparin too early to Yvonne Lesforis, a college lecturer.2

The decision by Mr Justice Martin Spencer last June caused consternation among neurosurgeons, and Tolias sought permission to appeal on 11 grounds relating to the judge’s approach, his findings, and his assessment of the expert evidence. But 10 of the grounds were deemed not to have a real prospect of success, and the surgeon was allowed to appeal …
CLO19-060: Blood Exosomal Long RNA Profiling Identifies Diagnostic and Prognostic Markers in Pancreatic Ductal Adenocarcinoma
Authors: Shulin Yu, Peng Wang, Zhen Chen
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Long RNAs have been recently identified in human blood exosomes, posing clinical implications. Whether exosomal long RNAs (exoLRs) could constitute key future biomarkers for noninvasive diagnosis, therapeutic evaluation, and prognosis in cancer remains unknown. The study aimed to explore the exoLR landscape of human blood exosomes and evaluate the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of pancreatic ductal adenocarcinoma (PDAC) based on exoLR profiling. Methods: A case-control study of 267 cases including 137 patients with PDAC and 39 with chronic pancreatitis (CP) plus 91 blood donors as healthy participants was conducted. The exoLR profile of pretreated blood samples was analyzed by exoLR-sequencing (exoLR-seq). Results: An average of 15,000 exoLRs were reliably detected for each sample through exoLR-seq, and 1,053 exoLRs were differentially expressed in PDAC. Based on these data, we constructed a diagnostic signature (d-signature) that showed high accuracy with an area under the curve (AUC) of 0.977 (95% CI: 0.958–0.996), a sensitivity of 92.42% (95% CI: 83.2%–97.49%), and a specificity of 95% (95% CI: 87.69%–98.62%) in a training cohort (n=146), which was further confirmed in a validation cohort (n=93). Notably, the combination of d-signature and CA19-9 yielded an AUC of 0.963 (95% CI: 0.909–1.017), with a sensitivity of 98.13% (95% CI: 93.41%–99.77%) and specificity of 94.59% (95% CI: 81.81%–99.34%). Additionally, we constructed a prognostic prediction model (exoLR p-signature) that effectively predicted prognosis and survival in patients with PDAC ( P =9.838e-08). Conclusions: This study clearly demonstrated the value of exoLR profiling in cancer marker discovery and the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of PDAC.
Abstract 14059: High Serum Erythropoietin Levels and the Development of Heart Failure in the General Population
Authors: Niels Grote Beverborg, Haye H van der Wal, IJsbrand T Klip, Adriaan A Voors, Rudolph A de Boer, Wiek H van Gilst, Dirk J van Veldhuisen, Ron T Gansevoort, Hans L Hillege, Pim van der Harst, Stephan J Bakker, Peter van der Meer
Journal: Circulation (2015)

Aims: In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Clinical trials with erythropoiesis-stimulating agents in HF and chronic kidney disease showed more adverse events. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown. Methods and results: Serum EPO levels were measured at baseline in 6,686 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Mean age (±SD) was 53±12 years, 49.8% were male, and median (IQR) EPO level was 7.7 (5.9-10.2) IU/L. During a median follow-up of 8.3 (7.7-8.8) years, 209 (3.1%) subjects were newly diagnosed with HF, 97 (1.5%) died of a cardiovascular cause and 386 (6.0%) subjects had a non-fatal cardiovascular event (277 cardiac events and 93 strokes). Each doubling of EPO level was multivariably associated with new onset HF (HR: 1.41, 95% CI: 1.14-1.76, P=0.002). EPO levels showed interaction with urinary albumin excretion (P=0.002) and were only associated with HF in subjects with microalbuminuria (HR: 1.53, 95% CI: 1.21-1.92, P&lt;0.001, Figure 1). Also, EPO levels were only independently associated with HF of ischemic origin (HR: 1.58, 95% CI: 1.14-2.20, P=0.006), not with HF of other etiologies. There was an independent association of EPO levels with stroke in women (HR: 1.82, 95% CI: 1.24-2.65, P=0.002), but not in men. No association was observed for EPO levels with other cardiovascular events or cardiovascular mortality. Conclusion: High serum EPO levels are independently associated with an increased risk of new onset HF in subjects with microalbuminuria. The interaction between EPO and microalbuminuria might be indicative for a role of the vascular endothelium in the mechanism linking EPO to HF. However, more research is needed to understand this association.
QIM19-125: Nonclinical Needs of Cancer Patients in Spain Under Different Perspectives: A Comparative Study
Authors: Juan Jesús Cruz, Isabel Ruiz Martin, Ana Fernandez, Rosana Martín, Enrique Aranda, Alfredo Carrato, Eduardo Díaz-Rubio, Vicente Guillem, Rafael López, Margarita Feyoo, Nerea Gonzalez-Garcia, Ana Nieto-Librero, Ramón Ferrer, Alicia Gonzalo, Carlos Camps
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Patients with cancer and their caregivers express unmet needs beyond the clinical approach to cancer. The ECO Foundation (Quality and Excellence in Oncology) and the Spanish Association Against Cancer (AECC) have promoted a qualitative research study with the objective to identify and compare the perceptions of newly diagnosed and 2–3 years after diagnosis cancer patients, caregivers, oncologists, nurses, and social workers in relation to a set of nonclinical needs expressed by cancer patients and caregivers, and to obtain concrete and feasible proposals for improvement aimed at satisfying these needs. Methods: A multidisciplinary group of experts developed a questionnaire about information processes for cancer patients and caregivers, shared decision-making, satisfaction with healthcare circuits, the architecture of consultations, psychological support, support of associations, and the received support of hospital social workers. 14 Medical Oncology Services of Spanish hospitals have participated in this study collecting opinions from the study groups. 310 forms were collected, and data were statistically analyzed using Fisher's exact test. Results: Information processes: The opportunity to have a second opinion is positively valuated for 72.6% of patients and 70.2% of caregivers. However, although 62.5% of oncologists referred to offer this option to their patients, only 10.9% of patients reported having received it. Shared decision-making: For 58% of oncologists, patients are sufficiently trained to share decision-making, but only 24.6% of newly diagnosed patients consider being prepared. In addition, although 95.8% of oncologists report offering the participation of their patients in decision-making, only 45.8% of newly diagnosed patients and 64.4% of 2–3 years after diagnosis patients consider having received this opportunity. Psychological support: Psychological assistance was considered positive for 94.2% of the patients, 97.4% of the caregivers, 85.4% of the oncologists, and 97.1% of the nurses. However, only 21.3% of oncologists and 31.4% of nurses recognize offering such care to patients. Conclusions: Knowing the nonclinical needs, not only of patients and caregivers, but also from the healthcare professionals, is essential when designing health strategies that should align the perceptions of patients and healthcare professionals.