tbuckley/cabot-search huggingface dataset:
TIME: A phase IIb/III randomized, double-blind, placebo-controlled study comparing first-line therapy with or without TG4010 immunotherapy product in patients with stage IV non-small cell lung cancer (NSCLC).
Authors: Elisabeth A. Quoix, John J. Nemunaitis, Tomasz Burzykowski, Berangere Bastien, Gisele Lacoste
Journal: Journal of Clinical Oncology (2012)

TPS7610 Background: TG4010 is an immunotherapy product based on a poxvirus (MVA) coding for the MUC1 tumor-associated antigen and interleukin-2. A previous study, TG4010.09, which evaluated the combination of first-line chemotherapy with and without TG4010 in advanced NSCLC, achieved its primary endpoint based on 6-month progression-free survival (PFS) and showed that the pre-treatment level of activated Natural Killer (aNK) cells may be a potential predictive biomarker for TG4010 efficacy (E. Quoix et al., Lancet Oncol. 2011;12:1125-33). Methods: TIME is a double-blind phase IIb/III study comparing the combination of first-line therapy with TG4010 or placebo in stage IV NSCLC patients, Performance Status (PS) 0 or 1 with a MUC1 expressing tumor by immunohistochemistry. The Phase IIb part of the study aims at prospectively validating aNK level as a predictive biomarker with PFS as a primary endpoint, by comparing the two treatment arms in two subgroups defined according to the level of aNK cells at baseline (normal or high). Bayesian criteria, derived from the TG4010.09 study results, will be used to confirm that, with a large probability, the true hazard ratio is &lt;1 in patients with normal level of aNK cells and &gt;1 in patients with high level of aNK cells. The Phase III part of the study will then compare, by using a frequentist approach, the two treatment arms with overall survival as a primary endpoint in the patient population confirmed to be of interest in the Phase IIb part. The phase III part is powered to detect a 27% reduction in the hazard rate of death. Phase IIb and III parts of the study will enroll respectively 206 and 800 patients. A dynamic minimization procedure will be applied at randomization for histology, prescription of bevacizumab, type of chemotherapy, PS and center. If qualifying for, patients will receive maintenance therapy after chemotherapy according to labeling. The study TIME is open to recruitment and referenced in ClinicalTrials.gov with the identifier NCT01383148.
ETV2/ER71 Transcription Factor as a Therapeutic Vehicle for Cardiovascular Disease
Authors: Dong Hun Lee, Tae Min Kim, Joo Kyung Kim, Changwon Park
Journal: Theranostics (2019)

Cardiovascular diseases have long been the leading cause of mortality and morbidity in the United States as well as worldwide.Despite numerous efforts over the past few decades, the number of the patients with cardiovascular disease still remains high, thereby necessitating the development of novel therapeutic strategies equipped with a better understanding of the biology of the cardiovascular system.Recently, the ETS transcription factor, ETV2 (also known as ER71), has been recognized as a master regulator of the development of the cardiovascular system and plays an important role in pathophysiological angiogenesis and the endothelial cell reprogramming.Here, we discuss the detailed mechanisms underlying ETV2/ER71-regulated cardiovascular lineage development.In addition, recent reports on the novel functions of ETV2/ER71 in neovascularization and direct cell reprogramming are discussed with a focus on its therapeutic potential for cardiovascular diseases.
The cost of childhood atopic dermatitis in a multi‐ethnic Asian population: a cost‐of‐illness study
Authors: M. Olsson, R. Bajpai, L.W.Y. Wee, Y.W. Yew, M.J.A. Koh, S. Thng, J. Car, K. Järbrink
Journal: British Journal of Dermatology (2019)

Childhood atopic dermatitis can often have a negative impact on quality of life for affected children and their caregivers. The condition contributes to increased healthcare costs and can pose heavy economic burdens on healthcare systems and societies.The objective of this study is to provide a comprehensive estimate of the economic burden of childhood atopic dermatitis in a Singaporean sample and to investigate associated factors.This cross-sectional cost-of-illness study applied a societal perspective. Data was collected between December 2016 and December 2017 in Singapore. Caregivers to children below 16 years of age with a physician-confirmed diagnosis of atopic dermatitis were recruited and sociodemographics, clinical characteristics, health service utilization data and time spent on caregiving were collected from all eligible participants.The average annual cost per child with atopic dermatitis was estimated at U.S. dollars (USD) 7943 (mild USD 6651, moderate USD 7935 and severe USD 14 335) in 2017 prices. The major cost was for informal caregiving (46% of the total cost) followed by out-of-pocket expenses (37%). Healthcare utilization contributed to 17% of the total cost of which 43% was for medications.Childhood atopic dermatitis imposes substantial costs with a large proportion arising from informal caregiving and out-of-pocket expenses. The costs related to atopic dermatitis are also strongly related to disease severity. This information is important for policy makers and other health planners when considering how to better support affected families. What's already known about the topic? Childhood atopic dermatitis is a costly disease for society. However, comprehensive cost estimations are lacking. Previous cost studies are old, based on small sample sizes or are healthcare-setting specific. What does this study add? This study comprises a health economic evaluation assessing different levels of care and includes various categories of costs. The result showed that informal caregiving was the most prominent cost for children with atopic dermatitis.
T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response
Authors: Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. Impaired T cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.
FRI0097 Diagnosis of neuropsychiatric sle and other collagen-vascular diseases using infra-red oculography
Authors: DA Maclachlan, U Gschwandtner, A Steck
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Minor cognitive deficits such as impaired intellectual performance, poor concentration and mental fatigue are common in patients with SLE and other autoimmune diseases.<sup>1</sup> There is however no single reliable method for the detection of CNS involvement from autoimmune diseases. <h3>Objectives</h3> A non-invasive, highly-sensitive testing method, infra-red oculography<sup>2</sup> was used to investigate whether eye movements are affected in patients with suspected CNS involvement from various autoimmune diseases compared to a normal healthy control group. <h3>Methods</h3> 10 patients (5 with SLE, 5 with other autoimmune diseases) with cognitive deficits and 10 control subjects were examined using infra-red oculography to measure disturbances of eye movements and to assess the usefulness in the evaluation of these patients. <h3>Results</h3> There were no statistically significant differences between patients and controls when comparing amplitude, latency, duration and velocity of saccadic eye movements (SEM) but there was a significantly higher (p &lt; 0.05) number of undershoots with corrective saccades in both groups of patients. In smooth pursuit eye movements (SPEM), there was no significant difference in the gain and delay between the patients and controls but a significantly higher number of correction saccades in patients (p &lt; 0.01) could be shown. <h3>Conclusion</h3> We conclude that the measurement of SEM and SPEM is a simple and non-invasive method for identifying suspected neuropsychiatric central nervous system involvement in patients with autoimmune disease. <h3>References</h3> Carbotte RM, Denburg SD, Denburg JA. Cognitive deficit associated with rheumatic diseases: neuropsychiatric perspectives. Arthritis Rheum. 1995;38:1363–74 Meienberg O. Infrared reflection method for recording horizontal eye movements. An improved version for routine diagnostic studies. Fortschr Neurol Psychiatr. 1987;55(5):158–63
The efficacy of bronchoscopic intratumoral chemotherapy in palliation of inoperable lung cancer.
Authors: Hesham El Ghazaly, Tamer Mohammed, Ashraf Madkour, Emad Koraa
Journal: Journal of Clinical Oncology (2012)

e17556 Background: Endobronchial obstruction is a common complication of advanced-stage lung cancer. Patients presenting with severe bronchial obstruction are at a high risk for developing haemoptysis, post-obstructive pneumonia, or respiratory failure, this often leads to death in weeks to months.Tumor debulking and airway re-canalization has a considerable role in increasing survival in patients with inoperable non-small cell lung cancer (NSCLC). Bronchoscopic endobronchial intratumoral chemotherapy (EITC) is a new intervention to treat airway obstruction. This work aims to determine the efficacy of EITC in palliative care for patients with inoperable NSCLC. Methods: Between April 2009 and June 2011, patients with newly diagnosed non metastatic inoperable symptomatic non-life threatening airway obstruction secondary to NSCLC were selected for tumor debulking via EITC through flexible bronchoscopy. EITC of maximum 20mL cisplatin with the concentration of 50 mg/50 mL was injected into the tumor bulk through flexible needle (weekly for 4 sessions). Patients were followed according to the symptoms, performance and functional status and endobronchial lesions changes after EITC. Results: Forteen male and 1 female were studied in which 7 cases had squamous cell carcinoma, 5 cases had adenocarcinoma and 3 cases had unspecified NSCLC. After 4 sessions of EITC, the involved lumen was considerably opened (&gt; 25%) in 80% of cases in which 7 cases &gt;50% and 5 cases showed a 25–50% luminal opening. Significant improvement was found in dyspnea score, Karnofsky performance scale as well as spirometric and arterial blood gases indices after than before the 4 sessions of EITC. Conclusions: EITC was well tolerated by most of the patients with minimal non systemic complications. In conclusion, EITC is a promising, safe, effective and less invasive procedure for palliative treatment of obstructive non-life threatening endobronchial NSCLC lesions.
BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus MEK inhibitor trametinib (GSK1120212).
Authors: Ryan Bruce Corcoran, Gerald Steven Falchook, Jeffrey R. Infante, Omid Hamid, Wells A. Messersmith, Eunice Lee Kwak, David P. Ryan, Razelle Kurzrock, Adrienne A Brenner, Jennifer Luan, Peng Sun, Alicia J Allred, Shonda M Little, Kiran Patel, Scott Kopetz, Alan Paul Venook
Journal: Journal of Clinical Oncology (2012)

3528 Background: BRAF V600 mutations occur in 10-15% of CRC and may predict lack of response to standard chemotherapy and anti-EGFR treatment. There have been no significant recent changes in the treatment of CRC. Novel therapeutic strategies for BRAF mutant CRC are critically needed. To collect preliminary efficacy data, an expansion cohort of 25 BRAF mutant CRC patients (pts) was included in part 2 of a phase I/II study evaluating the combination of dabrafenib (BRAFi) and trametinib (MEKi). Methods: Eligible pts had BRAF V600 mutant CRC, measurable disease per RECIST 1.1, and previous treatment with anti-cancer therapies. Pts were treated with established dose of dabrafenib (150mg BID) and trametinib (2mg QD). Results: Data for 23 pts are available at data cut-off: median age 54 years, 74% female, ECOG performance status 0 (48%) or 1 (52%). 39% had received prior EGFR inhibitor treatment. 74% had received ≥ 2 prior chemotherapy regimens; 48% had ≥ 1 biologic therapy. 48% had ≥ 3 metastatic sites. Three of the 23 pts were non-evaluable at data cut-off as they had not reached the first restaging assessment. Among the 20 evaluable pts, 1 (5%) achieved partial response and 10 (50%) stable disease. Minor responses (&gt;10% to &lt;30% tumor shrinkage) were observed in 4/10 patients (40%) with stable disease. The most frequent adverse events observed in all Part 2 patients who received the same dosing combination (n=75) included pyrexia (65%), fatigue (47%), nausea (44%), chills (41%), vomiting (31%), constipation (28%), diarrhea (24%) and rash (21%). Conclusions: Dabrafenib at 150 mg BID combines safely with trametinib 2 mg QD in this BRAF mutant CRC cohort. Based on the preliminary anti-tumor activity seen, further investigation is warranted in BRAF mutant CRC pts. Updated safety and efficacy data and an analysis of the relationship between efficacy and potential predictive biomarkers, including microsatellite status, PTEN loss, PIK3CA mutation, and total and phosphorylated EFGR levels, will be presented.
Addressing gaps in care of people with conditions affecting sex development and maturation
Authors: Olaf Hiort, Martine Cools, Alexander Springer, Ken McElreavey, Andy Greenfield, Stefan A. Wudy, Alexandra Kulle, S. Faisal Ahmed, Arianne Dessens, Antonio Balsamo, Mohamad Maghnie, Marco Bonomi, Mehul Dattani, Luca Persani, Laura Audi
Journal: Nature Reviews Endocrinology (2019)
Malaria outbreak in Burundi reaches epidemic levels with 5.7 million infected this year
Authors: Pat Lok, Stijntje Dijk
Journal: BMJ (2019)

Over 5.7 million people in Burundi—almost half of the total population—have been infected with malaria since the start of 2019.1

The ongoing epidemic has taken the lives of 1801 people, equalling the death toll caused by Ebola in the neighbouring Democratic Republic of Congo.

Despite the outbreak reaching epidemic proportions Burundi has not yet declared a national emergency. This delay coincides with the country’s upcoming elections of 2020. A senior government official said that the president, Pierre Nkurunziza, fears that such a declaration would be seen as a failure of his health policy.

Since December 2018 the …
Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population: Analysis of the "Health and Anemia" Study
Authors: Marianna Rossi, Manja Meggendorfer, Matteo Zampini, Mauro Tettamanti, Emma Riva, Elena Saba, Nicla Manes, Chiara Milanesi, Ubezio Marta, Lucio Morabito, Erica Travaglino, Clelia Peano, Solda Giulia, Rosanna Asselta, Stefano Duga, Karolina Malik, Carlo Selmi, Efrem Civilini, Sara Mandelli, Niccolò Bolli, George S. Vassiliou, Wolfgang Kern, Armando Santoro, Ugo Lucca, Torsten Haferlach, Matteo Giovanni Della Porta
Journal: Blood (2018)
Change in Cardiovascular Health and Incident Type 2 Diabetes and Impaired Fasting Glucose: The Whitehall II Study
Authors: Rachel E. Climie, Thomas T. van Sloten, Marie-Cécile Périer, Muriel Tafflet, Aurore Fayosse, Aline Dugravot, Archana Singh-Manoux, Jean-Philippe Empana
Journal: Diabetes Care (2019)

OBJECTIVE Most previous studies on cardiovascular health (CVH) and incident type 2 diabetes (T2D) have used a single measure of CVH, and none have investigated the association with impaired fasting glucose (IFG). We examined the association between changes in CVH and incident T2D and IFG. RESEARCH DESIGN AND METHODS Within the Whitehall II study, CVH was examined every 5 years from 1991/93 until 2015/16. Subjects with 0–2, 3–4, and 5–6 ideal metrics of CVH from the American Heart Association were categorized as having low, moderate, or high CVH, respectively. RESULTS There were 6,234 participants (mean age 49.8 ± 6.0 years, 70% male) without prior cardiovascular disease and T2D, including 5,015 who were additionally free from IFG at baseline. Over a median follow-up of 24.8 (interquartile range 24.0–25.2) years, 895 and 1,703 incident cases of T2D and IFG occurred, respectively. Change in CVH between 1991/93 and 2002/04 was calculated among 4,464 participants free from CVD and T2D and among 2,795 participants additionally free from IFG. In multivariate analysis, compared with those with stable low CVH, risk of T2D was lower in those with initially high CVH (hazard ratio [HR] 0.21; 95% CI 0.09, 0.51), those who had persistently moderate CVH or changed from moderate to high CVH (moderate-moderate/high; HR 0.53; 95% CI 0.41, 0.69), low-moderate/high (HR 0.62; 95% CI 0.45, 0.86), and moderate-low (HR 0.74; 95% CI 0.56, 0.98). Results were similar for IFG, but the effect sizes were smaller. CONCLUSIONS Compared with stable low CVH, other patterns of change in CVH were associated with lower risk of T2D and IFG.
Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study
Authors: Pier Luigi Zinzani, Armando Santoro, Giuseppe Gritti, Pauline Brice, Paul M. Barr, John Kuruvilla, David Cunningham, Justin Kline, Nathalie A. Johnson, Neha Mehta-Shah, Thomas Manley, Stephen Francis, Manish Sharma, Alison J. Moskowitz
Journal: Journal of Clinical Oncology (2019)

Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL.The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety.Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths.In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.
Combined modality therapy for pancreatic carcinoma: An Australian Pancreatic Cancer Group study of the addition of gemcitabine (G) to concurrent infusional 5-fluorouracil (CI 5FU) and 3D conformal radiotherapy (RT)—Final outcomes
Authors: D. Goldstein, N. Spry, G. Van Hazel, C. Underhill, D. Kotasek, J. Harvey, M. Links, J. Shapiro, B. Iacopetta, Eli Lilly Australia
Journal: Journal of Clinical Oncology (2006)

4104 Background: This open-label Phase II study (B9E-AY-S168) examined whether CI 5FU plus 3D conformal planning RT is well tolerated and may be combined with G pre and post chemoradiotherapy in patients (pts) with pancreatic cancer (PC). Methods: Eligible pts were enrolled in two strata: (1) inoperable PC in head or body without metastases (LAD) or (2) resected PC at high risk of relapse (Surg). G was given at 1000 mg/m 2 weekly for 3 wks followed by 1 wk rest and a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m 2 /day). The defined target volume was treated to 54Gy in 30# of 1.8Gy (LAD) or 45Gy in 25# (Surg). After 4 wks rest, G was given for 12 wks. Results: 63 pts were enrolled: 39 females, 24 males; mean age 61 yr, range 31–79; 43% ECOG PS 0, 51% PS 1, 5% PS 2. Follow-up was 2 yr. 1- and 2-yr survival (KM) were 46% and 10% (LAD) and 59% and 27% (Surg). 1- and 2-yr local control (KM) were 48% and 21% (LAD) and 80% and 80% (Surg). The % planned dose delivered was (i) G pre RT: 87.6% (LAD)/94.6% (Surg); (ii) 5FU: 100.7%/96.4%; (iii) RT: 96.2%/99.5%; (iv) G post RT: 67.4%/65.3%. The baseline CA 19.9 level was significantly associated with a shorter TTPD (p=0.0002) and a shorter survival time (p=0.0071). Using Time Dependent Covariate analysis, CA 19.9 levels were strongly associated with TTPD and survival (both p &lt; 0.0001); a person with a 10-fold higher level has a 1.95-fold higher risk of death over the next time period than their counterpart (95% CI: 1.53–2.49-fold). In 22 pts we found no statistically significant associations between outcome and mutations in K-RAS or TP53 or with microsatellite instability. Grade 3/4 hematological and non-hematological toxicity was reported by 29 (46%) and 42 pts (67%), respectively. There was one treatment-related death. Conclusions: This approach to treatment is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomized trial. [Table: see text] [Table: see text]
Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas
Authors: Han Shen, Man Yu, Maria Tsoli, Cecilia Chang, Swapna Joshi, Jie Liu, Scott Ryall, Yevgen Chornenkyy, Robert Siddaway, Cynthia Hawkins, David S Ziegler
Journal: Neuro-Oncology (2019)

Abstract Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.