tbuckley/cabot-search huggingface dataset:
Abstract P199: Small HDL-C is Associated to Subclinical Hypothyroidism. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)
Authors: Isabela M Bensenor, Alessandra C Goulart, Marcio S Bittencourt, Michael Blaha, Steven Jones, Peter P Toth, Paulo A Lotufo
Journal: Circulation (2019)

Introduction: Although epidemiologic studies have associated subclinical thyroid disorders with coronary heart disease, the role of lipoprotein levels are not well defined as a mediator or moderator of this association. Purpose: To test the association of lipoprotein particle concentration and size measured by nuclear magnetic resonance with subclinical hyperthyroidism and subclinical hypothyroidism using baseline data from the Brazilian Longitudinal Study of Health (ELSA-Brasil) of apparently healthy 5024 men and women aged 35 to 74 years old. Methods: We measured lipids and lipoproteins subfractions using a new nuclear magnetic resonance spectroscopy (NMR LipoProfile® test spectra, LabCorp, Raleigh, NC): triglyceride-rich lipoprotein particles (TRLP, containing IDL-P and VLDL-P), 3 LDL-P subclasses (large, medium and small) and 3 HDL-P subclasses (large, medium and small). Subclinical thyroid disorders were defined as TSH &gt;4 IU/ml and TSH &lt;0.4 IU/ml for people with normal free-thyroxine levels. We excluded from the sample participants reporting previous cardiovascular disease, those who used lipid-lowering medications and/or other drugs that interfere with thyroid function remaining 3,947 subjects. The cross-sectional relationship between subclinical thyroid diseases (independent variable) and lipids and lipoproteins (dependent variable) were evaluated by linear regression models using euthyroid subjects as the reference. Models were presented as crude and after adjustment for sociodemographic (age, sex, race, and education), cardiovascular risk factors (body-mass index, hypertension, diabetes, smoking habit, alcohol use, and physical activity) and LDL-C, HDL-C and triglycerides measured by enzymatic methods. Results: After exclusions, we detected 47 persons with subclinical hyperthyroidism (mean age 53.1 (±9.4 years; 61.7% women), 258 with subclinical hypothyroidism (mean age 52.3 (±8.9); 58.1% women) and 3,642 participants with normal thyroid function (mean age: 50.1 (±8.6); 52% women). After multivariate adjustment, subclinical hyperthyroidism was associated with a decrease in triglyceride-rich lipoprotein particles (Beta coefficient (B) -15.2; P=0.04) and with the very small triglyceride-rich lipoprotein subclass (B, -16.9; P=0.04). Subclinical hypothyroidism was associated with a decrease in small HDL-P subclass (B, 0.42; P=0.03). No association was found for any subclinical conditions with LDL-C. Conclusions: Subclinical hyperthyroidism does not show any possible association with an atherogenic profile, and subclinical hypothyroidism revealed an association with lower small HDL-cholesterol levels.
Identification of infants at risk of child undernutrition in India: building a predictive algorithm with data from a nationally representative survey
Authors: Apurv Soni, Jeroan Allison
Journal: The Lancet Global Health (2019)

BackgroundIndia is at the centre of global child undernutrition, with a burden of malnourished children nearly twice that of all sub-Saharan African countries. The Indian government has established many national-level initiatives to address this public health crisis. However, there is substantial variation between and within states in the prevalence of child undernutrition, and strategies to identify at-risk populations are needed in the context of limited resources. Here, we describe the development of an algorithm that can be deployed at the time of delivery to characterise newborns' risk of undernutrition in the first 5 years of life.MethodsWe extracted data on 232 440 children younger than 5 years from the 2015–16 National Family Health Survey. A child was considered undernourished if either height-for-age, weight-for-height, or weight-for-age was more than 2 SD below median WHO child growth standards. We used predictor variables identified in published studies if they could be measured at the time of delivery and used multilevel logistic regression to model the outcome. Model calibration was assessed using the Hosmer-Lemeshow test. We tested internal validity of the model using 200 bootstrapped samples to derive an optimism-adjusted c-statistic. All analyses were done with svy command in STATA to account for complex clustered sampling.FindingsIn 2016, 54·7% of Indian children younger than 5 years were either stunted (38·4%), underweight (35·8%), or wasted (21·0%). The predictive model for overall undernutrition included maternal factors (height, education, reproductive history, number of antenatal visits), child factors (sex and birthweight), and household characteristics (district of residence, caste, rural residence, toilet availability, presence of a separate kitchen). The model demonstrated good discrimination ability (c-statistic: 0·688, optimism-adjusted c: 0·686). The prevalence of child undernutrition in the lowest decile risk group was 24·0%, and in the highest decile risk group it was 77·9%.InterpretationWe are developing a mobile-based app to collect the information and categorise children into a risk decile at the time of delivery. Since more than 80% of births in India are registered by community health workers, who are also responsible for implementing child nutrition programmes, this tool could help workers identify infants at risk of malnutrition and prioritise their interventions.FundingAS: NIH-NCATS (TL1-TR001454) and NIH-NICHD (1F30HD091975-01A1) [AS] and NIH-NIMH (P60-MD006912-05) [JA].
The TGF-β/SMAD Signaling Pathway As a Mediator of NK Cell Dysfunction and Immune Evasion in Myelodysplastic Syndrome
Authors: May Daher, Rafet Basar, Hila Shaim, Elif Gokdemir, Nadima Uprety, Alexander Kontoyiannis, Mayela Carolina Mendt, Nobuhiko Imahashi, Lucila Nassif Kerbauy, Francesca Lorraine Wei Inng Lim, Li Li, Muharrem Muftuoglu, Pinaki P Banerjee, Richard E Champlin, Peter P. Ruvolo, Michael Andreeff, Hagop M. Kantarjian, Guillermo Garcia-Manero, Elizabeth J Shpall, Katayoun Rezvani
Journal: Blood (2017)
Treament of multi-drug-resistant pancreatic cancer cells using combination of high-intensity focused ultrasound and low-dose gemcitabine.
Authors: Howard Q. Vo, Yoo-Shin Kim, Brian E. O'Neill
Journal: Journal of Clinical Oncology (2015)

e15297 Background: In this study, we seek to evaluate a new strategy in which the combination of high-intensity focused ultrasound (HIFU) and low-dose Gemcitabine (Gem) is utilized to attack MDR pancreatic cancer cells. Methods: This strategy, motivated by limitations in HIFU clinical trial to treat pancreatic cancer, led to the in vitro study during which human pancreatic cell line AsPC1 (ATCC), known for resistance to Gem, was paradoxically treated with low-dose Gem. Day 1: Each data sample consisted of ~10K cells grown inside a well of 8-well glass slides (Lab-Tek). Each slide was then filled with growth media, sealed, submerged in a 37ºC degassed water bath and secured onto a fixture. The targets for HIFU therapy are the center points of the 4 quadrants of each well's base. The constant HIFU parameters for each slide were duty cycle (DC) 50%, repetition rate 1Hz, focal-zone depth and 30 sec/sonication/center point while acoustic pressure ranged 0-5MPa among slides. After HIFU treatment, the slides were incubated for 24h. Day 2: Cell media for each slide was replaced with fresh media containing [Gem] 0-1000 uM prior to repeating the HIFU procedure from day 1. Day 4: After 48h of exposure to Gem, cell survivability study was performed to determine the contribution of HIFU-mediated necrosis as well as Gem-mediated apoptosis. Survivability is defined as live cell count under treatment divided by live cell count without treatment. Results: Cell survivability decreased by increasing [Gem] or acoustic pressure. Cell survivability point estimate ± confidence interval was 58% ± 4% at {[Gem] 1 uM, 0 MPa; N=8} and 32% ± 8% at {[Gem] 0 uM, 4.5 MPa; N=8}. In contrast, survivability point estimate ± confidence interval was 24% ± 4% at {[Gem] 1 uM, 4.5 MPa; N=8}. Conclusions: The combination of HIFU and low-dose Gemcitabine was successful in eliminating MDR pancreatic cancer cells in 3 days. Treatment of AsPC1 pancreatic cancer cells using HIFU+Gem. [Gem], (uM) 0 0.1 1 10 100 500 1000 Cell survivability point estimate ± margin of error (%) on day 4; 0 MPa, N=8 100±25 68±16 58±4 30±7 40±8 47±7 44±6 Cell survivability point estimate ± margin of error (%) on day 4; 4.5 MPa, N=8 32±8 29±4 24±4 23±3 16±3 15±2 13±2
Mass Cytometry Identifies T Cell Populations Associated with Severe Hepatotoxicity in CLL Patients on Upfront Idelalisib
Authors: Alexander R. Vartanov, Tiago R Matos, Emily M. McWilliams, Deepti Gadi, Deepak Rao, Siddha Kasar, Benjamin L. Lampson, Stacey M. Fernandes, Jerome Ritz, Jennifer R. Brown
Journal: Blood (2018)
Real-world PROCEED registry data: Sipuleucel-T in elderly men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Andrew J. Armstrong, Carl A Olsson, Ian D. Schnadig, Raoul S Concepcion, Jeffrey L. Vacirca, Ronald F Tutrone, Shaker R. Dakhil, Nancy N. Chang, Hong Tang, Bruce Brown, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2019)

177 Background: Managing patients ≥ 80 years old (yo) with mCRPC is challenging, given the high prevalence of comorbidities, polypharmacy, organ dysfunction, and reduced performance status (PS). Balancing treatment benefit with safety and quality of life is particularly germane for this group. Sipuleucel-T, an autologous cellular immunotherapy for mCRPC, is generally well-tolerated. Prior analyses from PROCEED, a large registry for sipuleucel-T in men with mCRPC, demonstrated that upregulation of immune cells in these elderly patients is similar to that of younger men. Here, we report on this clinical experience. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T given every 2 weeks x 3, with no dose adjustment for organ dysfunction or drug interactions. The elderly cohort included those ≥ 80 yo. Men were followed until death, study withdrawal, or a minimum of 3 years. Results: Of 1902 patients who received ≥1 sipuleucel-T infusion, 374 (19.7%) were ≥ 80 yo. Compared to men &lt; 80 yo (Table), this cohort was 14 years older, had worse Eastern Cooperative Oncology Group (ECOG) PS and higher prostate-specific antigen (PSA) at baseline. All grade (16.3% elderly v. 13.7% younger) and grade 3-5 (10.7% elderly v. 9.9% younger) serious adverse events were comparable between groups. However, the median overall survival (OS) of elderly men was 10.7 mo shorter than that of younger men (&lt; 80 yo). Conclusions: Sipuleucel-T was generally well-tolerated in those ≥ 80 yo in a real-world setting and may be considered a first-line option for the elderly with asymptomatic or minimally symptomatic mCRPC. As expected, OS was shorter than in younger patients. Clinical trial information: NCT01306890. [Table: see text]
Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors: ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines
Authors: Susan M. Chang, Hans Messersmith, Manmeet Ahluwalia, David Andrews, Priscilla K. Brastianos, Laurie E. Gaspar, Na Tosha N. Gatson, Justin T. Jordan, Mustafa Khasraw, Andrew B. Lassman, Julia Maues, Maciej Mrugala, Jeffrey Raizer, David Schiff, Glen Stevens, Ashley Sumrall, Martin van den Bent, Michael A. Vogelbaum
Journal: Journal of Clinical Oncology (2019)

The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations.Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement.The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations.Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .
Antibiotics in a Haitian neonatal intensive care unit: findings from a Plan-Do-Study-Act quality-improvement project
Authors: Jack Long, Delight Wing, Rose Pascale Paul
Journal: The Lancet Global Health (2019)

BackgroundIn the critical care setting, delay in the administration of antibiotics has been associated with as much as a three-fold rise in mortality. Working in a neonatal intensive care unit (NICU) in rural Haiti, we attempted to reduce the time between patient admission and the administration of the first dose of antibiotics and to reduce the frequency of dosing errors by implementing a Plan-Do-Study-Act (PDSA) cycle-based quality improvement project.MethodsThe study took place at St Boniface Hospital—a 130 bed hospital serving 2·3 million people in rural Haiti. A retrospective chart review was done for every patient admitted to the 24-bed NICU over a 2-week period. Baseline data were recorded by noting the time of patient admission and the time of administration of the first doses of antibiotics. In addition, the dosage of each antibiotic was checked for accuracy. Two subsequent 2-week data collections were performed over 6 months, interspersed with PDSA cycles. These cycles included training and interventions to: improve staff awareness about the risks of delaying treatment and of incorrect dosing; identify barriers to care; introduce nurse-initiated standing orders; review data; and disseminate results to the staff. This study was approved by the Research Ethics Committee at St Boniface Hospital.FindingsThe baseline data collection between Jan 29, 2018, and Feb 11, 2018, included 26 patients; period 2 (April 25, 2018 to May 8, 2018), included 33 patients; and period 3 (July 5–18, 2018), 28 patients. At baseline, mean delay in antibiotic administration was 6·2 h (95% CI 4–8·4). In periods 2 and 3, mean delays were 0·6 h (0·35–0·85) and 0·4 h (0·16–0·64), respectively. At baseline, dosing errors were noted in 13 of 22 ampicillin orders (59%) and four of 22 gentamicin orders (18%). Four patients received antibiotics other than ampicillin or gentamicin. In periods 2 and 3 there were no errors reported. In the baseline period, two of 26 patients (7·6%) received the first dose of antibiotic within 1 h and in periods 2 and 3, 30/33 (91%) and 24/28 patients (86%), respectively, received antibiotics within 1 h.InterpretationIn a low-resource setting, errors in antibiotic dosing and delays in administration of antibiotics to newborns admitted to the NICU can be successfully reduced using a PDSA-based quality improvement project. This approach does not require expensive interventions nor new technology but it does have the potential to reduce neonatal morbidity and mortality.FundingNone.
Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Julie Bailis, Petra Deegen, Oliver Thomas, Pamela Bogner, Joachim Wahl, Mike Liao, Shyun Li, Katja Matthes, Virginie Nägele, Doris Rau, Benno Rattel, Tobias Raum, Peter Kufer, Angela Coxon
Journal: Journal of Clinical Oncology (2019)

301 Background: mCRPC is a disease of high unmet medical need, especially for patients who fail novel hormonal therapies and chemotherapy. BiTE molecules provide an off the shelf therapy that activates a patient’s own immune system and redirects T cells to kill tumor cells. The BiTE mechanism of action is distinct from other immunotherapies and may unlock immune response in mCRPC. PSMA is a compelling BiTE target that is highly expressed on PCa compared to normal tissue and has increased expression in mCRPC. Methods: AMG 160 is a fully human, half-life extended (HLE) BiTE that targets PSMA on tumor cells and CD3 on T cells. AMG 160 comprises two tandem single chain variable fragments fused to an Fc domain. Results: AMG 160 binds human and non-human primate (NHP) PSMA and CD3, leading to T cell activation and proliferation and cytokine production. AMG 160 redirects T cells to kill PSMA-positive cancer cell lines in vitro, including those with low PSMA levels or androgen-independent signaling. Weekly dosing of AMG 160 induces significant antitumor activity in established PCa xenograft model. The pharmacokinetics (PK) and pharmacodynamics of AMG 160 were tested in NHP. AMG 160 treatment led to BiTE target engagement in vivo, including transient T cell activation and cytokine release in blood, and mixed cellular infiltrates in multiple organs known to express PSMA. AMG 160 treatment was well tolerated. Cytokine release associated with the first dose could be attenuated using a step dose regimen. The half-life of AMG 160 in NHP was about one week. Based on allometric scaling, the PK profile of AMG 160 may be projected to enable dosing every other week in humans. Conclusions: AMG 160 is a potent HLE BiTE with specificity for PSMA-positive tumor cells. A Phase 1 study is planned to evaluate the safety and efficacy of AMG 160 in patients with mCRPC.
DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.
Authors: James Vu, Marcus Marie Moses, Lahiru Ranasinghe, Patrick Cotogno, Charlotte Manogue, Brian E. Lewis, Jodi Lyn Layton, A. Oliver Sartor, Elisa Ledet
Journal: Journal of Clinical Oncology (2019)

245 Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients with a DNA repair pathogenic mutation were more likely to have &gt; 2 family members affected by cancer, regardless of cancer type or degree of relationship (p = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.
Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity.
Authors: Andrea Rocca, Giovanni Brigliadori, Daniele Calistri, Flavia Foca, Monia Dall'Agata, Claudia Rengucci, Serenella Cerasoli, Marina Faedi
Journal: Journal of Clinical Oncology (2015)

2017 Background: Adult glioblastoma (GBM) is the most common type of malignant primary brain tumor. Despite advances in treatment, median survival is between 12 and 15 months. Standard care is concomitant radiotherapy (RT)/chemotherapy (CT) and adjuvant temozolomide (TMZ) for 6 cycles. At progression, subsequent treatments are at the discretion of the patient’s physician. MGMT gene promoter methylation status is acknowledged worldwide as a predictive marker. When MGMT promoter values fall into a “methylated” range, a better response to TMZ treatment is expected. Methods: We retrospectively analyzed data from 105 patients with GBM treated from 2011 to 2014 within the oncology network of the wide catchment area of Romagna, Italy. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. We evaluated whether variability in the methylation profile of each patient can influence the predictive capacity of MGMT promoter methylation and also aimed to identify the best cutoff value. Results: All patients were treated by RT followed by TMZ. MGMT promoter methylation status was classified into three types: unmethylated 0 – 9%, methylated 10 – 29% and methylated 30 - 100%. Statistical analysis showed that an assumed methylation cut-off of 9% led to an overestimation of responders. All of the patients in the 10–29% methylation group relapsed before the 18-month evaluation. Patients with a methylation status > 30% showed a median overall survival (OS) of 25.2 months compared to 15.2 months in all other patients, indicating that this is the best methylation cut-off. We also analyzed the methylation status of each CpG island in patients’ profiles but, despite observing a great variability among individual profiles, did not find any correlation between single CpG island values and relapse or death (Wilcoxon test and ROC curves). Conclusions: Our results did not highlight an impact of specific CpG island methylation status on the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only when 30% was used as cut-off value.