tbuckley/cabot-search huggingface dataset:
Association between lifestyle factors and completion of neoadjuvant chemotherapy for breast cancer.
Authors: Ilana M Usiskin, Fangyong Li, Melinda L Irwin, Brenda Cartmel, Tara Beth Sanft
Journal: Journal of Clinical Oncology (2018)

91 Background: Completion of chemotherapy has been associated with improved breast cancer outcomes. We evaluated whether lifestyle factors, such as physical activity and diet, may contribute to neoadjuvant chemotherapy completion in breast cancer. Methods: We conducted a retrospective study of women treated with neoadjuvant chemotherapy for early stage (I-III) breast cancer. A medical record review recorded BMI, blood pressure, diabetes and hypertension medication, and chemotherapy completion. Completers received full doses of all prescribed chemotherapy, with or without cycle delays. We conducted a telephone survey about exercise and fruit/vegetable intake (&gt;5 servings/day) during the year prior to cancer diagnosis. Exercisers completed at least 7.5 MET-hours/week (i.e., 150 minutes of moderate-intensity exercise). Multi-variable adjusted analyses were conducted to identify factors associated with chemotherapy completion. Results: Sixty-seven patients (45%) answered the survey. Chemotherapy completers were on average 11 years younger than non-completers (p&lt;0.001), more likely premenopausal (p=0.02), and less likely on diabetes medication (p=0.05). Exercisers were more likely to complete chemotherapy than non-exercisers (p=0.002). After controlling for age, diastolic blood pressure, menopausal status, and diabetes medication, the adjusted odds ratio for exercise on chemotherapy completion was 4.1 (95% CI 1.1 – 15.3) (p=0.04). Conclusions: Women who reported exercising at recommended levels in the year prior to breast cancer diagnosis were more likely to complete neoadjuvant chemotherapy regimens, suggesting a potentially important role for lifestyle factors in chemotherapy completion. Factors associated with chemotherapy completion [Table: see text]
Extracellular Vesicles as Markers and Mediators in Sepsis
Authors: Pierre Raeven, Johannes Zipperle, Susanne Drechsler
Journal: Theranostics (2018)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a highly lethal condition in which current tools for early diagnosis and therapeutic decision-making are far from ideal. Extracellular vesicles (EVs), 30 nm to several micrometers in size, are released from cells upon activation and apoptosis and express membrane epitopes specific for their parental cells. Since their discovery two decades ago, their role as biomarkers and mediators in various diseases has been intensively studied. However, their potential importance in the sepsis syndrome has gained attention only recently. Sepsis and EVs are both complex fields in which standardization has long been overdue. In this review, several topics are discussed. First, we review current studies on EVs in septic patients with emphasis on their variable quality and clinical utility. Second, we discuss the diagnostic and therapeutic potential of EVs as well as their role as facilitators of cell communication via micro RNA and the relevance of micro-organism-derived EVs. Third, we give an overview over the potential beneficial but also detrimental roles of EVs in sepsis. Finally, we focus on the role of EVs in selected intensive care scenarios such as coagulopathy, mechanical ventilation and blood transfusion. Overall, the prospect for EV use in septic patients is bright, ranging from rapid and precise (point-of-care) diagnostics, prevention of harmful iatrogenic interventions, to using EVs as guides of individualized therapy. Before the above is achieved, however, the EV research field requires reliable standardization of the current methods and development of new analytical procedures that can close the existing technological gaps.
A longitudinal monitoring of left ventricular ejection fraction (LVEF) during reduced dosing anthracycline based chemotherapy in patients with breast cancer.
Authors: Yazan Numan, Ahmed Amro, Rani Shah, Hisham Hirzallah, Gaurav Sahay, Damir Kusmic, Yasir Jawaid, Alaa Gabi, Ellen Thompson, Maria R. B. Tria Tirona, Alessandra Ferrajoli
Journal: Journal of Clinical Oncology (2018)

e12666 Background: American Society of Echocardiography recommends that echocardiography is performed at baseline and after treatment completion in patients who received a cumulative anthracycline dose of 240mg/m2 or less. This is in contrast to more frequent evaluations in patient receiving higher doses. Obesity is a known risk factor for cardiac dysfunction after anthracycline. We, therefore, decided to evaluate the role of a more frequent monitoring in obese breast cancer patients receiving reduced dosing of anthracycline. Methods: 50 patients are planned to be enrolled in an observational clinical trial. Inclusion criteria were: breast cancer diagnosis, cumulative dose of 240mg/m2 of anthracycline, BMI of more than 24 kg/m2. Patients underwent echocardiographic evaluation at 0, 3 & 6 months (M) later. Single operator - single oncologist - single cardiologist (SOSOSC) approach was used to minimize measurement variation. At each visit measurements included: Ejection fraction (EF), Three Dimensional Ejection Fraction (3DEF), Global longitudinal strain (GLS). Additionally, we measured ultra-sensitive Troponin-I and recorded the use of lisinopril for hypertension. We used one sample T test to compare different means at different intervals. Results: 16 patients have completed the intended 3M follow up and 13 have completed 6M follow up. Median age is 53.4 years and median BMI is 30.4 kg/m2. In the evaluable patients, EF has significantly dropped from baseline (60.6%) to 3M (56.3%) to 6M visit (53.9%) (p value < 0.035). 3DEF decreased significantly from 61.2% at baseline to 57.4% at 3M (p value < 0.0252), however at the 6M it increased to 58.1%. Furthermore, we noted that GLS has dropped from an average -17.56 to -13 at 6M. Additionally we noted that 6 patient who were on lisinopril treatment had a median higher EF than those who are not at . (59.8 vs 54.3 p value of 0.09). Troponin I found to be higher at 3M visit than at baseline (0.015 vs 0.09 p value < 0.06). Conclusions: In obese breast cancer patients, 3DEF values are decreased while receiving reduced-dose anthracycline and continue to be depressed at treatment completion. 3-month visit allowed an earlier detection.
Effective Alcohol Policies—Saving Lives on US Roadways
Authors: Mark R. Rosekind
Journal: JAMA Internal Medicine (2018)

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Molecular alterations in the Ras-Raf-Erk (MAPK) pathway in metastatic hormone receptor positive (HR+)/HER2- breast cancer: Incidence and impact on clinical outcomes.
Authors: Arielle Medford, Andrzej Niemierko, Beverly Moy, Laura Spring, Giuliana Malvarosa, Jerry Younger, Richard B. Lanman, Rebecca J Nagy, Ryan Bruce Corcoran, Steven J. Isakoff, Leif W. Ellisen, Dejan Juric, Aditya Bardia
Journal: Journal of Clinical Oncology (2018)

1021 Background: While molecular alterations in PI3K pathway, including PIK3CA mutations, are common in HR+ breast cancer, molecular alterations in MAPK pathway, including KRAS and BRAF mutations, are considered rare in HR+ breast cancer. However, tumors can acquire new molecular alterations over time, and blood-based genotyping via circulating tumor DNA (ctDNA) could provide a more accurate molecular snapshot. Methods: This study analyzed data collected from metastatic breast cancer (MBC) patients who had genotyping (2016-2017) via a next generation sequencing-based (NGS) assay that detects ctDNA mutations (Guardant 360 panel), including alterations in MAPK pathway. Mutation profiles were also analyzed in tissue biopsies via SNaPshot-NGS, an institutional genotyping assay. Multivariate analysis was performed to evaluate the hazard ratio (HR) for the association between these mutations and time to progression (TTP), adjusting for key prognostic variables. Results: Among the HR+ MBC patients (N = 174), 25% (N = 44) were found to have molecular alterations in MAPK pathway in ctDNA, including mutations in BRAF (7.5%), KRAS (5.7%), NRAS (0.57%), MAP2K1 (1.1%) and NF-1 (14.4%); 14.5% had a concurrent PIK3CA mutation, 9.2% had a concurrent TP53 mutation, and multiple alterations were acquired. Among patients with MAPK molecular alterations versus not, there was no significant difference in baseline characteristics, including age at metastatic diagnosis (57 vs 55; p = 0.78) and visceral metastases (74% vs 81%; p = 0.87). In multivariate analysis, patients with MBC harboring MAPK molecular alterations had worse TTP (HR: 2.08; p = 0.02) compared to controls. However, there was no difference among those with PIK3CA mutant tumors versus not (HR: 1.09; p = 0.74). Conclusions: Molecular alterations in MAPK pathway, hitherto considered rare in primary HR+ breast cancer, are not uncommon in metastatic HR+ breast cancer and are associated with worse outcomes. The study highlights the value of blood-based assays for identification of novel targets and their potential clinical utility in development of genotype driven trials for patients with MBC.
The 100 000 Genomes Project: feeding back to patients
Authors: Celia Moss, Aaron Wernham
Journal: BMJ (2018)

The 100 000 Genomes Project described by Clare Turnbull and colleagues1 is a world leading initiative offering welcome opportunities for patients with rare and undiagnosed conditions. But the challenges of delivering results cannot be minimised.

Recruitment is behind schedule and only reached halfway in February, three years into the project, which is due to end this October. Reporting times remain longer …
Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial.
Authors: Geertjan Van Tienhoven, Eva Versteijne, Mustafa Suker, Karin B.C. Groothuis, Olivier R. Busch, Bert A. Bonsing, Ignace H.J.T. de Hingh, Sebastiaan Festen, Gijs A. Patijn, Judith de Vos-Geelen, Aeilko H. Zwinderman, Cornelis J. A. Punt, Casper H.J. van Eijck
Journal: Journal of Clinical Oncology (2018)

LBA4002 Background: Standard of care for patients with (borderline) resectable pancreatic adenocarcinoma is resection followed by adjuvant chemotherapy. Previous studies suggest a benefit of neoadjuvant treatment. We conducted a multicenter phase III randomized controlled trial to evaluate the effect of preoperative chemoradiotherapy. Methods: Patients with (borderline) resectable pancreatic cancer, pathologically confirmed, were randomized between immediate surgery (arm A) and preoperative chemoradiotherapy (arm B), both followed by adjuvant chemotherapy. The preoperative chemoradiotherapy consisted of 15 times of 2.4 Gray (Gy) combined with gemcitabine, 1,000 mg/m 2 on days 1, 8 and 15, preceded and followed by a cycle of gemcitabine. Primary endpoint was overall survival (OS), secondary endpoints were (R0) resection rate, disease free survival (DFS), distant metastases free interval (DMFI), locoregional recurrence free interval (LRFI) and toxicity. Accrual was completed between April 23, 2013 and July 25, 2017. Results: In total, 246 patients were included in the intention-to-treat analysis (127 patients in arm A and 119 in arm B). Currently, 142 of the 176 needed events for the primary outcome are observed. OS was significantly better in arm B (median 13.5 vs. 17.1 months; HR 0.71; p = 0.047). This was also the case for R0 resection rate (31% vs. 65%, p = &lt; 0.001), DFS (median 7.9 vs. 11.2 months; HR 0.67; p = 0.010), DMFI (median 10.2 vs 17.1 months; HR 0.63; p = 0.012) and LRFI (median 11.8 vs not reached; HR 0.47; p &lt; 0.001). Resection rates were 72% (91/127) in arm A vs. 62% (74/119) in arm B (p = 0.15). No significant difference was observed in grade ≥ 3 adverse events between both groups (p = 0.17). A subgroup analysis of patients who actually underwent a resection was performed which showed a median OS of 16.8 and 29.9 months respectively (p &lt; 0.001). Conclusion: Our preliminary data show that preoperative chemoradiotherapy significantly improves outcome in (borderline) resectable pancreatic cancer compared to immediate surgery. Updated results will be presented at the meeting. Clinical trial information: NTR3709.
Ribociclib (RIB) + tamoxifen (TAM) or a non-steroidal aromatase inhibitor (NSAI) in premenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) who received prior chemotherapy (CT): MONALEESA-7 subgroup analysis.
Authors: Sara A. Hurvitz, Paul Wheatley-Price, Debu Tripathy, Yen-Shen Lu, Louis Chow, Thomas Denis Bachelot, Roberto Hegg, Stephen K. L. Chia, Denise A. Yardley, Oliver Kong, Jahangir Alam, Ivan Diaz-Padilla, Johan Baeck, Aditya Bardia
Journal: Journal of Clinical Oncology (2018)

1047 Background: Although endocrine therapy (ET) and ovarian function suppression is an established first-line treatment for premenopausal patients (pts) with HR+, HER2– ABC, in some cases first-line CT is administered before ET. In the Phase 3 MONALEESA-7 trial (NCT02278120), RIB + TAM/NSAI and goserelin significantly prolonged progression-free survival (PFS) vs placebo (PBO) + TAM/NSAI and goserelin in premenopausal pts with HR+, HER2– ABC. Here, we report results in pts with and without prior CT for ABC. Methods: 672 pts with ≤1 line of prior CT and no prior ET for ABC were randomized 1:1 to RIB (600 mg/day, 3-weeks-on/1-week-off) or PBO + TAM (20 mg/day) or an NSAI (letrozole [2.5 mg/day] or anastrozole [1 mg/day]) and goserelin (3.6 mg every 28 days). The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR) and safety. Prespecified subgroup analyses were performed in pts with and without prior CT for ABC. Results: 47 (14%) pts in each arm had received prior CT for ABC. The most common reason for treatment discontinuation in the RIB vs PBO arm was disease progression (prior CT: 47% vs 55%; no prior CT: 35% vs 51%). Median PFS was increased in the RIB vs PBO arm both in pts with prior CT (16.6 vs 9.0 months; hazard ratio: 0.547; 95% confidence internal [CI]: 0.314–0.954) and without prior CT (24.7 vs 14.5 months; hazard ratio: 0.566; 95% CI: 0.443–0.724). In pts with measurable disease (n = 559), the ORR was 32% vs 27% for those with prior CT (RIB vs PBO arm; P= 0.262) and 54% vs 38% for those with no prior CT (P= 2.90×10–4). Common all-grade adverse events (≥35% of pts in either arm; RIB vs PBO arm) were neutropenia (prior CT: 77% vs 4%; no prior CT: 76% vs 8%), leukopenia (prior CT: 36% vs 4%; no prior CT: 31% vs 6%), and hot flash (prior CT: 23% vs 36%; no prior CT: 36% vs 33%). Conclusions: Although pt numbers were small, those with prior CT had a numerically shorter PFS and lower ORR vs pts with no prior CT. However, consistent treatment benefit with RIB + TAM/NSAI vs PBO + TAM/NSAI was observed in premenopausal pts with HR+, HER2– ABC, regardless of prior CT for ABC. Clinical trial information: NCT02278120.
Effect of silicone oil on the microstructure, gelation and rheological properties of sorbitan monostearate–sesame oil oleogels
Authors: Mya Thet Htar Swe, Panida Asavapichayont
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Oleogels contain oil or a non-polar liquid which is gelled with an agent called an organogelator. The aim of this study was to evaluate the effects of the addition of silicone oil (cyclopentasiloxane) to the gelation process and to the properties of sorbitan monostearate (SMS)-sesame oil oleogel and compared with that of SMS-sesame oil oleogel and SMS-cyclopentasiloxane oleogel. Three different oil phases; sesame oil phase, cyclopentasiloxane phase and a mixture of cyclopentasiloxane and sesame oil, were used to prepare oleogels with SMS gelator. The critical gelling concentrations (CGC) for oleogels were determined using different concentration of SMS in a range of 5%-22% (w/w). The characterization of the developed oleogels was done using Fourier transform infrared spectroscopy (FTIR), polarized light microscope, rheometer, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The addition of cyclopentasiloxane reduced the CGC of SMS-sesame oil oleogel from 20% to 10% (w/w). In microscopic characterization, the oleogels with a mixture of oil phases showed the longer and thicker three-dimensional gel network than that of oleogels with sesame oil and cyclopentasiloxane. FTIR studies demonstrated that this network formation was mainly due to hydrogen bonding. Rheological measurements revealed that the combination of cyclopentasiloxane and sesame oil produced strong gel with higher complex modulus values and longer linear viscoelastic region than oleogels prepared with sesame oil and cyclopentasiloxane. In addition, oleogels with the combination of the two oils had higher enthalpy (ΔH m) and entropy (ΔS m) thus could increase thermodynamic stability of the oleogels. Therefore, the addition of cyclopentasiloxane can improve the physical, thermal properties and stability of SMS-sesame oil oleogel, provide greater sensory profile and better product aesthetics. The developed oleogel can be a novel carrier for topical drug delivery.
Duration of extended adjuvant therapy with neratinib in early-stage HER2+ breast cancer after trastuzumab-based therapy: Exploratory analyses from the phase III ExteNET trial.
Authors: Michael Gnant, Hiroji Iwata, Anna Elizabeth Bashford, Robert Separovic, Adolfo Murias, Elena Vicente, Julie Ann Means-Powell, Ingrid A. Mayer, Francis Mark Senecal, Rina Hui, Richard H. De Boer, Joanne Chiu, Anne Armstrong, Amparo Ruiz, Richard Bryce, Yining Ye, Arlene Chan
Journal: Journal of Clinical Oncology (2018)

524 Background: The optimal duration of adjuvant therapy with targeted agents remains a question of ongoing relevance in oncology. ExteNET, an international, randomized, placebo-controlled phase III trial, showed that neratinib given for 12 months after trastuzumab-based therapy significantly improved 2- (HR 0.67, p = 0.009) and 5-year (HR 0.73, p = 0.008) invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer [Chan et al. Lancet Oncol 2016; Martin et al. Lancet Oncol 2017]. We examined the influence of duration of neratinib therapy on efficacy in the ExteNET study. Methods: Patients with early-stage HER2+ breast cancer were randomly assigned to oral neratinib 240 mg/day or placebo for 12 months (or until disease recurrence) after standard primary therapy and trastuzumab-based (neo)adjuvant therapy. Patients who received neratinib for ≤3 or ≥11 months (the median duration of neratinib treatment) were each compared with the ITT placebo group. iDFS (primary endpoint) was analyzed using Kaplan-Meier methods and Cox proportional-hazards models adjusted for prognostic factors. Data cut-off: March 1, 2017. Clinicaltrials.gov: NCT00878709. Results: ITT population comprised 2840 patients (neratinib, n = 1420; placebo, n = 1420). Median treatment duration (ITT population) was 11.6 and 11.8 months in the neratinib and placebo groups, respectively. 391 patients received neratinib for ≤3 months. 872 patients received neratinib for ≥11 months or stopped treatment prior to 11 months due to recurrence. Results after a median of 5.2 years' follow-up are shown below. Conclusions: These exploratory data suggest that patients who remained on neratinib for ≥11 months derived clear benefits from therapy, whereas neratinib efficacy was considerably reduced in those who stopped treatment early (≤3 months).Clinical trial information: NCT00878709.Duration of neratinib N 5-year iDFS rate, % HR (95% CI) Neratinib Placebo ≤3 months 1811 88.4 87.7 0.90 (0.59–1.32) ≥11 months 2292a 91.0 87.7 0.67 (0.50–0.88) ITT 2840 90.2 87.7 0.73 (0.57–0.92)b a14 patients stopped treatment before 11 months due to recurrence.bAdjusted for stratification factors.
Conditional Toxicity Value (CTV) Predictor: An <i>In Silico</i> Approach for Generating Quantitative Risk Estimates for Chemicals
Authors: Jessica A. Wignall, Eugene Muratov, Alexander Sedykh, Kathryn Z. Guyton, Alexander Tropsha, Ivan Rusyn, Weihsueh A. Chiu
Journal: Environmental Health Perspectives (2018)

Background: Human health assessments synthesize human, animal, and mechanistic data to produce toxicity values that are key inputs to risk-based decision making. Traditional assessments are data-, time-, and resource-intensive, and they cannot be developed for most environmental chemicals owing to a lack of appropriate data. Objectives: As recommended by the National Research Council, we propose a solution for predicting toxicity values for data-poor chemicals through development of quantitative structure–activity relationship (QSAR) models. Methods: We used a comprehensive database of chemicals with existing regulatory toxicity values from U.S. federal and state agencies to develop quantitative QSAR models. We compared QSAR-based model predictions to those based on high-throughput screening (HTS) assays. Results: QSAR models for noncancer threshold-based values and cancer slope factors had cross-validation-based Q2 of 0.25–0.45, mean model errors of 0.70–1.11 log10 units, and applicability domains covering >80% of environmental chemicals. Toxicity values predicted from QSAR models developed in this study were more accurate and precise than those based on HTS assays or mean-based predictions. A publicly accessible web interface to make predictions for any chemical of interest is available at http://toxvalue.org. Conclusions: An in silico tool that can predict toxicity values with an uncertainty of an order of magnitude or less can be used to quickly and quantitatively assess risks of environmental chemicals when traditional toxicity data or human health assessments are unavailable. This tool can fill a critical gap in the risk assessment and management of data-poor chemicals. https://doi.org/10.1289/EHP2998