tbuckley/cabot-search huggingface dataset:
Detecting predictive androgen receptor modifications in circulating prostate cancer cells.
Authors: Julie Steinestel, Manuel Luedeke, Annette Arndt, Thomas Schnoeller, Jochen K Lennerz, Christiane Maier, Marcus Cronauer, Konrad Steinestel, Martin Boegemann, Andres Jan Schrader
Journal: Journal of Clinical Oncology (2015)

5067 Background: Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) and chemotherapy in prostate cancer patients. When resistance to therapy ensues, lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications and some patients may thus receive ineffective therapy. Methods: We devised a single-tube assay to detect the two most common AR-modifications (AR-V7 splice variants and ARpoint mutations) in circulating tumor cells (CTC) using immunomagnetic CTC isolation followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 prostate cancer patients with PSA progression and molecularly uninformed therapy switch. Comparison of newly administered therapy and CTC-AR-status allowed effect size estimation. Results: Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Specifically, 17 patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We found a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. We estimated the overall benefit from molecularly informed therapy switch by subtracting the molecularly uninformed (31%) and the AR-status unmatched (6%) response rates from the AR-status matched response rate (72%). Thus, for prospective clinical trial planning our data suggest an estimated effect size of ~33%. Conclusions: In summary, the ability to detect key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.
Predictive biomarker analysis of early tumor shrinkage induced by FOLFIRI+Bev for patients with metastatic colorectal cancer in WJOG4407G study.
Authors: Yasushi Tsuji, Kentaro Yamazaki, Mari Saito Oba, Kazuko Sakai, Michitaka Nagase, Shinya Ueda, Hiroshi Tamagawa, Takao Tamura, Toshikazu Moriwaki, Kohei Murata, Koichi Taira, Tadamichi Denda, Sadao Funai, Takashi Tsuda, Takahiro Tsushima, Narikazu Boku, Ichinosuke Hyodo, Takeharu Yamanaka, Junji Tsurutani, Kazuto Nishio
Journal: Journal of Clinical Oncology (2015)

e14616 Background: The WJOG4407G study was a randomized, open-label, phase III trial. Patients with previously untreated metastatic colorectal cancer (mCRC) were randomized to receive either mFOLFOX6+Bevacizumab (Bev) or FOLFIRI+Bev. We previously reported FOLFIRI+Bev was non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC (Yamazaki et al. ASCO2014). In addition, early tumor shrinkage (ETS) has been reported as an important predictor of favorable outcomes in patients with mCRC receiving 1st-line chemotherapy. Here, we report the results of preplanned tumor gene expression analysis to identify predictive markers that are associated with patients’ outcome including ETS. Methods: Tumor samples were obtained from the 168 patients. Expression of the 44 genes related with chemosensitivity and angiogenesis in manual dissected FFPE tumor samples were measured by MassArray. Expression levels of each gene were dichotomized at its median. Results: For interaction test, a p-value of less than 0.10 was considered to be statistically significant and was used for this study. ERCC6, CES1, and XRCC3 showed the moderate association with ETS (30% reduction at 8 weeks) by multivariate logistic regression analysis including treatment arm, gene expression, age, sex and arm-gene interaction term; ERCC6, interaction p = 0.062; CES1, p = 0.080, and XRCC3, p = 0.038. While the patients with high CES1 tumor showed the 39% and 55% (p = 0.165) ETS by mFOLFOX6+Bev and by FOLFIRI+Bev, those with low CES1 tumor showed 45% and 34% (p = 0.302), respectively. Furthermore, patients with higher CES1 level showed favorable prognosis (OS) than those with lower CES1 level in FOLFIRI+Bev (40.25 vs 31.28m, p = 0.354) but not in mFOLFOX6+Bev (35.45 vs 29.96m, p = 0.913), although these are not statistically significant. Conclusions: It is hypothesized that high CES1 expression enhances the efficacy of irinotecan containing regimen, because CES1 converts irinotecan to its active form SN-38 in tumor (Cancer Res. 52:328, 1992). High CES1 gene expression in tumor could be a predictive biomarker for ETS by FOLFIRI+Bev and may define patient subset that would benefit from FOLFIRI+Bev. Clinical trial information: UMIN000001396.
IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses <i>In Vivo</i>
Authors: Alison J. Harris, Ananda S. Mirchandani, Ruairi W. Lynch, Fiona Murphy, Liam Delaney, Donna Small, Patricia Coelho, Emily R. Watts, Pranvera Sadiku, David Griffith, Rebecca S. Dickinson, Eilidh Clark, Joseph A. Willson, Tyler Morrison, Massimilliano Mazzone, Peter Carmeliet, Bart Ghesquiere, Cecilia O’Kane, Danny McAuley, Steve J. Jenkins, Moira K. B. Whyte, Sarah R. Walmsley
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.
Abstract P416: Objectively Measured Snoring is Not Associated With Maladaptive Arterial Remodeling in Overweight and Obese Adults
Authors: Christy Taylor, Christopher Kline, Chunzhe Duan, Emma Barinas-Mitchell
Journal: Circulation (2019)

Introduction: We previously reported that snoring severity was related to carotid arterial remodeling as characterized by wider inter-adventitial diameter (IAD) and greater intima-media thickness (IMT) in overweight and obese adults without obstructive sleep apnea (OSA). Considered to be an adaptive mechanism to maintain circumferential wall and shear stress homeostasis and a natural process in the setting of aging, early arterial remodeling is associated with cardiovascular morbidity and mortality. Elevations in arterial circumferential wall tension (CWT) and stress (CWS) in the setting of this compensatory arterial remodeling is considered maladaptive. We aimed to examine the association between snoring severity and CWT and CWS in adults with or without OSA. Methods: Cross-sectional analyses were conducted using 24-month follow up data from the Slow Adverse Vascular Effects lifestyle intervention study. The original population consisted of 349 overweight/obese (BMI 25-40 kg/m 2 ) adults aged 20-45 years old without hypertension or diabetes. The snoring index (SI) and oxygen desaturation index (ODI) were measured by the ResMed ApneaLink device among 122 participants. Snoring/OSA was categorized into three groups: OSA (ODI≥5; n=41), heavy snoring (ODI&lt;5, ≥median SI; n=40), and low snoring (ODI&lt;5, below-median SI; n=41). B-mode carotid ultrasound was used to measure end-diastole mean common carotid artery (CCA) IMT and lumen diameter (LD). Mean CWT (kPa*mm) and CWS (kPa) were calculated using Laplace’s law: CWT=MAP*(LD/2) and CWS= CWT/IMT; CCA wall to lumen ratio (WLR) = IMT/ LD. We used multiple linear regression to assess the association between snoring/OSA categories and CWT, CWS, and WLR adjusting for intervention group, age, sex, race, pulse pressure, BMI, non-HDL cholesterol, and fasting glucose, . Results: Participants were, on average, 40.1 ± 5.9 years old with a BMI of 31.6 ± 4.4 kg/m 2 ; 76.2% were women and 82% were white. Most CVD risk factors differed across snoring/OSA categories, including age, BMI, lipids, and fasting glucose, with risk factors worse in the OSA and heavy snoring groups compared to the low snoring group (all p &lt;0.05). In unadjusted analyses, CWT was higher in both heavy snoring (32.71 ± 4.74) and OSA (33.74 ± 5.09) groups compared to the low snoring group (29.94 ± 4.51; all p&lt;0.01). Differences were also noted in WLR between the low snoring and OSA groups (0.11 ± 0.01 vs. 0.12 ± 0.02; p&lt;0.05). Between-group differences in CWT were attenuated (p=0.09) and eliminated in WLR after multivariable adjustment. Differences in CWS across snoring/OSA categories were not observed. Conclusion: Our findings suggest that, in overweight and obese young to middle-aged adults without hypertension or diabetes, objectively measured snoring may not be associated with maladaptive arterial remodeling after accounting for traditional CVD risk factors.
Case 8-2019: A 58-Year-Old Woman with Vision Loss, Headaches, and Oral Ulcers
Authors: James T. Rosenbaum, Lana M. Rifkin, Karen A. Buch, Miriam B. Barshak, Mai P. Hoang
Journal: New England Journal of Medicine (2019)

A 58-year-old woman presented with vision loss, headaches, and rashes. Imaging of the head revealed no acute intracranial or intraocular abnormalities. CSF analysis revealed a total protein level of 160 mg per deciliter and a nucleated-cell count of 64 per cubic millimeter. Diagnostic test results were received.
Docetaxel, 5FU, oxaliplatin (TEFOX) in 1st line treatment of signet ring cell and/or poorly differentiated gastric adenocarcinoma: a retrospective study of AGEO.
Authors: Simon Pernot, Olivier Dubreuil, David Tougeron, Damien Soudan, Jean Baptiste Bachet, Céline Lepère, Karine Le Malicot, Julien Taieb, Philippe Rougier
Journal: Journal of Clinical Oncology (2015)

e15048 Background: Docetaxel, 5FU and oxaliplatin (TEFOX) in 1st line treatment (trt) of advanced gastric cancer has shown high response rate (Pernot et al, Gastric Cancer 2014; Van Cutsem et al, Ann Oncol 2014), progression-free survival (PFS) and overall survival (OS), and seems better tolerated than Docetaxel-cisplatin-5FU. TEFOX could have even more interest in poor prognosis type, including signet ring cell carcinoma (SRCC), linitis and poorly differentiated adenocarcinomas (PDA), wich are deemed drug-resistant. Methods: We retrospectively analyzed data of all consecutive patients (pts) with advanced SRCC (>50%) or PDA, treated with TEFOX in 1st line trt in 4 French centers between 2008 and 2014. TEFOX combined docetaxel (50 mg / m2), oxaliplatin (85 mg / m2) on day 1, and 5FU continuous infusion (2400 mg / m2) for 46h, every 14 days. The primary endpoint was objective response rate (ORR) in RECIST. Results: Forty-five pts were included (mean 53 years (33-74)) with PDA (13) or SRCC (32), including 11 linitis. Thirty-nine pts had metastatic disease and 6 locally advanced. They received a median number of 7 cycles (1-16). ORR in intention to treat is presented in Table. Within 11 pts with linits, 9 had an Objective response with 2 complete response. The median PFS and OS were respectively 6.9 months [95% CI: 5.6; 11.3] and 11.3 months [95% CI: 6.5; 14.6]. No toxic deaths occured and 48% of pts experienced grade 3-4 toxicity (neuropathy: 22%; neutropenia: 15%, febrile neutropenia 2% vomiting 8.9 %). TEFOX allowed a secondary curative surgery in 27% of cases, R0 in 67% (liver resection: 1; intraperitoneal hyperthermic chemotherapy: 3; Gastrectomy: 6; Gastrectomy + lymph node irradiation: 2). Conclusions: TEFOX is effective in 1st line trt in pts with advanced SRCC/PDA, with an manageable toxicity profile, in forms of poor prognosis and should be specifically evaluated in a prospective trial. In addition, it allowed a secondary resection in 27% of pts, initially unresectable. N % IC 95% OR (CR) 32 (3) 71 (7) 55.7; 83.6 SD 5 11 PD 6 13 NE 2 4 CR: Complete Response; OR: Objective response; SD: Stable Disease; PD: Progressive Disease; NE: Non Evaluable.
Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy: results from a systematic literature review and modelling study
Authors: Matshediso C. Mokoka, Melissa J. McDonnell, Elaine MacHale, Breda Cushen, Fiona Boland, Sarah Cormican, Christina Doherty, Frank Doyle, Richard W. Costello, Garrett Greene
Journal: European Respiratory Journal (2019)

Adherence to inhaled maintenance therapy in severe asthma is rarely adequately assessed, and its influence on trial outcomes is unknown. We systematically determined how adherence to maintenance therapy is assessed in clinical trials of “add-on” therapy for severe asthma. We model the improvement in trial power that could be achieved by accurately assessing adherence. A systematic search of six major databases identified randomised trials of add-on therapy for severe asthma. The relationship between measuring adherence and study outcomes was assessed. An estimate of potential improvements in statistical power and sample size was derived using digitally recorded adherence trial data. 87 randomised controlled trials enrolling 22 173 participants were included. Adherence assessment was not reported in 67 trials (n=13 931, 63%). Studies that reported adherence used a range of self-report and subjective methods. None of the studies employed an objective assessment of adherence. Studies that reported adherence had a significantly reduced pooled variance in forced expiratory volume in 1 s (FEV 1 ) compared to those that did not assess adherence: s 2 =0.144 L 2 versus s 2 =0.168 L 2 , p&lt;0.0001. Power to detect clinically relevant changes in FEV 1 was significantly higher in trials that reported adherence assessment (mean power achieved 59% versus 49%). Modelling suggests that up to 50% of variance in FEV 1 outcomes is attributable to undetected variations in adherence. Controlling for such variations could potentially halve the required sample size. Few trials of add-on therapy monitor adherence to maintenance inhaled therapy, resulting in a greater variance in trial outcomes and inadequate power for determining efficacy.
Dual Receipt of Prescription Opioids From the Department of Veterans Affairs and Medicare Part D and Prescription Opioid Overdose Death Among Veterans
Authors: Patience Moyo, Xinhua Zhao, Carolyn T. Thorpe, Joshua M. Thorpe, Florentina E. Sileanu, John P. Cashy, Jennifer A. Hale, Maria K. Mor, Thomas R. Radomski, Julie M. Donohue, Leslie R.M. Hausmann, Joseph T. Hanlon, Chester B. Good, Michael J. Fine, Walid F. Gellad
Journal: Annals of Internal Medicine (2019)

Background: More than half of enrollees in the U.S. Department of Veterans Affairs (VA) are also covered by Medicare and can choose to receive their prescriptions from VA or from Medicare-participating providers. Such dual-system care may lead to unsafe opioid use if providers in these 2 systems do not coordinate care or if prescription use is not tracked between systems. Objective: To evaluate the association between dual-system opioid prescribing and death from prescription opioid overdose. Design: Nested case–control study. Setting: VA and Medicare Part D. Participants: Case and control patients were identified from all veterans enrolled in both VA and Part D who filled at least 1 opioid prescription from either system. The 215 case patients who died of a prescription opioid overdose in 2012 or 2013 were matched (up to 1:4) with 833 living control patients on the basis of date of death (that is, index date), using age, sex, race/ethnicity, disability, enrollment in Medicaid or low-income subsidies, managed care enrollment, region and rurality of residence, and a medication-based measure of comorbid conditions. Measurements: The exposure was the source of opioid prescriptions within 6 months of the index date, categorized as VA only, Part D only, or VA and Part D (that is, dual use). The outcome was unintentional or undetermined-intent death from prescription opioid overdose, identified from the National Death Index. The association between this outcome and source of opioid prescriptions was estimated using conditional logistic regression with adjustment for age, marital status, prescription drug monitoring programs, and use of other medications. Results: Among case patients, the mean age was 57.3 years (SD, 9.1), 194 (90%) were male, and 181 (84%) were non-Hispanic white. Overall, 60 case patients (28%) and 117 control patients (14%) received dual opioid prescriptions. Dual users had significantly higher odds of death from prescription opioid overdose than those who received opioids from VA only (odds ratio [OR], 3.53 [95% CI, 2.17 to 5.75]; P < 0.001) or Part D only (OR, 1.83 [CI, 1.20 to 2.77]; P = 0.005). Limitation: Data are from 2012 to 2013 and cannot capture prescriptions obtained outside the VA or Medicare Part D systems. Conclusion: Among veterans enrolled in VA and Part D, dual use of opioid prescriptions was independently associated with death from prescription opioid overdose. This risk factor for fatal overdose among veterans underscores the importance of care coordination across health care systems to improve opioid prescribing safety. Primary Funding Source: U.S. Department of Veterans Affairs.
Abstract MP32: Mid-Life Fitness and Plasma Markers of Alzheimer’s Pathology
Authors: Mini E Jacob, Adrienne O’Donnell, Claudia Satizabal, Matthew Pase, Joanne Murabito, Alexa Beiser, Sudha Seshadri
Journal: Circulation (2019)

Introduction: Motor function in older adults is known to correlate with neurodegenerative changes and Alzheimer’s Disease (AD) pathology in the brain, however the relationship between mid-life fitness and AD pathology is unknown. AD pathology accumulates early and is difficult to measure; precise estimation requires brain imaging not accessible beyond research settings. Plasma Amyloid and Tau, on the other hand are easy to measure, and are markers of AD pathology and neuronal loss. We tested the association between physical fitness measures in mid-life (gait speed, grip strength and chair stand speed) and plasma markers of AD in the Framingham Heart Study (FHS) Offspring cohort. If these measures correlate with and predict plasma measures of AD burden, these could potentially be used to screen for risk of dementia. Hypothesis: We hypothesized that superior physical fitness will be cross-sectionally associated with higher plasma Amyloid Aβ42 and lower Tau; also, that physical fitness measures will be longitudinally associated with Tau measured at a later exam. Methods: The FHS Offspring cohort had plasma Aβ40 and Aβ42 measured at their 7th clinic exam (1998-01) and plasma total Tau measured at Exam 8 (2005-08). They had grip strength, gait speed and chair stand speed measured at Exam 7, and grip strength and gait speed measured at Exam 8. Grip strength was measured using the Jamar dynamometer, fast gait speed was measured over a 4-meter walkway and chair stand speed was assessed by asking the participants to stand up and down five times, as quickly as they can with their hands folded across their chest. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and tau using Single Molecule Array technology.We used linear regression models to examine the association between physical fitness measures and plasma markers of AD adjusting for known confounders (diabetes, cardiovascular disease, atrial fibrillation, smoking, APOE4, systolic blood pressure, waist-to-hip ratio, total cholesterol level, physical activity index, and plasma homocysteine). Results: In this sample of 1886 community living adults (mean age 61, 54% women), hand grip strength was independently associated with plasma Aβ40 (Beta coefficient -0.28; SD 0.10; p value 0.003) and plasma Tau measured 5 years later (Beta coefficient -0.003; SD 0.001; p value 0.001). Gait speed and chair stand speed demonstrated associations with Aβ40 and total Tau which were attenuated by vascular risk factors. Conclusions: Hand grip strength is associated with AD pathology. Grip strength measurement could be a valid screening tool for identifying individuals at a higher risk for AD alongside other validated markers. Future research should examine the correlation between grip strength and AD burden measured by PET imaging.
Assessing the real-world (RW) efficacy and toxicity of docetaxel (D) for the treatment of metastatic castrate sensitive prostate cancer (mCSPC): A single institution experience.
Authors: Seanthel Delos Santos, Cameron Phillips, Urban Emmenegger
Journal: Journal of Clinical Oncology (2019)

270 Background: While D has been shown to prolong survival and improve quality of life in men with mCSPC in clinical trial settings, less is known about its effectiveness in the RW setting. Furthermore, it is uncertain whether the timing of D affects toxicity and outcome. We aimed to identify effectiveness and toxicity outcomes as well as patient (pt) characteristics and prescribing patterns at our institution. Methods: In this retrospective chart analysis, we identified 70 pts with mCSPC who were treated with D between June 2014 and September 2018 at an academic cancer centre in Toronto. The main outcomes studied included time to castrate resistance (TCR), change in PSA, number of cycles completed, and rates of febrile neutropenia (FN). We also analyzed pt subgroups including pts starting D &lt;50 days after the start of androgen deprivation therapy (ADT) versus those starting &gt;50 days after ADT initiation. Results: The median age of our pts was 69 (IQR: 64-74). The median follow-up time was 598 days. 79% of pts had high volume disease per CHAARTED criteria, 73% had de novo metastatic disease and 85% had bone-only disease. The median TCR from the start of ADT was 12.3 months. The median change in PSA from pre-ADT to post-D nadir was 99%. The mean D dose intensity was 86% of the ideal dose and 91% of pts completed all 6 cycles of D. 11% of pts were diagnosed with FN during treatment. 6% of pts required treatment delays and 19% required toxicity-related dose reductions. Subgroup analysis showed that patients (n=41) who received D &gt;50 days from the start of ADT did not have significant differences in TCR, rates of FN, need for a decrease in dose intensity or treatment delays compared to those starting &lt;50 days after ADT (n=29). Conclusions: D can be delivered safely in RW pts, with low rates of FN, however, there is evidence of an efficacy-effectiveness gap with a shorter TCR compared to that observed in CTs. The timing of D (&lt;50 days vs. &gt;50 days) does not appear to have an impact on outcome or toxicity.