tbuckley/cabot-search huggingface dataset:
Abstract P011: Hypoglycemia Unawareness is Associated With Impaired Cognition Among Older Adults With Type 1 Diabetes: the Study of Longevity in Diabetes
Authors: Mary E Lacy, Paola Gilsanz, Michal Schnaider-Beeri, Andrew J Karter, Charles P Quesenberry, Rachel A Whitmer
Journal: Circulation (2019)

Introduction: Severe hypoglycemia is common among those with type 1 diabetes (T1D). Hypoglycemia unawareness (HU) in T1D increases the risk of severe hypoglycemia more than five-fold. Prior work has established an association between severe hypoglycemia and impaired cognition. However, it is unknown if HU is associated with impaired cognition. Hypothesis: We hypothesized that HU would be associated with impaired cognition in a large cohort of older adults with T1D. Methods: We examined the association between HU and cognitive function using baseline data collected on 544 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Self-reported HU was assessed using the 8-item Clarke Hypoglycemia Awareness Questionnaire, which captures frequency of hypoglycemia and awareness of symptoms. Participants with responses indicating ‘reduced awareness’ on ≥4 of the 8 items were categorized as having reduced awareness. Cognitive tests assessed four cognitive domains identified via factor analysis (language, executive function, episodic memory, attention). All cognitive test scores were standardized. Using generalized linear regression, we examined the association between HU and cognition on each of the four cognitive domains and on global cognition (average of scores on the 4 domains) in models adjusted for age and age, sex, education, race/ethnicity, and diabetes duration. Results: Overall, 27% of participants (n=149) had reduced hypoglycemia awareness. In fully adjusted models, compared to those with normal awareness, those with reduced hypoglycemia awareness had significantly lower scores on measures of language and global cognition; however, executive function, episodic memory and simple attention did not differ by HU status. Conclusions: Our results suggest that, among older adults with type 1 diabetes, HU may be associated with poorer cognition, specifically through language-related processes.
The Cancer Genome Atlas Expression Subtypes Stratify Response to Checkpoint Inhibition in Advanced Urothelial Cancer and Identify a Subset of Patients with High Survival Probability
Authors: Jaegil Kim, David Kwiatkowski, David J. McConkey, Joshua J. Meeks, Samuel S. Freeman, Joaquim Bellmunt, Gad Getz, Seth P. Lerner
Journal: European Urology (2019)
Aspirin Use and Risk of Hepatocellular Carcinoma in Hepatitis B
Authors: Rena K. Fox, Tamar H. Taddei, David E. Kaplan
Journal: JAMA Internal Medicine (2019)

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German health service research with the focus on effectiveness of secondary-antiandrogen deprivation therapy (s-ADT) in prostate cancer patients with buserelin in daily practice.
Authors: Gerson Luedecke, Goetz Geiges, Matthias Schulze, Monica Lange
Journal: Journal of Clinical Oncology (2019)

291 Background: Aim of the health service research was to answer the questions: 1.) Is the s-ADT with buserelin a successful therapy perspective in biochemical progressive PCA patients after any ADT therapy performed prior? 2.) What is the response rate over all and with a PSA decline more than 50% from the starting level? Methods: In a time period of 2.5 years (2013-2016) a study collective of 1233 PCA patients was treated with buserelin of which 355 got a s-ADT therapy after biochemical progress. In follow-up controls the effectiveness was proven in respect to PSA decline after 6 and 12 months. Results: The cohort of 355 men had an age of 77.3 years with a risk distribution of 26.2% low risk, 33% intermediate and 40.8% high risk PCA. The initial PSA level before ADT change ranged from &lt; 0.4 up to &gt; 1000 ng/ml. Therapy effects over 12 month: 17.7% stayed unchanged, 49.7% progressed, 32.7% remitted and 23.8% declined in PSA more than 50% (effective). During the 12 month of follow-up 7.5% showed an initial PSA flair with a following remission, 15.6% an initial remission switching to progression. The PSA progression varied from 10 to 5229% increase and 40% had a PSA increase of more than 100% over 12 month. Conclusions: The s-ADT manipulation by buserelin after any prior ADT therapy induced in 33% over 1 year a positive PSA response and over all in 24% an effective PSA remission ( &gt; 50% PSA decline) over 1 year. On the other hand 50% of the patients will progress with buserelin in s-ADT. The decision if s-ADT will succeed can be maid after 6 month of therapy with buserelin until a treatment change must be decided. Today, in respect to the early onset of abiraterone and docetaxcel in PCA management since 2017 the value of s-ADT must be discussed critically and again re-evaluated.
Retrospective study of BRAF-mutant metastatic colorectal cancer patients and influence of the mismatch repair efficiency.
Authors: Laetitia Mais, Matthieu Sarrabi, Françoise Desseigne, Pierre Guibert, Christine Castillo, Margaux Foulfoin, Andy Karabajakian, Christelle De La Fouchardiere
Journal: Journal of Clinical Oncology (2015)

e14677 Background: BRAF V600E mutations are rare in colorectal cancers, being present in less than 10% of the cases. The prognosis of BRAF mutant tumors seems heterogeneous but usually poor, especially when associated with proficient mismatch repair (MMR). Until now, this heterogeneity is not exactly explained. Methods: This is a retrospective study of BRAF-mutant metastatic colorectal cancer patients. We analyzed first 24 patients treated in Lyon (Centre Leon Berard) between May 2004 and November 2014 and secondly enlarged our study with patients from other French centers (results will be presented at the ASCO meeting). We analyzed the overall survival as first clinical endpoint. Results: 24 patients (16 women; 8 men) constituted our first cohort at our center. Median age was 64.3 years. Primitive tumor was localized in the right colon in 13 patients (54%). 23 patients had BRAF mutation V600E, and one had an exon 15 (pG596R) mutation. 20% (4) of the BRAF mutant tumors exhibited deficient MMR (microsatellite instable tumors) (exclusively in the right colon) whereas 16 patients (66.7%) had proficient MMR tumors. We don’t have yet the status for 4 patients. Almost every patient received chemotherapy (between 1 to 7 lines) and only one had a BRAF specific treatment (Vemurafenib) without any tumor response (stable disease). The median overall survival of the entire population was 22.6 months. Conclusions: Despite their pejorative signification, BRAF mutations are sometimes associated with long survival in some metastatic patients, independently of their association with mismatch repair (MMR) efficiency. This heterogeneity may be explained by other associated mutations and will be investigated. Final results will be presented during the meeting.
TALAPRO-2: Part 2 (P2) of the placebo-controlled phase 3 study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Neeraj Agarwal, Neal D. Shore, Curtis Dunshee, Lawrence Ivan Karsh, Beth Sullivan, Nicola Di Santo, Mohamed Elmeliegy, Xun Lin, Ruben G.W. Quek, Akos Gabor Czibere, Karim Fizazi
Journal: Journal of Clinical Oncology (2019)

TPS5092 Background: ENZA is approved to treat men with CRPC. TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. A combination of TALA with ENZA in mCRPC may improve clinical outcomes. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate the efficacy, safety, pharmacokinetics and (patient) pt-reported outcomes of the combination treatment. The focus here is on P2 of TALAPRO-2. Methods: Approximately 860 pts are planned to be enrolled in P2 from multinational sites. Pts are aged ≥18 years, have asymptomatic/mildly symptomatic mCRPC, Eastern Cooperative Oncology Group performance status ≤1, no brain metastases, and have not received taxanes/novel hormonal therapy (NHT). P2 is a randomized double-blind study that will evaluate safety, efficacy, and pt-reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Pts will be randomized to 1 of 2 treatment groups: TALA + ENZA, or matching placebo + ENZA. Randomization will be stratified by prior treatment with NHT for castration-sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no) and DDR mutation status (deficient vs. nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8-12 weeks thereafter. The analyses of rPFS will be compared between TALA in combination with ENZA and placebo in combination with ENZA by using a 1-sided stratified log-rank test. OS will be evaluated separately in the all comers and the DDR-deficient populations. Pt recruitment is ongoing. Results: n/a. Conclusions: n/a. Clinical trial information: NCT03395197.
The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting
Authors: Joshua Pan, Zachary M. McKenzie, Andrew R. D’Avino, Nazar Mashtalir, Caleb A. Lareau, Roodolph St. Pierre, Lu Wang, Ali Shilatifard, Cigall Kadoch
Journal: Nature Genetics (2019)
Abstract P413: Association Between High Sensitivity Troponin T and N-Terminal Pro B-Type Natriuretic Peptide and Fall Risk in Older Adult Participants of the Atherosclerosis Risk in Communities Study (ARIC)
Authors: Stephen P Juraschek, Natalie Daya, Lawrence J Appel, Edgar R Miller, Kunihiro Matsushita, Erin D Michos, Beverly G Windham, Christie M Ballantyne, Elizabeth Selvin
Journal: Circulation (2019)

Background: Many health practitioners worry that treating cardiovascular disease (CVD) risk factors (e.g. blood pressure) could contribute to falls in older adults. While prior CVD is a known risk factor for falls, it is unknown whether subclinical measures of myocardial injury and wall stress are related to falls among older adults without known CVD. Hypothesis: Markers of subclinical CVD, i.e. high sensitivity troponin T (hs-cTNT) and N-terminal pro b-type natriuretic peptide (NT-proBNP), are associated with new falls among older adults without known CVD. Methods: We examined the prospective association between hs-cTNT and NT-proBNP assessed at visit 5 (2011-2013) in ARIC participants who did not have a history of coronary heart disease, stroke, or heart failure. Falls were identified from hospital discharge ICD-9 codes or CMS claims. We determined fall incidence rates across the following categories approximating quartiles of hs-cTNT (&lt;8, 8-10, 11-16, ≥17 ng/L) and NT-proBNP (&lt;75, 75-124, 125-274, ≥275 pg/mL) via Poisson models adjusted for age, sex, and race. The relative risk between markers and fall risk was modelled via Cox models adjusted for demographic characteristics and fall risk factors. Results: In 4,303 participants (mean age 76 ± 5 yrs, 63% women, 24% black), there were 429 new falls during a median follow-up of 4.5 years. Incidence rates across categories of hs-cTNT were 10.9, 16.0, 18.9, and 26.5 per 1,000 person-years; and incidence rates across categories of NT-proBNP were 8.1, 15.6, 21.5, and 33.0 per 1,000 person-years. Hs-cTNT ≥17 vs &lt;8 ng/L was significantly associated with a higher risk of falls (adjusted HR 2.22, 95%CI 1.56-3.18). Similarly, NT-proBNP ≥275 vs &lt;75 pg/mL was significantly associated with a higher risk of falls (2.46; 1.72-3.51). Associations with fall risk were curvilinear for both markers ( Figure ). Conclusions: Subclinical CVD was associated with risk of falls in older adults. Further research is needed to delineate mechanisms by which subclinical CVD might contribute to falls.
Abstract P220: Whole Blood Selenium Concentration is Inversely Associated With Prevalence of Stroke: Results From the Canadian Health Measures Survey and the US National Health and Nutrition Examine Survey
Authors: Xue Feng Hu, Saverio Stranges, Hing Man Chan
Journal: Circulation (2019)

Introduction: Each year, over 140,000 Americans and 10,000 Canadians die from stroke. Selenium is an essential trace element involved in antioxidant and anti-inflammatory processes, as well as in intracellular redox regulation and modulation. Observational studies have suggested that Se may have beneficial effects on certain cancer and cardiovascular outcomes. Hypothesis: We assessed the hypothesis that blood selenium concentration might be inversely associated with prevalence of stroke and the relationship between blood selenium and prevalence of stroke would be non-linear. Methods: Adult respondents (aged 20 and over) from the Canadian Health Measures Survey (CHMS 2007-2011, n = 7065) and the US National Health and Nutrition Examination Survey (NHANES 2011-2012, n = 5030) were analyzed. Age, sex, and other major risk factors for stroke were comparable between the two datasets. Whole blood and urinary selenium were measured in the CHMS, whole blood and serum selenium were measured in the NHANES. First, we examined the differences in selenium concentrations by stroke status. Second, we used logistic regressions to investigate the difference in prevalence of stroke by whole blood Se tertiles, adjusting for established risk factors. Third, we quantified the potential non-linear association between Se and stroke by restricted cubic spline regression. Results: A total of 82 (1.16%) and 202 (4.02%) stroke cases were identified in CHMS and NHANES, respectively. Respondents with stroke had lower Se levels comparing with those without stroke, with a mean difference of 16 μg/L in CHMS and 12 μg/L in NHANES, respectively. Respondents with high blood selenium concentration (tertile 3) had a lower prevalence of stroke compared to those with low selenium concentration (tertile 1). The adjusted odds ratios were 0.38 (95% CI: 0.15, 0.92) and 0.57 (95% CI: 0.31, 1.03) for CHMS and NHANES, respectively. A continuous decreasing trend of stroke with whole blood selenium was observed in CHMS, whereas the curve plateaued starting at 190 μg/L for NHANES, based on cubic restricted spline regression. Each 10-μg/L increase in whole blood selenium was associated with a 14% decreased prevalence of stroke in CHMS and 19% in NHANES. Sensitivity analysis using serum and urinary selenium demonstrate that our results were consistent across different selenium biomarkers. Conclusion: We observed inverse cross-sectional associations between whole blood Se and prevalence of stroke in representative samples of the Canadian and the US population.
Impact of prostate specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients.
Authors: Stephen J. Freedland, Krishnan Ramaswamy, Stanislav Lechpammer, Jack Mardekian, Neil M. Schultz, Ahong Huang, Li Wang, Onur Baser, Daniel J. George
Journal: Journal of Clinical Oncology (2019)

211 Background: Prostate-Specific Antigen Doubling Time (PSADT) can help predict prostate cancer (PC) patient outcomes, particularly in hormone sensitive disease. However, PSADT has not been well validated in non-metastatic castration-resistant (nmCR) PC patients. This study examined the prognostic impact of PSADT on time to metastasis (TTM) and overall survival (OS) among nmCRPC patients in the Veterans Health Administration (VHA) database. Methods: VHA patients in this retrospective study were males with PC who had medical or surgical castration between Jan 1, 2012 and Dec 31, 2016. Patients actively receiving luteinizing hormone-releasing hormone treatment with ≥2 PSA post-castration increases were identified. The 3rd PSA value ≥25% and 2 ng/ml &gt; the 1 st PSA value was the CRPC (index) date; patients had continuous VHA enrollment for ≥12-months pre- to post-index date. Patients were followed until the earliest of death or disenrollment. PSADT was calculated as the natural log of 2 divided (Ln2) by the log slope of PSA using all PSA values after CRPC until metastases, and patients were categorized into 2-month cohorts. A demographically and clinically adjusted Cox regression model explored associations between PSADT cohorts and TTM and OS. Results: We identified 3,579 patients from which 1,389 (38.8%) progressed to mCRPC while 2,190 (61.2%) remained nmCRPC. Overall, patients averaged 73 years of age. PSADT was calculable in 2,800 patients with an average PSA value of 25.49 ng/mL. After a median follow-up of 820 days, the median PSADT was 17 months. Compared with the PSADT &gt; 12 months cohort, PSADT ≤2, &gt; 2 to ≤4, &gt; 4 to ≤6, &gt; 6 to ≤8, and &gt; 8 to ≤10 month cohorts were associated with higher risk of metastasis (hazard ratio [HR]: 33.77, CI: 25.93-43.96; HR: 14.32, CI: 11.83-17.32; HR: 6.58, CI: 5.42-7.98, HR: 4.14, CI: 3.27-5.25; HR: 3.14, CI: 2.45-4.03, respectively) and death (HR: 12.27, CI: 9.20-16.35; HR: 5.32, CI: 4.26-6.64; HR: 3.50, CI: 2.74-4.47, HR: 2.29, CI: 1.68-3.14; HR: 1.64, CI: 1.14-2.37, respectively). Conclusions: Short PSADT strongly associated with TTM and poor OS in nmCRPC patients. Newer nmCRPC treatments are advisable for high-risk patients.
Comparison of metachronous epithelial ovarian carcinomas.
Authors: David Arguello, Courtney D. Ackerman, Sandeep K. Reddy, Zoran Gatalica, Scott Daniel Richard
Journal: Journal of Clinical Oncology (2015)

5545 Background: Epithelial ovarian carcinoma (EOC) is a relatively common malignancy with high, initial response rates to standard chemotherapy but frequent relapses. Next-generation sequencing (NGS) is a promising technology with the potential to alter how this disease is managed. However, much remains unknown regarding its applicability in ovarian carcinomas. The purpose of this study is to compare metachronous epithelial ovarian carcinoma specimens arising from different sites in an attempt to better understand how to apply NGS in the management of this disease. Methods: A retrospective analysis of sequencing results for 83 metachronous (defined as specimens collected greater than 28 days apart) EOC specimens was performed. In most instances, comparisons involved two different metastatic sites (n = 50), while the rest involved a comparison of the primary and a subsequent metastatic specimen (n = 33). All specimens had up to 47 genes analyzed using the Illumina MiSeq NGS platform. Tumors were sequenced to a depth of 1500x, enabling the detection of mutations down to 10% variant frequency. Results: Metachronous paired specimens were collected from 43 to 2793 days apart (mean = 519). Mutations were detected in 23 different genes (48.9%, 23/47). A majority (56.6%, 47/83) shared just one mutation, with TP53 being the most common (59.0%, 49/83). Only twelve paired specimens had disagreement in gene results and all of these disagreed in only one gene. A change from wild type to mutated status was found in APC (I1307K, I1317K), BRAF (I463T), PIK3CA (E542K), PTPN11 (G503V), SMO (S342F), and TP53 (G245S, R248Q, R282W). Meanwhile, a reversion from mutated status to wild type was detected in APC (E1317Q, A1474T) and NOTCH1 (R1568K). Overall, 85.5% (71/83) of paired samples showed complete agreement. Conclusions: This metachronous paired analysis indicates that, at least utilizing this 47-gene panel, a majority of patients with EOC showed no change in their molecular profile, regardless of where the metastatic lesion was located. Utilizing NGS argues for a more comprehensive approach to EOC therapy, and to obtain the most therapeutic options in this disease. These findings, and their clinical impact, should be validated in further studies.
Clinical events associated with cumulative corticosteroid use in patients with castration-resistant prostate cancer: An administrative claims analysis.
Authors: Benjamin H Lowentritt, David F. Penson, Samuel C. Wilson, Yan Song, Hongbo Yang, Krishnan Ramaswamy, Neil M. Schultz
Journal: Journal of Clinical Oncology (2019)

236 Background: Corticosteroids (CSs) are used in the treatment of castration-resistant prostate cancer (CRPC) to manage adverse events and tumor-related symptoms. This study evaluated the impact of cumulative CS use on the risk of developing specific clinical events in men with CRPC. Methods: Adult chemotherapy-naïve patients who initiated a CRPC treatment following surgical or medical castration were identified from the MarketScan database (2007–2016). Patients were grouped into 4 cohorts based on their cumulative CS dose since 1 year before initiating their CRPC treatment: no use (0 g); low use ( &lt; 0.5 g); medium use (0.5–2.0 g); and high use ( &gt; 2.0 g). Time-dependent Cox proportional hazards models adjusting for baseline characteristics were used to evaluate the association between CS use and the risk of events (fracture, infection, endocrine disorders, acute cardiovascular [CV] events, peptic ulcer, and mental health conditions), with no CS use as the reference group. Results: This study included 9425 patients: 6765 no CS use; 1660 low use; 655 medium use; and 345 high use. On average, the no-CS-use cohort was older and had a lower comorbidity burden than the other 3 cohorts. During the study period, cumulative CS exposure (across all categories) was associated with a significantly higher risk of developing an infection (comparing high-use vs. no-use cohort, adjusted hazard ratio [HR] = 2.55; p for trend &lt; 0.001), fracture (HR = 1.59; p for trend &lt; 0.001), and acute CV events (HR = 1.62; p for trend &lt; 0.001). Also, patients in the high-CS-use cohort were more likely to develop endocrine disorder (HR = 1.61; p for trend &lt; 0.001), peptic ulcer (HR = 1.91; p for trend &lt; 0.001), or mental health condition (HR = 1.28; p for trend = 0.014) in comparison with patients in the no-use cohort. Conclusions: Cumulative CS exposure was associated with a greater risk of clinical events such as infection, fracture, and acute CV events among men with CRPC. The risk was more pronounced with higher cumulative CS doses of &gt; 2.0 g. The study provides important data on the impacts of cumulative CS use on the risk of clinical events among CRPC patients who tend to be older and more prone to these events.