tbuckley/cabot-search huggingface dataset:
Alliance A091104: A phase II trial of MK-2206 in patients (pts) with progressive, recurrent/metastatic adenoid cystic carcinoma.
Authors: Alan Loh Ho, Nathan R. Foster, Jeffrey P. Meyers, Shyamprasad Deraje Vasudeva, Nora Katabi, Cristina R. Antonescu, David G. Pfister, Laura E. Horvath, Charles Erlichman, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2015)

6039 Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease with no standard treatments. MYB is an oncogenic driver in ACC that is often overexpressed via a t(6;9) translocation. Based on preclinical data that Akt inhibition with the allosteric inhibitor MK-2206 (Merck) can decrease MYB expression, we conducted this NCI/CTEP, Alliance cooperative group trial of MK-2206 in ACC pts. Methods: Pts with incurable ACC were enrolled. Radiographic or symptomatic progression documented within 6 months (mo) of enrollment was required. MK-2206 150 mg weekly was given; escalation to 200 mg was allowed. Primary endpoint was response (RR); secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 10%; beta = 90%). > 1 response(s) in the first 12 would trigger accrual to 37; > 4 responses would be considered promising. Archival tissues were analyzed for MYB expression and rearrangement. Pre-/post-MK-2206 biopsies were obtained in 5 pts. Results: 16 pts were enrolled (10 F, 6 M). 12 of 16 were escalated to 200 mg. 9 of 16 pts (56%) had a grade 3/4 treatment-related adverse event (rash (38%), fatigue (19%) hyperglycemia (13%)). 14 pts were evaluable for efficacy. Best response included 13 stable disease and one disease progression. PFS at 12 mo was 9.2% (95% CI: 0.6-33.3%); median PFS (mPFS) was 9.2 mo (95% CI: 3.8-11.0). With a median follow-up of 17.1 mo, OS at 12 mo was 77.4% (95% CI: 44.9-92.1%). 12 of 14 tumors had detectable MYB by IHC; 8 of 14 had MYB gene rearrangement by FISH. Analysis of serial biopsies revealed Akt inhibition and MYB downregulation with MK-2206 therapy in 4 of 5 cases. Conclusions: The study was stopped after no PR was observed in the first stage. In this limited sample, the 9.2 mo mPFS may reflect disease stabilization in progressive pts that compares favorably to other ACC trials (axitinib phII: 3 PRs, mPFS 5.7 mo). Correlative tissue analyses provide the first in vivo evidence that clinical Akt inhibition can diminish MYB levels. Future studies should focus on PFS and further elucidate the therapeutic relevance of MYB suppression. (NCI-supported) Clinical trial information: NCT01604772.
Higher HIV Rates in Adolescent Girls Related to Drought in Lesotho
Authors: M.J. Friedrich
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cost implications of multi-parametric magnetic resonance imaging in prostate cancer active surveillance.
Authors: Michelle Yu, Avinash Maganty, Liam C Macleod, Jonathan G Yabes, Mina M Fam, Jathin Bandari, Alessandro Furlan, Robert Turner, Christopher Paul Filson, Benjamin John Davies, Bruce Lee Jacobs
Journal: Journal of Clinical Oncology (2019)

65 Background: Multi-parametric resonance imaging (mpMRI) has emerged to improve disease risk-stratification and decrease number of repeat biopsies in men on prostate cancer active surveillance (AS). However, the impact of mpMRI on cost of AS has not been established. We thus characterize the impact mpMRI on cost of AS in the Medicare population. Methods: Using SEER-Medicare files we identified men ≥66 years old with localized grade group I-II prostate cancer diagnosed 2008-2013. With an established algorithm, we classified men into active surveillance with and without mpMRI. We then determined cost of surveillance in each group using inflation-adjusted Medicare payments for surveillance-related procedures and their sequalae (i.e. PSA tests, prostate biopsies, post-biopsy complications and mpMRIs). Multivariable median regression compared cost and procedural-intensity for men who received mpMRI and those who did not. Results: We identified 9,081 men on AS with median follow up 45 months (IQR 29-64 months). 7,856 (87%) men did not receive mpMRI and 1,225 (13%) did. On multivariable median regression, receipt of mpMRI was associated with an additional $449 (95%CI $391-$507) in Medicare payments per year. Younger age, treatment in the west or northeast, greater population density and treatment later in the study period were associated with increased cost of AS. Conclusions: Among Medicare beneficiaries on AS, mpMRI is associated with additional annual cost to Medicare. MpMRI may be a marker of more stringent AS, which is likely more costly than watchful waiting. Future studies are needed to determine optimal use of mpMRI during AS to maximize value.
First-in-field small molecule inhibitors targeting BRN2 as a therapeutic strategy for small cell prostate cancer.
Authors: Daksh L. Thaper, Ravi Munuganti, Shaghayegh Nouruzi, Sahil Kumar, Soojin Kim, Sepideh Vahid, Olena Sivak, Adeleke Aguda, Loredana Puca, Himisha Beltran, Amina Zoubeidi
Journal: Journal of Clinical Oncology (2019)

260 Background: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumours shed their dependence on AR signaling and emerge with neuroendocrine features. These tumours, termed treatment induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies; therefore, targeted therapies are desperately needed. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC. Methods: Study the effects of BRN2 inhibition using siRNA, small molecule inhibitors (BRN2i) and CRISPR K/O models. The efficacy of the small molecules was examined using reporter assays, florescence polarization assays, Biolayer Interferometry, DARTS, chromatin fractionation, RNA-seq and ChIP-seq. Pharmacokinetic studies measured stability and bioavailability of the molecules and in-vivo efficacy is to be measured in NCI-H660 xenograft model. Results: Inhibition of BRN2 drastically reduced cell proliferation in NEPC cell lines 42D ENZR and NCI-H660 cell lines. Targeting BRN2 with our first-in-field small molecule inhibitors lead to downregulation several known targets in NEPC like EZH2, ASCL1, SOX2 and PEG10. Treatment with BRN2i reduced recruitment of BRN2 to the chromatin by approximately 93% within 16 hours. Moreover, these BRN2 inhibitors displayed adequate pharmacokinetic properties and reduced NEPC proliferation in vivo. Conclusions: No therapies exist for highly lethal NEPC. Hence, the described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small cell prostate cancer.
Abstract 14623: Age and Quality of Life in Adults With Congenital Heart Disease Worldwide: Evidence for a Non-Linear Relationship
Authors: Philip Moons, Silke Apers, Koen Luyckx, Adrienne H Kovacs, Corina Thomet, Werner Budts, Junko Enomoto, Maayke A Sluman, Hsiao-Ling Yang, Jamie L Jackson, Paul Khairy, Stephen C Cook, Shanthi Chidambarathanu, Luis Alday, Katrine Eriksen, Mikael Dellborg, Malin Berghammer, Bengt Johansson, Andrew S Mackie, Samuel Menahem, Maryanne Caruana, Gruschen Veldtman, Alexandra Soufi, Susan M Fernandes, Kamila White, Edward Callus, Shelby Kutty, Eva Goossens
Journal: Circulation (2018)

Objectives: The relationship between age and quality of life (QOL) in congenital heart disease (CHD) is ambiguous. Some studies observed better QOL with increasing age, whereas others found lower Q...
Soluble Urokinase Plasminogen Activator Receptor Predicts Cardiovascular Events, Kidney Function Decline, and Mortality in Patients With Type 1 Diabetes
Authors: Viktor Rotbain Curovic, Simone Theilade, Signe A. Winther, Nete Tofte, Jesper Eugen-Olsen, Frederik Persson, Tine W. Hansen, Jørgen Jeppesen, Peter Rossing
Journal: Diabetes Care (2019)

Soluble urokinase plasminogen activator receptor (suPAR) is an important inflammatory biomarker implicated in endothelial and podocyte dysfunction. However, suPAR's predictive qualities for complications in type 1 diabetes have yet to be determined. We investigated the prognostic value of suPAR for the development of cardiovascular events, decline in renal function, and mortality in patients with type 1 diabetes.We included 667 patients with type 1 diabetes with various degrees of albuminuria in a prospective study. End points were cardiovascular events (cardiovascular death, nonfatal acute myocardial infarction, nonfatal stroke, or coronary or peripheral arterial interventions), estimated glomerular filtration rate (eGFR) decline ≥30%, progression from lower to higher albuminuric state, development of end-stage renal disease (ESRD), and mortality. Follow-up was 5.2-6.2 years. Results were adjusted for known risk factors. Hazard ratios (HRs) are presented per doubling of suPAR with 95% CI. Relative integrated discrimination improvement (rIDI) was calculated.Quantification of suPAR was available in all participants; median (interquartile range) was 3.4 ng/mL (2.7-4.5). The adjusted HR (95% CI) for cardiovascular events (n = 94), progression in albuminuria (n = 36), eGFR decline (n = 93), ESRD (n = 23), and mortality (n = 58) were 3.13 (1.96-5.45, P < 0.001), 1.27 (0.51-3.19, P = 0.61), 2.93 (1.68-5.11, P < 0.001), 2.82 (0.73-11.9, P = 0.13), and 4.13 (1.96-8.69, P < 0.001), respectively. rIDI was significant for cardiovascular events (22.6%, P < 0.001), eGFR decline (14.4%, P < 0.001), and mortality (23.9%, P < 0.001).In patients with type 1 diabetes and a broad range of albuminuria, a higher level of suPAR is a significant and independent risk factor for cardiovascular events, decline in eGFR ≥30%, and mortality. In addition, suPAR contributes significantly to discrimination for the end points.
PREDICTORS OF CONSENT TO PHARMACOGENOMICS TESTING IN THE IDEAL STUDY
Authors: Alison Jazwinski, Paul J. Clark, Alexander J. Thompson, Stuart C. Gordon, Eric Lawitz, Jonathan McCone, Stephanie Noviello, Clifford A. Brass, Lisa Pedicone, Janice K. Albrecht, Mark S. Sulkowski, Andrew J. Muir
Journal: Hepatology (2011)
Abstract P362: Race and Gender Differences in the Association Between Experiences of Everyday Discrimination and Arterial Stiffness Among Patients With Coronary Artery Disease
Authors: Samantha G Bromfield, Samaah Sullivan, Ryan Saelee, Lisa Elon, Irina Uphoff, Lian Li, Arshed Quyyumi, Viola Vaccarino, Tene T Lewis
Journal: Circulation (2019)

Introduction: Self-reported experiences of discrimination have been linked to indices of cardiovascular disease (CVD). However most studies have focused on healthy populations. Thus, we examined the association between experiences of everyday discrimination and arterial stiffness (a known correlate of adverse outcomes among clinically ill and healthy populations) among Black and White patients with a history of myocardial infarction (MI). Hypothesis: We hypothesized that higher reports of discrimination would be associated with greater arterial stiffness; and that associations would be more pronounced among Blacks overall, and Black women in particular, potentially due to a “double-jeopardy” effect. Methods: Data were from 253 participants (48.6% female, mean age: 50.8 years) who were 6 months post-MI in the Myocardial Infarction and Mental Stress 2 study. Data were collected via self-reported questionnaires, medical chart review, and a clinic visit during which pulse wave velocity was measured noninvasively following a standardized protocol. Results: Reports of discrimination were highest in Black men and women (p=0.008) and arterial stiffness was greatest in Black and White women (p=0.290). After adjustment for demographics and relevant clinical variables, discrimination was not associated with arterial stiffness in the overall cohort, or among Blacks. However, discrimination was associated with increased arterial stiffness among Black women but not White women, White men, or Black men (Table 1). Conclusions: In conclusion, despite no apparent association between discrimination and arterial stiffness in the overall study sample, further stratification revealed an association among Black women but not other race-gender groups. These data not only support the double-jeopardy hypothesis, but also suggest the importance of implementing psychosocial interventions and coping strategies into the care of clinically ill Black women.
SelectMDx versus Prostate Health Index in the identification of high-grade prostate cancer.
Authors: Gretchen Hoyer, E. David Crawford, Paul Arangua, Whitney Stanton, Francisco G. La Rosa, Wendy Poage, M. Scott Lucia, Adrie van Bokhoven, Priya N. Werahera
Journal: Journal of Clinical Oncology (2019)

30 Background: A major clinical challenge is to identify patients at increased risk of high-grade prostate cancer (PCa) (Gleason scores ≥ 7) before biopsy. Thus, we evaluated the clinical utility of SelectMDx and Prostate Health Index (phi) tests for diagnosis of high-grade PCa as compared with transperineal mapping biopsy (TMB) results, where an average of 80 prostate needle biopsies are taken every 5 mm for a diagnostic accuracy of 98%. Methods: 70 patients were selected who had TMB. They were evaluated with both SelectMDx and phi tests from before or after TMB; all had serum and post-digital rectal examination urine samples collected prior to treatment, stored in our biorepository. phi was evaluated using proPSA, free PSA and total PSA in serum. SelectMDx test measured mRNA levels of the HOXC6 and DLX1 in post-DRE urine. Published data shows that phi &lt;27 and SelectMDx score = 0% correlate with patients free of HG PCa. Test results were compared against TMB histopathology data. Multivariate logistic regression (MLS) analyses and receiver operating characteristic (ROC) curves were used to determine diagnostic accuracy. DeLong test was used to determine statistical significance of ROC curves. All analyses were done for diagnosis of any PCa and high-grade PCa. Results: TMB histopathology showed 17/70 patients with no PCa and 22/53 with high-grade PCa. The sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of each test are shown in the table below. Pairwise ROC comparison showed no statistically significant difference in the area under the curve of diagnosing PCa (0.75 vs 0.65) and high-grade PCa (0.71 vs 0.81) by phi and SelectMDx tests respectively. MLS analyses showed phi was significantly better than SelectMDx for diagnosing PCa (β = 0.054; p=0.005) and SelectMDx was significantly better than phi for diagnosing high-grade PCa (β = 8.45; p=0.0002). Conclusions: With high sensitivity and NPV, SelectMDx test is more useful than phi for screening patients at risk of high-grade PCa prior to biopsy. [Table: see text]
Lessons from tracheal tube development for understanding congenital tracheal malformations
Authors: Heena Kumra, Neha E.H. Dinesh, Dieter P. Reinhardt
Journal: European Respiratory Journal (2019)

<b>Novel functions of the extracellular protein fibrillin-2 were discovered in tracheal tube development: fibrillin-2 has important roles in tracheal cartilage development and smooth muscle cell orientation and polarity, all required for tracheal contraction</b>http://ow.ly/rn3Z30nId3N
The Landscape of <i>KMT2A</i>‐PTD AML: Concurrent Mutations, Gene Expression Signatures, and Clinical Outcome
Authors: Adil S.A. Al Hinai, Marta Pratcorona, Tim Grob, François G. Kavelaars, Elena Bussaglia, Mathijs A. Sanders, Josep Nomdedeu, Peter J.M. Valk
Journal: HemaSphere (2019)

Supplemental Digital Content is available in the text
Detection of circulating tumor cells (CTCs) in locally advanced head and neck squamous cell carcinoma using the isolation by size of epithelial tumor cell (ISET) method: Preliminary results of a prospective study.
Authors: Thiago Bueno Oliveira, Ulisses Ribaldo Nicolau, Daniel Garcia, Victor Hugo Fonseca Jesus, Vanessa Alves Silva, Juliana Valim Romero, Marcilei Eliza Cavicchioli Buim, Clovis Antonio Lopes Pinto, Luiz Paulo Kowalski, Marcello Ferretti Fanelli, Ludmilla T.D. Chinen
Journal: Journal of Clinical Oncology (2015)

e17057 Background: The majority of head and neck cancer (HNC) cases will be locally advanced (LA) at presentation, and currently there are different options of treatment for these patients like upfront surgery followed by radiotherapy (RT), RT with chemotherapy (CT) or cetuximab preceded or not by induction CT (ICT). Despite efforts, there are no predictive biomarkers to guide the choice of therapy. The aim of this study is to determine the prognostic role of CTCs in LAHNC patients treated with a curative intent and to correlate its counts and biomarkers expression with response to treatment. Methods: In this prospective study, peripheral blood samples of 15 patients with non metastatic LAHNC, stages III/IV, were analyzed for CTCs using the ISET method, in two clinical scenarios: patients undergoing curative surgical resection and adjuvant treatment (RT associated or not to CT) and candidates for a non-surgical strategy (unresectable or organ preservation) based on combination of RT concurrent with CT or cetuximab, with or without ICT. The CTCs were analyzed pre and post RT and, if applicable, pre and post ICT. The analysis included number of CTCs, presence of tumor microemboli and CTC membrane expression of potential predictive biomarkers, and its relation with of response to treatment and survival. Results: The median number of CTCs at baseline was 3.5/ml (0.3-6.8); nine of 15 patients had CTCs analyzed after treatment, with a median count of 4.75/ml. There was no correlation of CTCs counts at baseline and survival, however, post treatment CTCs counts greater than 5 were correlated with worse disease free survival (DFS): 8.5 versus 13.5 months (p = 0.9). The presence of CTCs microemboli was also related to poor prognosis with a DFS of 5.3 versus 14.8 months (p = 0.003). Biomarker analysis was available only for EGFR at this moment, and its expression was correlated with worse DFS, 7 versus 14.6 months (p = 0.4). Conclusions: To our knowledge this is the first report of CTCs analysis using the ISET method in LAHNC. Post treatment CTC counts, presence of microemboli and expression of EGFR correlated with a worse DFS in these patients.
Reduced risk of prostate cancer in a cohort of Lithuanian diabetes mellitus patients.
Authors: Ausvydas Patasius, Marius Kincius, Donata Linkeviciute-Ulinskiene, Lina Zabuliene, Giedre Smailyte
Journal: Journal of Clinical Oncology (2019)

130 Background: An inverse association has been shown between diabetes and prostate cancer risk. The aim of this study was to determine whether type 2 diabetes mellitus (T2DM) and metformin is associated with prostate cancer risk. Methods: A retrospective cohort design was used to examine the relationship between diabetes and prostate cancer risk. The cohort was composed of male patients identified with diagnosis of T2DM in the National Health Insurance Fund database during 2000–2016. Cancer cases were identified by record linkage with the Lithuanian Cancer Registry which is a nationwide population-based cancer registry that contains personal and demographic information, as well as information on diagnosis of all people diagnosed with cancer in Lithuania since 1978. We calculated standardized incidence ratios (SIRs) for prostate cancers as a ratio of observed number of cancer case in people with diabetes diagnosis to the expected number of cancer cases in the underlying general population. Results: Overall, 68,449 males were diagnosed with diabetes in Lithuania between 2000 and 2016 were included in final cohort. 2,754 prostate cancers were observed versus 3,111.26 expected within a period of observation entailing an SIR of 0.89 (95% CI: 0.85–0.92). Significantly lower risk of prostate cancer was found in diabetic patients in all age groups, there were no differences in prostate cancer risk by time since diabetes diagnosis. Significantly lower risk of prostate cancer also was found in both metformin users and never-users groups, with higher risk reduction in metformin users (SIR 0.71, 95% CI: 0.68–0.75) than in T2DM patients never-users (SIR 0.88, 95% CI: 0.80–0.96). Conclusions: In the large population-based study we found significantly decreased risk of prostate cancer among men with T2DM. Our study suggests that metformin use in patients with T2DM may be associated with reduced risk of developing prostate cancer.
Can somatic copy number alterations detected by ultradeep targeted sequencing predict prognosis in oral squamous cell carcinoma?
Authors: Tzu-Chen Yen, Shu-Jen Chen, Chun-Ta Liao, Hua-Chien Chen, Hsuan Liu
Journal: Journal of Clinical Oncology (2015)

6027 Background: Targeted sequencing technologies have greatly advanced our knowledge of the incidence and functional significance of somatic genomic copy number alterations (CNA) in various malignancies. To understand the underlying genetic alterations in oral squamous cell carcinoma (OSCC) and aid in molecular classification of OSCC and patient prognosis, CNA were analyzed using ultradeep-targeted sequencing (UDT-Seq) with DNA from formalin-fixed paraffin-embedded (FFPE) OSCC specimens. Methods: First, a linear model was developed to overcome uneven coverage across target regions. We then designed 189 primer pairs to selectively amplify mutational hotspots targeting 46 cancer-relevant genes. Samples were obtained from 310 FFPE tissue specimens from OSCC resections and 14 control samples. The 5-year rates of local recurrence, distant metastases, and overall survival served as the main outcome measures. We finally confirmed the prognostic signatures by profiling an additional 105 primary OSCC samples. Results: We found that CNA burden across 16 targeted genes was associated with clinical outcomes in the two cohorts. FGFR1 and PIK3CA amplifications were significant predictors of prognosis independent of traditional risk factors. Moreover, we identified CNA in genes involved in proteoglycan metabolism as well as FOXO and PI3K-AKT signaling pathways, for which targeted drugs are already available or under development. Conclusions: We observed that CNA detected by UDT-Seq may predict prognosis in OSCC patients, complementing the clinicopathological information. Prognostically detrimental CNA can provide added value in the combined molecular and clinical prognostication of OSCC.