tbuckley/cabot-search huggingface dataset:
Response to Comment on American Diabetes Association. <i>Standards of Medical Care in Diabetes—2017</i>. Diabetes Care 2017;40(Suppl. 1):S1–S135
Authors: William H. Herman, Matthew Petersen, Rita R. Kalyani
Journal: Diabetes Care (2017)

We thank Sonne and Hemmingsen (1) for their thoughtful critique of the American Diabetes Association’s Standards of Medical Care in Diabetes—2017 (Standards of Care) (2). As they point out, the Standards of Care now highlight a prediabetes screening tool that was developed in 1995 (3), revised in 2012 (4), and most recently validated in 2016 (5). The Standards of Care also recommend regular monitoring for those with prediabetes, intensive lifestyle intervention for diabetes prevention, and consideration of metformin therapy for selected individuals with prediabetes (6).

We acknowledge that the use of three different diagnostic tests to define prediabetes identifies heterogeneous groups. Although values above the diagnostic threshold for each of the tests have been associated with increased risk of progression to type 2 diabetes (T2D) (7,8), the thresholds for the individual …
Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment
Authors: Michel Eisenblaetter, Fabian Flores-Borja, Jae Jin Lee, Christina Wefers, Hannah Smith, Rebekka Hueting, Margaret S Cooper, Philip J Blower, Dominic Patel, Manuel Rodriguez-Justo, Hanna Milewicz, Thomas Vogl, Johannes Roth, Andrew Tutt, Tobias Schaeffter, Tony Ng
Journal: Theranostics (2017)

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis -the premetastatic niche.As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression.We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice.A SPECT-probe has been generated and tested for visualization of S100A9 release.Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001).The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r 2 =0.788; p<0.0001).CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.
Heterogeneity in Treatment Effects
Authors: Frank Davidoff
Journal: Annals of Internal Medicine (2017)

Letters20 June 2017Heterogeneity in Treatment EffectsFrank Davidoff, MDFrank Davidoff, MDFrom Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0156 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Clinical researchers routinely obtain data from entire heterogeneous trial populations to establish whether specific treatments actually can work, not just seem to do so. But, as Mr. Matthews succinctly notes, careful examination of individual-patient data from many large trials reveals that only some treated patients in such trials actually do benefit from treatment, some of the time ( 1). Unfortunately, researchers generally remain blind to this very real and substantial heterogeneity in treatment effects and therefore only rarely use trial data to establish whether the treatment they are studying really does (or does not) work in specific patients—even ...References1. Kent DM, Nelson J, Dahabreh IJ, Rothwell PM, Altman DG, Hayward RA. Risk and treatment effect heterogeneity: re-analysis of individual participant data from 32 large clinical trials. Int J Epidemiol. 2016. [PMID: 27375287] CrossrefMedlineGoogle Scholar2. Basu S, Sussman JB, Hayward RA. Detecting heterogeneous treatment effects to guide personalized blood pressure treatment: a modeling study of randomized clinical trials. Ann Intern Med. 2017;166:354-360. [PMID: 28055048]. doi:10.7326/M16-1756 LinkGoogle Scholar3. Vohra S, Shamseer L, Sampson M, Bukutu C, Schmid CH, Tate R, et al; CENT Group. CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement. J Clin Epidemiol. 2016;76:9-17. [PMID: 26272792] doi:10.1016/j.jclinepi.2015.05.004 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1721. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoCan Knowledge About Heterogeneity in Treatment Effects Help Us Choose Wisely? Frank Davidoff Heterogeneity in Treatment Effects Robert A.J. Matthews Metrics 20 June 2017Volume 166, Issue 12Page: 914-915KeywordsBlindnessClinical trialsDisclosureForecastingPatient advocacyPatientsPopulation statisticsRandomized trials ePublished: 20 June 2017 Issue Published: 20 June 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Comparison of genotype-specific progression free survival (PFS) outcomes in the control (ctrl) arms of randomized clinical trials (RCTs).
Authors: Rossanna C. Pezo, Lisa Wang, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2016)

2536 Background: PFS is often used as the primary outcome measure in RCTs involving patients (pts) with metastatic cancers. For RCTs evaluating new targeted agents, there is uncertainty about how somatic mutation status affects clinical outcomes under standard therapy. Our aim was to identify differences in genotype-specific PFS outcomes in the comparator arm of advanced solid tumor RCTs. Methods: A MEDLINE search was conducted to identify published RCT reports evaluating systemic therapies (tx) with PFS outcomes for wildtype (WT) versus (vs) mutant (MT) genotypes in the ctrl arm. Genotype-specific PFS data was available for cutaneous melanoma (BRAF), CRC (KRAS) and NSCLC (EGFR). Insufficient data was reported for other solid tumor genotypes, including HER2+ gastric, HPV+ SCC, PIK3CA breast, BRCA1/2 ovarian and KRAS NSCLC. We extracted data including sample size, type of tx, hazard ratios (HR), and genotype-specific median PFS (mPFS) for the ctrl arms. Trials were grouped according to type of tx, targeted (T) vs chemotherapy (C) and line of tx (first line (1L) vs non-1L). The t- test was used to compare mPFS difference and HRs for WT vs MT pts. Results: A total of 60 reports involving 29,631 pts were included in this analysis. For NSCLC, mPFS difference between WT and MT pts was 1.8 months (p = 0.01), in favor of EGFR MT pts receiving 1L C. For non-1L trials of T agents in NSCLC, mPFS difference was 6.7 months in favor of the EGFR MT pts (p = 0.05). In CRC and melanoma, there was no difference in mPFS for WT vs. MT genotypes. Mean difference in HRs between WT vs MT ctrl is listed in the Table below. Conclusions: EGFR MT NSCLC had a superior PFS under standard therapy with 1L C and non-1L T agents. For other groups analyzed, there was no difference in outcome under standard therapy according to genotype. Further reporting of RCTs that analyze outcome by genotype is required to establish standards for genotype-specific outcomes under standard therapy. Tumor type (# trials) Tx line and type (C or T) Mean HR difference, WT vs MT (95% CI) P value NSCLC (28) 1 L C Non-1 L C Non-1L T 1.4 (1.1-1.6) 1.6 (0.1-3.0) 4.8 (1.6-7.9) 0.02 0.30 0.04 CRC (20) 1L C 1.0 (0.9-1.1) 0.90 Melanoma (12) 1L C 0.9 (0.0-6.7) 0.92
A Novel Dendritic Cell-Derived Vaccine in Multiple Myeloma
Authors: Rebecca Karp Leaf, Dina Stroopinsky, Athalia Rachel Pyzer, Ada M. Kruisbeek, Sandra Van Wetering, Abigail J. Washington, Leandra Cole, Myrna R. Nahas, Salvia Jain, Arie Apel, Jon Arnason, Ayad Hamdan, Jacalyn Rosenblatt, David E. Avigan
Journal: Blood (2016)
Apport de l'exploration de l'intestin grêle par la videocapsule endoscopique au diagnostic des colites indéterminées
Authors: M Jarry, E Ben Soussan, A Bourreille, G Savoye, S Sacher-Huvelin, JF Colombel, P Ducrotté, JP Galmiche, V Maunoury
Journal: Endoscopy (2005)

Rationnel Environ 10% des malades atteints d'une maladie inflammatoire chronique de l'intestin ont une colite indéterminée (CI), pour laquelle le diagnostic différentiel entre une maladie de Crohn (MC) et une rectocolite hémorragique (RCH) est impossible. L'examen de l'intestin grêle par la videocapsule endoscopique (VCE) permet de mettre en évidence chez des patients avec une MC des lésions méconnues par les examens radiographiques et endoscopiques habituels. Le but de ce travail a été d'évaluer l'apport diagnostique de la VCE chez des malades avec une CI.
L'abord endoscopique des lésions bénignes du cardia
Authors: B Gayet, C Christidis, T Perniceni, H Levard, A Blain, F Mal
Journal: Endoscopy (2006)

Le traitement des tumeurs villeuses ou des tumeurs sous épithéliales du cardia est rare mais difficile au risque de sous traiter une tumeur stromale par une énucléation, geste actuellement contre indiqué dans ce diagnostic, ou de surtraiter un leiomyome ou une villeuse non dégénérée par une exérèse qui peut être majeure telle une gastrectomie totale ou polaire supérieure avec un temps thoracique.
The role of palliative radiotherapy and or chemotherapy in-patients diagnosed with recurrence after surgery with curative intent for oesophago-gastric cancers in a tertiary referral centre
Authors: PP Vassallo, B Gurney, N Wadd, BR Gopinath, P Davis, YKS Viswanath
Journal: Endoscopy (2005)

Background: The role of palliative radio and or chemotherapy in-patients with recurrence following radical surgery for operable oesophago-gastric (OG) cancers is unclear. This study sets out to assess whether palliative chemotherapy or radiotherapy improves survival time in these patients.
EVESOR, the first model-based multi-parameter academic phase 1 trial meant to optimize the benefit/toxicity ratio of everolimus (EVE) and sorafenib (SOR) combination: Initial results.
Authors: Benoit You, Mevidette El Madani, Emilie Henin, Michel Tod, Denis Maillet, Julien Peron, Rodriguez-Lafrasse Calire, Pierre-Jean Valette, Thibaud Lefort, Philippe Cassier, Juliette Hommel-Fontaine, Jerome Guitton, Catherine Barrois, Gilles Freyer
Journal: Journal of Clinical Oncology (2016)

2532 Background: “Drug development of targeted agent associations is a challenge”. Previous traditional industry phase I trials failed to define the tolerable dose/dosing schedules of EVE & SOR combo. The optimal dosing schedule, maximizing the benefit/toxicity ratio, may be identified using modeling & simulation (M&S) of data derived from adequately designed multi-parameter trial. Methods: EVESOR was composed of 4 arms with different dosing schedules/doses of EVE & SOR (Continuous A & B arms EVE 5mg + SOR 200mg bid after reverse run-in periods; Intermittent arms: C, EVE qd and SOR bid for 7 days alternating every weeks; D, EVE continuous qd and SORA bid 3days-on 4 days-off). Dose-escalations planned in intermittent arms. Multi-parameter assessments: pharmacokinetics (PK); serial pharmacodynamics (PD) on signaling pathways (ERK, AKT, S6K) in PBMCs; kinetics of circulating tumor DNA & angiogenesis markers; repeated DCE-ultrasounds. The optimal doses/dosing schedules of EVE & SOR will be searched using M&S and then tested. Results: 26 solid tumor patients were enrolled: cholangiocarcinoma (n = 8); CRC (n = 5); breast (n = 3); pancreas (n = 3); endometrial (n = 2); others (n = 5). Grade 3-4 toxicity incidences were lower than expected: fatigue 23%; hypophosphatemia 11%; liver transaminase increase 11%. AEs were more frequent in continuous arms (A & B, 60%) than in intermittent arms (C & D, 40%). Two grade 3 DLTs occurred on arms C: post-biopsy liver abscess; toxidermia. Overall response rates (ORR): PR 11%; SD 77%. ORR was better in intermittent arms (C & D, SD 80%; PR 20%) than in continuous arms (A & B, PD 20%; SD 80%). Of note, cholangiocarcinoma: SD 62% with long responses > 10 months for 50% patients. No PK interaction between EVE & SOR was identified. PD interactions between SOR & EVE schedules were found on angiogenesis & RAS/PI3K signaling pathways. Conclusions: The novel design of multiparameter EVESOR trial aims at optimizing the doses/dosing schedules of the 2 drug combination, ultimately with M&S works. Initial outcomes suggest PD interactions, and better tolerance & efficacy of intermittent schedules warranting further investigations. Clinical trial information: NCT01932177.
Venous vs Arterial Lactate and 30-Day Mortality in Pediatric Sepsis—Reply
Authors: Halden F. Scott, Allison Kempe, Lalit Bajaj
Journal: JAMA Pediatrics (2017)

In Reply We thank Schlapbach et al for their letter and their analyses showing the comparability of the association between venous and arterial lactate and odds of mortality in children critically ill with infection.
Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others
Authors: Michael W. Norsworthy, Fengfeng Bei, Riki Kawaguchi, Qing Wang, Nicholas M. Tran, Yi Li, Benedikt Brommer, Yiming Zhang, Chen Wang, Joshua R. Sanes, Giovanni Coppola, Zhigang He
Journal: Neuron (2017)
Abstract 124: Fetal-Like RNA Splicing Remodeling in Failing Heart Revealed by Total Transcriptome Analysis
Authors: Chen Gao, Vincent Ren, Grace (Xinshu) Xiao, Jaunian Chen, Yibin Wang
Journal: Circulation Research (2012)

The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is also implicated in many human diseases including cancer. However, little knowledge is available about the scope of alternative splicing at whole genome level in heart diseases and even less about the mechanisms underlying the regulation of mRNA splicing in response to pathological injury in heart. Using a genome-wide RNA-Seq analysis, we have identified global alternative splicing changes associated with both development and pathological remodeling in mouse heart. Most significantly, the alternative RNA splicing events observed in failing heart mimicked the splicing profile in fetal hearts, suggesting a fetal like RNA splicing remodeling in failing hearts. After examining the expression profiles of splicing regulators in neonatal, normal adult, and failing adult hearts, Fox-1 was identified as one to be significantly down regulated in the failing and fetal hearts. Morpholino mediated Fox-1 knock-down in zebrafish embryos led to lethal phenotype associated with impaired cardiac development and function. This phenotype could be rescued by re-expressing both zebrafish and mouse Fox1 gene. Therefore, our established functional significance of Fox1 mediated RNA alternative splicing serves as a key molecular player in transcriptome remodeling during cardiac development and pathology.
Is less more? Comparing chemotherapy alone to chemotherapy and radiation for high risk, grade II glioma—An analysis of the National Cancer Data Base.
Authors: Jaymin Jhaveri, Yuan Liu, Theresa Wicklin Gillespie, Mudit Chowdhary, Zachary Buchwald, Jeffrey J. Olson, Alfredo Daniel Voloschin, Hui-Kuo George Shu, Ian R. Crocker, Walter John Curran, Kirtesh R. Patel
Journal: Journal of Clinical Oncology (2017)

2031 Background: Grade II glioma patients with subtotal resection (STR) or age ≥ 40 are considered high risk. RTOG 9802 demonstrated that for these high-risk patients, chemotherapy and radiation therapy improved overall survival (OS) compared to radiation alone. The purpose of this study is to compare the OS of high risk, grade II glioma patients treated with adjuvant chemotherapy alone (CA) to chemotherapy and radiation therapy (CRT). Methods: Using the National Cancer Data Base (NCDB), high risk (age ≥ 40 or STR) grade II glioma patients with oligodendroglioma, astrocytoma, or mixed tumors were identified. Patients receiving CA were compared to patients receiving CRT. Univariate and multivariable analyses (MVA) were performed. Propensity score (PS) matching was utilized to account for difference in patient characteristics. Kaplan Meier statistics were utilized to compare OS. Results: 1054 high risk, grade II glioma patients were identified, 47.1% receiving CA and 52.9% receiving CRT. Median follow up time was 55.1 months. Patients treated with CA were statistically more likely (all p &lt; 0.05) to be oligodendroglioma histology (65.5% vs. 34.2%), 1p/19 co-deleted (22.8% vs. 7.5%), younger median age (47 vs. 48 years) and treated at an academic program (65.2% vs. 50.3%). MVA demonstrated treatment type was not a significant predictor for OS (p = 0.125), while tumor size &gt; 6cm, astrocytoma histology, and older age were predictors for worse survival (all p &lt; 0.05). Utilizing 1:1 PS matching, with 662 total patients, OS was statistically similar (p = 0.919) for CA and CRT at 5 years (69.1% vs. 68.5%, respectively) and 7 years (55.5% vs. 60.0%, respectively). Conclusions: In this retrospective analysis of the NCDB, long term OS for high-risk, grade II glioma patients treated with CA appears similar to CRT. These findings are hypothesis generating, with the standard of care still remaining CRT as established by RTOG 9802. Prospective clinical trials comparing CA and CRT are warranted.
Validation of RECIST 1.1 for use with cytotoxic agents and targeted cancer agents (TCA): Results of a RECIST Working Group analysis of a 50 clinical trials pooled individual patient database.
Authors: Saskia Litière, Gaëlle Isaac, Elisabeth De Vries, Jan Bogaerts, Alice P. Chen, Janet Dancey, Robert Ford, Steve J Gwyther, Otto S. Hoekstra, Erich Huang, Nancy U Lin, Yan Liu, Sumithra J. Mandrekar, Lawrence HOWARD Schwartz, Lalitha Shankar, Patrick Therasse, Lesley Seymour
Journal: Journal of Clinical Oncology (2017)

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.
THE SURGICAL TREATMENT OF ANGINA PECTORIS
Authors: T Moreno Herrero
Journal: JAMA (1924)

Coronary artery bypass grafting is a very effective therapy for the relief of angina pectoris. It has been demonstrated that, in certain subsets of patients, it prolongs life when compared to other treatment options. However, the introduction and development of less invasive percutaneous procedures has changed the profile of patients subject to coronary surgery. They are older, with more extensive coronary disease and comorbid conditions. The challenge of coronary artery bypass grafting is to maintain the excellent results obtained tha far and to compete with percutaneous revascularization procedures regarding morbidity and cost-effectiveness. We review the most important randomized trials of coronary surgery, especially those which consider its role in multivessel disease versus angioplasty and the new trends that try to make it cheaper and less invasive.
Loss of E-cadherin expression in colorectal cancer
Authors: E Fox, DT Leahy, R Geraghty, D Keegan, A White, H Mulcahy, D Fennelly, JM Hyland, D O'Donoghue, K Sheahan
Journal: Endoscopy (2006)

Aims: E-cadherin dysfunction is proposed to contribute to cancer progression, facilitating proliferation, invasion, and possibly metastasis. Loss of E-cadherin expression has been described secondary to somatic mutation and promoter hypermethylation in various cancers. This study sought to examine the significance of E-cadherin expression in an unselected series of colorectal cancers.
Comparison of endoxifen levels between male and female breast cancer patients treated with tamoxifen.
Authors: John Gordon Lenehan, Wendy A. Teft, Richard B. Kim
Journal: Journal of Clinical Oncology (2016)

578 Background: Male breast cancer is rare and accounts for less than 1% of breast cancer diagnoses. The majority of male breast cancers are hormone-receptor positive and tamoxifen is the standard adjuvant hormone treatment. Tamoxifen is metabolized primarily by CYP2D6 and CYP3A4 in the liver to the active metabolite endoxifen, increasingly recognized as a clinically relevant biomarker of therapeutic benefit. Plasma levels of endoxifen above a threshold of 15 nM appear to confer maximal anti-hormonal benefit and potentially improved outcomes. Methods: We have carried out a prospective assessment of endoxifen levels in men with breast cancer followed in a personalized tamoxifen clinic. Eleven men with breast cancer were assessed and compared with age and genotype matched female patients, with both groups initially treated at the usual tamoxifen dose of 20 mg/day. Results: Mean baseline endoxifen levels in male CYP2D6 extensive metabolizers (EM) were significantly lower than female EMs (30.88 ± 5.9 nM versus 53.92 ± 8.9 nM; p = 0.005), although all patients were in the therapeutic range. Baseline endoxifen levels in male intermediate metabolizers (IM) were not significantly different from matched females (17.68 ± 11.9 nM versus 25.74 ± 10.6 nM; p = 0.20), but were more likely to be sub-therapeutic (4/7 (57%) versus 5/19 (26%)). Male IMs remained more likely to be sub-therapeutic when all follow-up samples were considered (3/7 (43%) versus 1/19 (5%)). For those with plasma endoxifen levels below the threshold of 15 nM, increasing the tamoxifen dose to 30 or 40 mg/day resulted in attainment of therapeutic endoxifen levels in both groups. Conclusions: Our results suggest that endoxifen levels in men are more likely to be low, and they may benefit from CYP2D6 genotyping and plasma endoxifen level monitoring.