tbuckley/cabot-search huggingface dataset:
Association of Aurora kinase A and epidermal growth factor receptor (EGFR) gene copy number with overall survival in KRAS wild-type patients with metastatic colorectal cancer.
Authors: E. Dotan, N. J. Meropol, F. Zambito, B. Bove, F. Zhu, A. K. Godwin, E. Golemis, S. J. Cohen, I. A. Astsaturov
Journal: Journal of Clinical Oncology (2010)

e14056 Background: Aurora kinase A (AURKA) regulates cell cycle progression and is under investigation as a therapeutic target. Increased AURKA gene copy number (AURKA-CN) is common in metastatic colorectal cancer (mCRC) but its relationship with the RAS pathway and clinical outcome is unknown. Increased EGFR gene copy number (EGFR-CN) in mCRC is independent of KRAS mutation status with unknown correlation with AURKA. We evaluated the frequency of high AURKA-CN in mCRC patients and correlated this finding with KRAS mutation status, EGFR-CN, and clinical outcome. Methods: We analyzed tumor DNA samples from 61 mCRC patients for KRAS mutation status and AURKA-CN, and 45 samples for EGFR-CN. Treatment information was available for 53 patients. AURKA-CN and EGFR-CN were determined by quantitative genomic PCR (“high” > 4.0 copies/cell; normal < 4.0 copies/cell). KRAS mutations were identified by direct sequencing of codons 12 and 13 of the gene. Kaplan-Meier Curve and log-rank statistics were used to estimate and compare the median survival between the groups. Hazard ratios were estimated from Cox proportional hazard method. Results: High AURKA-CN and KRAS mutation were found in 48% and 30% of samples respectively without any correlation between the two (p = 0.381). High EGFR-CN was found in 38% of samples and correlated with high AURKA-CN (p = 0.02). No significant difference in overall survival (OS) was seen between high and normal AURKA-CN (HR = 0.53, p = 0.14), yet among KRAS wild type patients high AURKA-CN was associated with improved OS (HR = 0.26, p = 0.04). Improved OS was also seen among patients with high EGFR-CN compared to normal EGFR-CN (HR-0.14, p = 0.02). Among patients receiving first or second-line chemotherapy, no difference in progression-free survival was noted between high and normal AURKA-CN patients. Conclusions: Our data demonstrate a high frequency of increased AURKA-CN which correlates with increased EGFR-CN. High AURKA-CN is associated with improved survival in KRAS wild type tumors. Further study of AURKA-CN in larger groups of homogenously treated patients with mCRC is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, AstraZeneca, Genentech, Genomic Health, Helsinn Group, Saladax, sanofi-aventis Saladax Amgen
Phase II efficacy and safety study of nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) patients.
Authors: Tim Eisen, Yaroslav Shparyk, Robert Jones, Nicholas James MacLeod, Graham Temple, Helen Finnigan, Rolf Kaiser, Matus Studeny, Arsene Bienvenu Loembe, Igor Bondarenko
Journal: Journal of Clinical Oncology (2013)

4506 Background: Sunitinib (S) is established as a standard first-line therapy for patients (pts) with advanced RCC. However, treatment can be limited by the occurrence of drug-related adverse events (AEs). This Phase II study assessed the efficacy and safety of nintedanib (N) – a potent, triple angiokinase inhibitor of VEGFR-1–3, PDGFR-α/β, and FGFR-1–3, as well as RET and Flt3 – vs S in previously untreated pts with RCC. Methods: Ninety-nine eligible pts (96 of whom were treated) with advanced, unresectable/recurrent clear cell RCC, an ECOG performance status of 0–1, and no prior systemic therapy were randomized 2:1 to receive N 200 mg twice daily (n=64; given in 4-week cycles) or S 50 mg once daily (n=32; 4 weeks on, 2 weeks off schedule). Treatment continued until disease progression or unacceptable drug-related AEs. Primary endpoints were progression-free survival at 9 months (PFS-9) and, in N-treated pts only, QTc interval change (baseline to day 15). Secondary endpoints included PFS, objective response rate (ORR; RECIST 1.1), overall survival (OS), time to progression (TTP), time to treatment failure (TTF), and AEs. Results: Baseline characteristics were balanced between the arms. PFS-9 was not statistically significantly different between N- and S-treated pts (43 vs 45%; p=0.85). There were also no statistically significant differences between N and S with regard to PFS (median: 8.44 vs 8.38 mo; hazard ratio: 1.16; 95% CI: 0.71–1.89; p=0.56), confirmed ORR (18.8 vs 31.3%; p=0.19), OS (median: 20.37 vs 21.22 mo; p=0.63), TTP (median: 8.48 vs 8.54 mo; p=0.52), and TTF (median: 8.41 vs 8.36 mo; p=0.46). Grade ≥3 AEs occurred in 47% of N-treated pts and 56% of S-treated pts. Common AEs (all grades; N vs S) included diarrhea (61 vs 50%), nausea (38 vs 34%), fatigue (both 25%), and vomiting (16 vs 22%). Dermatologic AEs (8 vs 47%) were less frequent with N than S. There was no increase from baseline in QTc &gt;60 ms on days 1 or 15 in N-treated pts, and there was no relationship between N exposure and QT interval change. Conclusions: N demonstrated similar efficacy to S and had a manageable safety profile, including a lower incidence of dermatologic AEs vs S. In addition, N was not associated with QT prolongation. Clinical trial information: NCT01024920.
MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study
Authors: Christiane Copie-Bergman, Peggy Cuillière-Dartigues, Maryse Baia, Josette Briere, Richard Delarue, Danielle Canioni, Gilles Salles, Marie Parrens, Karim Belhadj, Bettina Fabiani, Christian Recher, Tony Petrella, Nicolas Ketterer, Frederic Peyrade, Corinne Haioun, Inga Nagel, Reiner Siebert, Fabrice Jardin, Karen Leroy, Jean-Philippe Jais, Herve Tilly, Thierry Jo Molina, Philippe Gaulard
Journal: Blood (2015)
‘Catch it early, save a life and save a breast’: this misleading mantra of mammography
Authors: Michael Baum
Journal: Journal of the Royal Society of Medicine (2015)

The one thing every layperson and politician knows with confidence with regard to breast cancer is that you’ve got to ‘catch it early,’ preferably before you can even feel it. It may come as a shock to some readers, but I disagree and there’s such a thing as ‘catching it too early’. Like Peter Gotzsche in the current edition of the JRSM, 1 I think that that the global breast cancer screening programme has to be considered a ‘failed experiment.’ I also agree that the service as now provided should be closed down. I would go on to suggest that all the human and technological resources released by the closure of the National Health Service Breast Screening Service (NHSBSP), be redeployed into more fruitful areas for enhancing women’s health. That aside we have much to learn from the fact that the experiment, set up in good faith, has indeed failed to live up to our expectations. The mantra, ‘Catch it early, save a life and save a breast’, turns out to be a false promise. Screening may have a borderline effect on reducing cause-specific mortality but does not save lives as judged by the outcome measure of all-cause mortality. 2 As far as saving breasts is concerned, the opposite is the truth. Populations of women attending for screening have a greater chance of a mastectomy than any control group. 2 The hypothesis being tested in the experiment originated in the last half of the 20th century and was based on the assumption of the log linear kinetics of cancer development with distant dissemination being determined by the size (a poor surrogate for ‘age’) of the cancer. This was considered so self-evident as to have been translated into an ideological expression of faith. Yet, the experiment failed. The national breast screening programmes around the world have provided us with a natural experiment of the greatest historical importance, first, because it failed to deliver and, second, because of the recognition that mammography in asymptomatic women leads to the over-diagnosis of ‘pseudo-cancers’. 3
Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Charles J. Ryan, Matthew Raymond Smith, Johann Sebastian De Bono, Arturo Molina, Christopher Logothetis, Paul L. De Souza, Karim Fizazi, Paul N. Mainwaring, Jose Maria Piulats Rodriguez, Siobhan Ng, Joan Carles, Peter Mulders, Thian San Kheoh, Thomas W. Griffin, Eric Jay Small, Howard I. Scher, Dana E. Rathkopf
Journal: Journal of Clinical Oncology (2012)

LBA4518 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer
Authors: Mariangela Russo, Giulia Siravegna, Lawrence S. Blaszkowsky, Giorgio Corti, Giovanni Crisafulli, Leanne G. Ahronian, Benedetta Mussolin, Eunice L. Kwak, Michela Buscarino, Luca Lazzari, Emanuele Valtorta, Mauro Truini, Nicholas A. Jessop, Hayley E. Robinson, Theodore S. Hong, Mari Mino-Kenudson, Federica Di Nicolantonio, Ashraf Thabet, Andrea Sartore-Bianchi, Salvatore Siena, A. John Iafrate, Alberto Bardelli, Ryan B. Corcoran
Journal: Cancer Discovery (2015)

How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient.Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.
Dose-Response Association Between Psychological Distress and Risk of Completed Suicide in the General Population
Authors: Steven Bell, Tom C. Russ, Mika Kivimäki, Emmanuel Stamatakis, G. David Batty
Journal: JAMA Psychiatry (2015)

Discussion | This analysis suggests that altitude of residence may impact the risk for dying of Alzheimer dementia.Ecologic studies of this type must be interpreted cautiously.Unexamined factors may account for differential reporting of cases across counties, including miscategorization of other forms of dementia.For instance, 1 high-altitude county (Alpine) reported no cases in 2005.We were not able to reliably assess many confounders, including comorbidities and air pollution.None of the sociodemographic factors we controlled for mitigated the estimated association, and the same results were found among the larger counties that had more reliable rate estimates.Altitude of residence might be associated with environmental, lifestyle, or health-related factors, which influence dementia rates.Oxygen levels might have direct long-term effects on brain physiology.Oxidative abnormalities have been long proposed to be central to the pathogenesis of dementia. 4ne group of researchers previously found that hypoxia prevents neurodegeneration in rats in experimental Alzheimer disease 5 and hypothesized that adaptation to induced hypoxia may prevent dementia. 6To our knowledge, our work is the first to find epidemiological evidence for such effects.Additional work is needed to determine whether this relationship holds in other populations.
Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year.
Authors: R. A. Larson, P. D. le Coutre, J. Reiffers, T. P. Hughes, G. Saglio, P. Edrich, A. Hoenekopp, N. J. Gallagher, H. Kantarjian, A. Hochhaus
Journal: Journal of Clinical Oncology (2010)

6501 Background: Study results of ENESTnd at 12 month (mo) demonstrated superior efficacy of nilotinib 300 and 400 mg bid over imatinib. Methods: 846 CML-CP pts were randomized to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283). Primary endpoint was major molecular response (MMR, ≤ 0.1% BCR-ABLIS) rate at 12 mo. Results: Rates of MMR and CCyR were superior for nilotinib 300 and 400 mg bid compared with imatinib and deeper molecular responses were also achieved with nilotinib at both doses (Table). Suboptimal responses and treatment failure (based on cytogenetic criteria) were less frequent on the nilotinib arms. Progression to advanced disease was lower for nilotinib at both doses compared with imatinib (Table); no pt who achieved MMR progressed; 3 pts who achieved CCyR on imatinib progressed. There were no unexpected safety events. Discontinuations due to adverse events or abnormal laboratory values were lowest for nilotinib 300 mg bid (7%). Overall, 1% of pts discontinued nilotinib due to hepatobilliary disorders; only 1 pt discontinued due to pancreatitis and 1 pt due to ischemic heart disease. Pleural effusions (any grade) occurred in <1% of nilotinib treated pts. Minimum 16 mo follow-up data will be presented (maximum, 29 mo). Conclusions: Nilotinib induced twice the MMR rate compared with imatinib and resulted in significantly lower rates of transformation to advanced disease, which support the potential of nilotinib to become the new standard of care in newly diagnosed CML. Nilotinib 300 mg bid (N = 282) Nilotinib 400 mg bid (N = 281) Imatinib 400 mg qd (N = 283) MMR, % At 12 mo 44*P < 0.0001 43* P < 0.0001 22 High-risk Sokal (12 mo) 41 32 17 Best molecular response with current follow-up, % ≤ 0.1% IS (MMR) 57 54 30 ≤ 0.01% IS 24 21 10 ≤ 0.0032% IS 13 12 4 CCyR, % By 12 mo 80* p < 0.0001 78* p = 0.0005 65 High-risk Sokal (12 mo) 74 63 49 Suboptimal response, % 5 5 13 Treatment failure, % 1 2 8 Progression to AP/BC, % Estimated rate at 12 mo 0.7 p = 0.0095** 0.4 p = 0.0037** 3.5 Above, including clonal evolution 0.7 p = 0.0006** 1.4 p = 0.0025** 4.8 * CMH test stratified by Sokal vs. imatinib. ** Log-rank test stratified by Sokal vs. imatinib for time to AP/BC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, MSD, Novartis Novartis Bristol-Myers Squibb, Celgene, MSD, Novartis Bristol-Myers Squibb, Genzyme, Novartis
The extent of metalloproteinase-mediated LAG3 cleavage limits the efficacy of PD1 blockade
Authors: Lawrence P Andrews, Andrea L Szymczak-Workman, Creg J Workman, Dario AA Vignali
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Inhibitory receptors control immune responses preventing exacerbated T cell activation and the onset of autoimmunity; however, they also limit antitumor immunity. Enhanced co-expression of PD1 and LAG3 phenotypically mark functionally exhausted tumor-specific T cells, with dual
Interaction between effector and memory cd8+ t cells enhances melanoma adoptive immunotherapy
Authors: Amanda Contreras, Andrew Tatar, Siddhartha Sen, Justin Meyers, Prakrithi Srinand, David Mahvi, Clifford Cho
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Our laboratory has previously demonstrated that adoptive cell transfer (ACT) of melanoma-specific memory T cells (TM) results in a more potent local and systemic T cell response than ACT with melanoma-specific effector T cells (TE). However, we have also seen that TM are not more
Statistical considerations on prognostic models for glioma
Authors: Annette M. Molinaro, Margaret R. Wrensch, Robert B. Jenkins, Jeanette E. Eckel-Passow
Journal: Neuro-Oncology (2015)

Given the lack of beneficial treatments in glioma, there is a need for prognostic models for therapeutic decision making and life planning. Recently several studies defining subtypes of glioma have been published. Here, we review the statistical considerations of how to build and validate prognostic models, explain the models presented in the current glioma literature, and discuss advantages and disadvantages of each model. The 3 statistical considerations to establishing clinically useful prognostic models are: study design, model building, and validation. Careful study design helps to ensure that the model is unbiased and generalizable to the population of interest. During model building, a discovery cohort of patients can be used to choose variables, construct models, and estimate prediction performance via internal validation. Via external validation, an independent dataset can assess how well the model performs. It is imperative that published models properly detail the study design and methods for both model building and validation. This provides readers the information necessary to assess the bias in a study, compare other published models, and determine the model's clinical usefulness. As editors, reviewers, and readers of the relevant literature, we should be cognizant of the needed statistical considerations and insist on their use.
Exercise reponses in the chronic fatigue syndrome
Authors: A. S Hutchison
Journal: BMJ (1995)

Further reanalysis of existing trials is unlikely to yield new insights, which will require new studies.Anderson and Tomenson recommend investigation of antidepressants prescribed in clinical practice rather than in clinical trials.Such observational studies are subject to many potential biases, which reduce the validity of comparisons.'What is needed are large, well designed pragmatic randomised controlled trials in primary care settings; such trials will allow both reliable and generalisable estimation of the relative effectiveness and cost effectiveness of different classes of antidepressants, as used in routine clinical practice and over a longer period.Future randomised controlled trials comparing classes of antidepress- ants should also use more relevant outcomes to measure quality of life in those who continue to use treatments and those who drop out.
Reasons for Rubella Susceptibility among Pregnant Women in West Lambeth
Authors: S Lawman, K Morton, J M Best
Journal: Journal of the Royal Society of Medicine (1994)

One hundred and thirty-three pregnant women who delivered at St Thomas' Hospital, in 1990 were noted to require rubella vaccination post partum. Fifty-three (39%) had completed a telephone questionnaire in order to determine reasons for susceptibility to rubella. Laboratory reports confirmed that 92 women were rubella seronegative and 27 had low levels of antibody. Of the 53 women interviewed, 25 gave a history of one or more rubella immunizations, 20 had no history of immunization and vaccination history was unknown for eight. Eleven of the 20 unvaccinated women had not been at school in the UK between 11 and 14 years of age. Eighty-seven per cent of the patients' general practitioners had no knowledge of their patients' rubella antibody status. Ninety-four per cent of the 133 women received rubella vaccine post partum. The Department of Health guidelines should be more vigorously implemented in order to identify and immunize remaining rubella susceptible women of child-bearing age. Susceptibility among women with a history of rubella immunization suggests that the seroconversion rate following rubella immunization in clinical practice may be lower than in vaccine trials.
For Patients With Cancer, Cure Is Not Enough
Authors: Karen E. Effinger, Michael P. Link
Journal: JAMA Oncology (2015)

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Abstract 17900: A Common Single Nucleotide Polymorphism Associated With Atrial Fibrillation Modulates Symptomatic Response To Antiarrhythmic Drug Therapy
Authors: Joseph Vaglio, Shane Rowan, Gayle Kucera, Tanya Stubblefield, Shannon Carter, Dan M Roden, Dawood Darbar
Journal: Circulation (2010)

Introduction: Recent genome wide association studies have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone atri...
G08 : Incidence of hepatocellular carcinoma (HCC) and complications in alcoholic compensated cirrhosis. Preliminary results of a multicenter prospective French and belgian cohort (INCA Cirral)
Authors: N. Ganne, V. Bourcier, C. Chaffaut, I. Archambaud, F. Oberti, J.-M. Perarnau, D. Roulot, A. Louvet, C. Moreno, T. Dao, R. Moirand, O. Goria, E. Nguyen-Khac, J. Henrion, S. Pol, A. Tran, V. de Ledinghen, J.-C. Duclos-Vallée, N. Carbonell, V. Ozenne, X. Amiot, J.-P. Zarski, S. Chevret
Journal: Journal of Hepatology (2015)