tbuckley/cabot-search huggingface dataset:
TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours
Authors: Francesca Mastropasqua, Flaviana Marzano, Alessio Valletti, Italia Aiello, Giuseppe Di Tullio, Annalisa Morgano, Sabino Liuni, Elena Ranieri, Luisa Guerrini, Giuseppe Gasparre, Elisabetta Sbisà, Graziano Pesole, Antonio Moschetta, Mariano Francesco Caratozzolo, Apollonia Tullo
Journal: Molecular Cancer (2017)

TRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway. We used RCC and CRC cell models for in-vitro experiments, and ccRCC patients and xenograft transplanted mice for in vivo assessments. To measure microRNAs levels we performed RT-qPCR, while steady-states of TRIM8, p53, p21 and N-MYC were quantified at protein level by Western Blotting as well as at transcript level by RT-qPCR. Luciferase reporter assays were performed to assess the interaction between TRIM8 and specific miRNAs, and the potential effects of this interaction on TRIM8 expression. Moreover, we treated our cell models with conventional chemotherapeutic drugs or tyrosine kinase inhibitors, and measured their response in terms of cell proliferation by MTT and colony suppression assays. We showed that TRIM8 is a target of miR-17-5p and miR-106b-5p, whose expression is promoted by N-MYC, and that alterations of their levels affect cell proliferation, acting on the TRIM8 transcripts stability, as confirmed in ccRCC patients and cell lines. In addition, reducing the levels of miR-17-5p/miR-106b-5p, we increased the chemo-sensitivity of RCC/CRC-derived cells to anti-tumour drugs used in the clinic. Intriguingly, this occurs, on one hand, by recovering the p53 tumour suppressor activity in a TRIM8-dependent fashion and, on the other hand, by promoting the transcription of miR-34a that turns off the oncogenic action of N-MYC. This ultimately leads to cell proliferation reduction or block, observed also in colon cancer xenografts overexpressing TRIM8. In this paper we provided evidence that TRIM8 and its regulators miR-17-5p and miR-106b-5 participate to a feedback loop controlling cell proliferation through the reciprocal modulation of p53, miR-34a and N-MYC. Our experiments pointed out that this axis is pivotal in defining drug responsiveness of cancers such ccRCC and CRC.
Lifestyle habits in females with metastatic breast cancer: A pilot study in support of future interventions.
Authors: Patricia M. Sheean, Christopher Kabir, Ruta D. Rao, Kent Hoskins, Melinda Stolley
Journal: Journal of Clinical Oncology (2015)

e20600 Background: Women with metastatic breast cancer are excluded from lifestyle trials under the assumptions that diet and physical activity are burdensome or such behaviors will have minimal impact on their disease trajectory. Recent treatment advances have significantly prolonged survivorship, potentially challenging these conventions. Our goals were to: 1) measure lifestyle behaviors and quality of life (QOL); 2) assess adherence to the diet and physical activity guidelines proposed by the American Cancer Society (ACS) for cancer survivors; and 3) inform future interventions in these women. Methods: Women with metastatic breast cancer were screened and recruited over a 4 month period from two university hospitals. Twenty-five women completed questionnaires providing cross-sectional demographic, clinical, dietary intake, exercise and QOL data. Adherence to the ACS diet and physical activity guidelines was determined, assigning each of the four lifestyle behaviors (healthy weight, regular physical activity, plant based diet, limited alcohol consumption) a score of 0-2, depending on level of concordance. Means (± standard deviations), frequencies and t-tests results are reported. Results: Participants were 58.8 (± 12.8) years old, predominantly minority, 36.9 (± 29.3) months post metastatic breast cancer diagnosis, receiving hormone (n = 11), chemo (n = 12) or targeted therapies (n = 2) and exhibited similar QOL scores compared to other women with metastatic breast cancer. The majority of women were overweight or obese (n = 14), not routinely physical active (n = 15), and displayed suboptimal dietary patterns (n = 22). The average ACS adherence score was 3.8 (± 1.1, range 2-6). Most participants desired lifestyle information at the time of diagnosis (n = 13) and thought future interventions should be clinic-based (n = 8), involve eHealth (n = 12) and address social support (n = 12). Conclusions: These preliminary data support that a subset of women with metastatic breast cancer are in need of and desire carefully tailored, lifestyle strategies to address symptom burden, including weight management. The implications of a lifestyle program on QOL in this population remain unexplored.
Inappropriate prescribing in older patients with cancer.
Authors: Jane Sze Yin Sui, Ciara Marie Kelly, Patrick Barry, Emmet Jordan, Zia Rehman, Mateen Akhtar, Loretto Gallagher, Anastasia Horan, Carmel O'Keeffe, Miriam O'Connor, Paula Calvert, Derek Gerard Power, Anne M. Horgan
Journal: Journal of Clinical Oncology (2013)

e20550 Background: Inappropriate medication use is common among community dwelling and hospitalized older adults but understudied in the oncology population. We measured the incidence of inappropriate prescribing among older cancer patients attending an oncology day-ward for systemic therapy. Methods: The tools used to identify inappropriate prescribing were the Beers’ criteria (both Independent [ID] of and Considering diagnosis [CD] – 2012 version) and the STOPP tool (Screening Tool of Older People’s potentially inappropriate Prescriptions). The setting was an urban based hospital oncology day-ward. Consecutive subjects ≥ 70 years were screened and all had both tools applied to their prescription drugs, cross referenced with their current active medical diagnosis. Results: Medication lists were collected from 96 patients from November 1 st 2012 to January 31 st 2013: 52% male, mean age 75 years (range 70-88). The most common cancers were colorectal (24%), breast (23%), lung (11%) and prostate (11%). 38 patients (40%) were on 0-4, 49 (51%) on 5-9 and 9 (9%) on &gt;9 medications. The total number of inappropriate prescriptions (Beers ID and CD “medications to avoid”) was 34, prescribed in 29 (30%) patients. The most common drug prescribed inappropriately as per these criteria was the antiemetic, metoclopramide (n=10, 29%). An additional 70 prescriptions were dispensed for Beers “medications to use with caution” in 55 (57%) patients - predominantly vasodilators. The STOPP tool identified 13 inappropriate prescriptions in 12 patients (13%). The two most commonly prescribed inappropriate medications were long acting benzodiazepines (n=4) and long term use of sedating antihistamines (n=3). Conclusions: This study identified a high rate of inappropriate prescribing among this population using both tools, with a higher rate identified by the Beers Criteria. Routine application of a validated tool to identify inappropriate prescribing has merit in the oncology setting to minimize risk to patients. However, the development of an easy to apply tool that considers the underlying cancer diagnosis, prognosis, cancer treatment and necessary supportive therapy is warranted.
Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate
Authors: Shumei Kato, Aaron Goodman, Vighnesh Walavalkar, Donald A. Barkauskas, Andrew Sharabi, Razelle Kurzrock
Journal: Clinical Cancer Research (2017)

Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. ©2017 AACR.
Comparing the outcome between multifocal, multicentric, and bilateral breast cancer and the impact of guideline-adherent adjuvant treatment: A retrospective multicenter cohort study of 5,308 patients.
Authors: Lukas Schwentner, Regine Wolters, Igor Novopashenny, Manfred Wischnewsky, Rolf Kreienberg, Achim Wöckel
Journal: Journal of Clinical Oncology (2012)

1078 Background: Beside unifocal-unilateral (UU) breast cancer (BC) there are several subtypes including multifocal, multicentric and bilateral BC. This study tries to answer the following questions:(1) Does localization (multifocal/multicentric/bilateral) influence outcome concerning BC mortality? (2) Is there an impact of guideline-adherent adjuvant treatment in these BC subtypes? Methods: This German multi-center retrospective cohort study called BRENDA included 5277 patients obtained from 1992 until 2005. The definition of guideline adherence was based on the German national S3 breast cancer guideline (2004). Results: 4085 (77.4%) were UU, 698 (13.2%) multifocal, 282 (5.3%) multicentric and 212 (4.0%) bilateral BC. RFS in multifocal [p=0.003; HR=1.35 (95% CI: 1.11-1.65)], multicentric [p&lt;0.001; HR=1.76 (95% CI: 1.31-2.34)] and bilateral [p&lt;0.001; HR=2.28 (95% CI: 1.76-2.97)] BC was significantly lower compared to unilateral-unifocal BC. Concerning OAS we found only a borderline difference between UU and unilateral-multifocal [p=0.057; HR=1.22 (95% CI: 0.99-1.48)], but a significant difference between multicentric [p= 0.018; HR=1.42 (95% CI: 1.06-1.90)] resp. bilateral [p&lt;0.001; HR=2.87 (95% CI: 2.21-3.74)] and UU-BC. There was a significant impact by guideline adherent adjuvant therapy [UU: p&lt;0.001, HR=2.76,95%C.I.:2.25-3.38], [unilateral-multifocal: p=0.001, HR=2.04,95%C.I.:1.33-3.14], [unilateral-multicentric: p=0.020, HR=2.13,95%C.I.:1.13-4.01] and [bilateral: p=0.042, HR=2.10,95%C.I.:1.03-4.31]. After stratifying for 100% guideline adherent treatment and adjusting for age, tumor size, nodal status and grading there was no significant difference in RFS/OAS in patients with multifocal [p=0.282/p=0.610], multicentric [p=0.829/p=0.609] or bilateral BC [p=0.457/p=0.773] compared to patients with UU-BC. Conclusions: Patients with multicentric and bilateral BC have primarily a worse prognosis in terms of RFS and OAS. However if guideline adherent adjuvant treatment was applied it was no more possible to demonstrate significant differences in survival.
Inhibition of the CRBN-DDB1-CUL4-ROC1 E3 Ubiquitin Ligase Mediates the Anti-Proliferative and Immunomodulatory Properties of Lenalidomide
Authors: Jan Krönke, Anupama Narla, Slater N. Hurst, Namrata Udeshi, Monica Schenone, Marie McConkey, Peter Grauman, Dirk Heckl, Randall McAuley, Christie Ciarlo, Eamon Comer, Xiaoyu Li, Steven A. Carr, Benjamin L. Ebert
Journal: Blood (2012)
Phase I/II study of LOC-paclitaxel (LOC-Pac) in patients (pts) with metastatic melanoma.
Authors: Agop Y. Bedikian, Kevin B. Kim, Nicholas E. Papadopoulos, Wen-Jen Hwu, Sapna Pradyuman Patel, Michael A. Davies, Sandy Mahoney, Patrick Hwu, Scott Woodman
Journal: Journal of Clinical Oncology (2012)

e19039 Background: LOC-Pac is a covalent conjugate of paclitaxel (Pac) and omega-3 fatty acid. In in-vivo animal studies in various tumor models LOC-Pac was found to be superior to Pac in safety as determined by maximum tolerated dose and efficacy as determined by delay in tumor growth and complete response rates. This is the first in human phase I study of LOC-Pac. Methods: Adult patients (pts) with confirmed metastatic melanoma (MM), life expectancy &gt; 3 months, with normal renal and liver profiles, failed prior systemic therapy (Rx) or ineligible for Rxs of higher priority, ECOG performance status 0-2 and with at least one measurable metastasis (met) were eligible to this trial. Pts with known CNS met, neuropathy &gt; grade 1, hypersensitivity to cremophor or Paclitaxel and HIV infection, serious concurrent medical conditions were excluded. LOC-Pac was given intravenously over 1 hour on days 1, 8, 15, 22 and 29 every 42 days. Each dose of LOC-Pac was preceded by a dose of dexamethasone, diphenhydramine and cimetidine. LOC-Pac dose was escalated from 100 to 150, 200, 300, 400, 500 and 600mg/m2 after safety of the prior dose level was confirmed in cohorts of 3 pts each. Responses were assessed by RECIST every 6 weeks. Results: 18 pts were treated. Median age was 61 (range 49-76) years, with 83% male and 100% Caucasian. 16 pts had received prior Rx with cytotoxics/ biologicals. Tumor stages were III/M1a/M1b/M1c in 2/1/3/12 pts. 4 pts had elevated baseline serum LDH levels. 53 cycles have been given. There were 3 responses. A pt with lung met had histologically confirmed complete response. A pt with l. node and spleen mets and another with adrenal mets had partial response. 5 pts had stable disease. The Rx related toxicities were mild and manageable. There were no grade 3/4 toxicities. Grade 2 toxicities included fatigue in 9 (17%) of cycles, Neuropathy and dyspnea each in 7(13%) anemia in 3 (6%), leucopenia and neutropenia, urinary tract infection and seizure occurred in 1(2%) of cycles each. No pt developed alopecia or discolored brittle nails. Currently pts are being accrued at 600mg/m 2 dose level. Conclusions: LOC-Pac is effective against MM with an acceptable toxicity profile and may provide a way to deliver higher dose of Pac and improve its clinical efficacy.
The impact of locoregional recurrence on survival in older patients with differentiated thyroid cancer.
Authors: David Mitchell Marcus, Renjian Jiang, Kevin C. Ward, Kristin A. Higgins, Nabil F. Saba, Trad Wadsworth, Jonathan Jay Beitler
Journal: Journal of Clinical Oncology (2014)

e17003 Background: Locoregional recurrence of differentiated thyroid cancer (DTC) is usually salvaged effectively with neck dissection (ND). It is unknown whether recurrence may negatively impact survival in patients with adverse prognostic factors, such as advanced age. We designed a study to examine the prognostic impact of locoregional recurrence of DTC on survival in Medicare patients age ≥65. Methods: The Surveillance, Epidemiology, and End Results database was linked to Medicare claim files to identify patients age ≥65 diagnosed between 1991-2007 with non-metastatic, first primary DTC. Patients who underwent ND >6 months after their initial diagnosis of DTC were considered to have recurrent disease (RD). We compared overall survival (OS) and cause-specific survival (CSS) for patients with RD versus a matched cohort of patients with non-recurrent DTC. Non-recurrent subjects were matched (5:1) on year of diagnosis and time until RD for their counterpart. Survival time was measured from the time of RD. Chi-square and t-tests were used to compare patient characteristics between groups. The Kaplan-Meier method was used to estimate unadjusted survival with a log rank test to compare survival between groups. Cox proportional hazards modeling was used to identify patient and disease factors independently associated with OS and CSS. Results: We identified 6,235 eligible patients, including 214 with treatment defined RD. Compared to their matched controls (n = 1,070), patients with RD were more likely to be non-Caucasian (p <0.05), male (p <0.05), and have more advanced stage at presentation (p <0.05). Patients with RD had inferior OS (p <0.01) and CSS (p <0.01) compared to their matched controls. For patients with RD, 5-year OS and CSS were 55.1% and 64.4%, compared to 72.1% and 92.9% for non-recurrent patients. On multivariate analysis that included age, stage, race, and gender as covariates, RD was independently associated with inferior 5 year OS (HR 1.51, p = 0.02) and CSS (HR 5.05, p <0.01). Conclusions: Locoregional recurrence of DTC as defined by treatment with ND ≥6 months after diagnosis negatively impacts OS and CSS in patients age ≥65. Adjuvant therapy may be warranted in at least some of these patients.
Identification through genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) associated with extreme phenotypes of tobacco-induced non-small cell lung cancer (NSCLC) risk.
Authors: Jose Luis Perez-Gracia, María José Pajares, Maria Pilar Andueza, Guillermo Pita, Juan Pablo de Torres Tajes, Ciro Casanova, Javier Zulueta, Alfonso Gurpide, José María López-Picazo, Rebeca Baz Davila, Rosario Alonso, Nuria Alvarez, Ignacio Melero, Miguel F. Sanmamed, Ruben Pio Oses, Antonio Agudo, Carlos Gonzalez, Javier Benitez, Luis M. Montuenga, Anna Gonzalez-Neira
Journal: Journal of Clinical Oncology (2014)

11046 Background: SNPs may modulate individual susceptibility to carcinogens. We used GWAS to identify SNPs associated with individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco induced NSCLC. We hypothesized that selection of extreme phenotypes would enrich the frequencies of alleles that contribute to the trait, thus increasing the power to identify them. Methods: From an identification cohort (n=3631) we selected caucasian heavy smokers that either developed NSCLC at an early age (cancer cohort) or that did not present NSCLC at an advanced age (cancer free cohort). We analyzed their genomic DNA using the array Illumina HumanOmni 2.5 Quad that includes over 2 million powerful markers selected from the 1000 Genomes Project, targeting genetic variation down to 1% minor allele frequency. Results: 96 patients (48 per cohort) were selected. Mean age for the cancer and cancer free cohorts was 49 (range 38-55) and 76 years (72-84). Mean tobacco consumption was 41 (range 18-99) and 68 pack-years (40-120). GWAS identified 8 SNPs differentially expressed by logistic regression and 54 SNP by Fisher´s test (p<10-5). Odds-ratio ranged between 0.08-0.29 for protective SNP and 3.4-11.2 for SNP that increased NSCLC risk. Candidate SNPs were located within or in adjacent regions of genes related to: a) oncogenic and tumor-suppressor pathways: CSMD1, FOXF1, MSX2, SOX11; b) tobacco induced NSCLC: ABCB5; c) regulation of transcription: DROSHA, HDAC9, KIAA0947; d) regulators of inflammation through the NF-kappa pathway: pellino E3, TRIM9; e) previously linked to carcinogenesis and cancer prognosis: ABHD6, GRIK1, RAB40B, SCN1A, SLC24A2, SLC25A26, ZFYVE26; and f) not previously linked to cancer: ACER3, AP000946.2, ATP10A, ATP10D, CNTN5, CYYR1, LINC00572, PDE10A, RP11-115D19.1, RP11-202D1.3, RP11-521E5.1, SYTL5, ZPBP. Conclusions: We identified candidate SNPs potentially associated with the risk of developing tobacco induced NSCLC in individuals with extreme phenotypes. Validation of the most significant SNPs in an independent set of individuals with similar phenotypes is ongoing.
Quality not quantity: Key success factors from the first decade of safety reports from the Research on Adverse Drug Events and Reports project (RADAR)
Authors: C. Bennett, B. J. Edwards, C. C. Tigue, D. W. Raisch, D. M. Courtney, J. M. McKoy, D. P. West
Journal: Journal of Clinical Oncology (2009)

6559 Background: RADAR is the only independent academic pharmacovigilance organization funded exclusively by peer-reviewed grants. We describe the role of high quality case reports in the detection of drug safety signals. Methods: RADAR has identified 11 cancer-related adverse drug reactions (ADRs). Initial reports for small numbers of cases were obtained from our own institution, NU, (4 ADRs) or from referral centers (7 ADRs). Clinicians at these centers voluntarily provided brief case reports to RADAR, who submitted detailed case reports to the FDA/manufacturer. Clinicians were promised that patient/provider data would be kept confidential and that these data would be submitted as peer-reviewed manuscripts. Results: See Table. Conclusions: RADAR was successful at signal generation and amplification because it focused on quality, not quantity of case reports. Pharmacovigilance efforts that allow clinicians to complete brief forms, maintain confidentiality of patient and provider, and result in submission of collaborative manuscripts may improve early detection of drug safety signals initiatives in oncology. [Table: see text] No significant financial relationships to disclose.
CURVA DE APRENDIZAJE DE DIAGNÓSTICO HISTOLÓGICO EN TIEMPO REAL DE PÓLIPOS DIMINUTOS CON NBI E I-SCAN: ESTUDIO PROSPECTIVO EN CENTRO NO TERCIARIO
Authors: A Huerta Madrigal, I Moraleja, J Fernández Francisco, M Aguirresarobe, S Torres, A Rocha, I Rodríguez, A Saiz, E De Miguel, A Bernal, JL Cabriada
Journal: Endoscopy (2015)

Introducción: El diagnóstico histológico en tiempo real con alta confianza (DHTRac) de pólipos colónicos diminutos (PD) permite políticas de “resecar y descartar” o “diagnosticar y dejar” si se logra una precisión de intervalos > 90% y un VPN > 90% para adenomas distales.
Should Patients Be Required to Undergo Standard Chemotherapy Before Being Eligible for Novel Phase I Immunotherapy Clinical Trials?
Authors: Benjamin S. Wilfond, Christian Morales, Holly A. Taylor
Journal: The American Journal of Bioethics (2017)

"Should Patients Be Required to Undergo Standard Chemotherapy Before Being Eligible for Novel Phase I Immunotherapy Clinical Trials?." The American Journal of Bioethics, 17(4), pp. 66–67