tbuckley/cabot-search huggingface dataset:
Relationship of low stathmin expression and benefit from TPF induction chemotherapy and its role in chemoresistance via mutant p53 in oral cancer.
Authors: Lai-Ping Zhong, Hai-long Ma, Wu-tong Ju, Zhi-yuan Zhang
Journal: Journal of Clinical Oncology (2018)

e18034 Background: A phase 3 trial (NCT01542931) demonstrated failure to improve survival when docetaxel, cisplatin, and 5-fluorouracil (TPF) based induction chemotherapy was added to standard therapy compared to standard therapy alone in patients with locally advanced oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the translational value of stathmin and its role in tumorigenesis and chemoresistance as well as its transcriptional regulation by mutant p53 in OSCC. Methods: We evaluated the stathmin expression in pretreatment biopsies from 256 OSCC patients in the phase 3 trial. Tumorigenicity and chemoresistance regulated by stathmin were investigated using in vitro and in vivo OSCC models. Regulation of mutant p53 on stathmin was detected by ChIP and dual-luciferase reporter assays. Results: OSCC patients with low stathmin expression benefited from TPF induction chemotherapy, which was associated with significantly increased overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival. Overexpression of stathmin was identified using 2-DE and LC-MS/MS and confirmed in OSCC tissues and lines. Down-regulation of stathmin expression in OSCC significantly inhibited cell proliferation, colony formation, migration and tumorigenesis, and enhanced sensitivity to docetaxel and cisplatin in vitro and in vivo. Mutant p53 (R175H, G245C, R282W) bound to the stathmin promoter and transcriptionally activated stathmin expression. Conclusions: Low stathmin expression is a predictive biomarker to identify the OSCC patients who may benefit from TPF induction chemotherapy on survival. Overexpression of stathmin promotes tumor progression and chemoresistance to docetaxel and cisplatin, and it is transcriptionally activated by mutant p53 in OSCC.
Cost of inpatient admissions for immune-related adverse effects from immune checkpoint inhibitor therapy: A single center experience.
Authors: Jacqueline N. Chu, Jin G. Choi, Sassan Ostvar, Justine Vanessa Cohen, Ian Matthew Allen, Michael Lawrence Dougan, Alexandra C Villani, Molly Thomas, Mazen Nasrallah, Amanda Guidon, Steven T Chen, Sara Schoenfeld, Meghan Sise, Rebecca Leaf, Tomas G Neilan, Alex Faje, Ryan J. Sullivan, Aditya Bardia, Chin Hur, Kerry Lynn Reynolds
Journal: Journal of Clinical Oncology (2018)

3060 Background: Immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1 antibodies represent a paradigm shift in the treatment of many advanced malignancies. However, immune related adverse effects (irAEs) result in increasing inpatient admissions and the cost burden related to irAEs is unknown. We describe the cost of admissions for irAEs to a tertiary academic center. Methods: Data were collected on patients treated with checkpoint inhibitors who were admitted to Massachusetts General Hospital (Feb 2011 to June 2017). Admissions were classified as irAE-related or non irAE-related after review by two independent physicians, including one sub-specialist. Admission costs were obtained using our institution's platform, a transition cost accounting system (TSI), to estimate total, variable, and direct costs, which were converted to 2017 USD. Results: The annual cumulative cost of all admissions for irAEs rose from $218,700 in 2011 to $1.3 million in 2016. However, the average cost of irAE admissions was significantly lower than that of non-irAE admissions ($3,142/day vs. $8,257/day, p = 10-10). irAE cost by therapy was not significantly different. irAE costs by organ varied from $1,990 to $6,674/day. Conclusions: Although total costs for irAE admissions have risen almost six-fold from 2011 to 2016, these admissions are less costly compared to other oncologic admissions, possibly because irAEs are more readily intervenable. The added cost burden to usual oncologic care from irAEs may be less than anticipated. Year N Annual cumulative cost of irAE admissions (US$) 2011 15 218,739 2012 14 247,592 2013 21 302,538 2014 44 774,399 2015 37 715,601 2016 59 1,271,187 Type of admission N Cost (US$) 95% CI Cost/day (US$) 95% CI LOS irAE 214 18,819 (16,983-20,654) 3,142 (2,744-3,541) 6.4 non-irAE 658 24,918 (22,612-27,223) 8,257 (6,770-9,745) 6.2 non-irAE (outliers removed) 601 18,092 (17,100-19,083) 4,807 (4,455-5,158) 6.3 Drug N Cost (US$) 95% CI Cost/day (US$) 95% CI LOS Ipilimumab + nivolumab 37 16,273 (8,032-24,515) 2,774 (2,443-3,104) 5.4 Nivolumab or pembrolizumab 67 22,374 (17,647-27,100) 3,088 (2,723-3,453) 7.6 Ipilimumab 59 19,433 (13,174-25,692) 3,519 (2,428-4,610) 5.9
P04.40 Telomere maintenance and glioma predisposition - relevance of telomere genetic score and telomere length
Authors: S Degerman, C Wibom, U Andersson, M Landfors, A M Dahlin, B S Melin
Journal: Neuro-Oncology (2018)

Germline variants associated with predisposition for cancer are frequently located in genes involved in genome integrity. The telomeres at the chromosome ends are important in maintaining genomic stability, and germline variants in telomere regulating genes have been associated with both telomere length and glioma risk in repeated studies. In this case-control study, we investigated the association of measured leukocyte telomere length with genetically estimated telomere length risk score (TL-GRS) and the 27 currently identified glioma risk loci. Peripheral blood samples from 421 glioma patients and 671 age- and gender- matched controls were analyzed for relative leukocyte telomere length (rLTL) by qPCR. Genetic variants in telomere and glioma associated genes were genotyped by SNP-arrays, and TL-GRS was calculated. Associations between the genotypes of interest and rLTL were characterized by means of “multinomial logistic regression analysis” including covariates. Glioma patients had similar TL-GRS, but longer rLTL, than controls. Long rLTL was a risk factor for glioma in contrast to TL-GRS that was not. Among controls, a correlation between rLTL and TL-GRS was found, but this association was not seen among glioma cases. Notably, the correlation between rLTL and TL-GRS was stronger among men than women. In this Swedish glioma case/control cohort, long rLTL was associated with increased risk of glioma but high TL-GRS was not. The association between rLTL and TL-GRS seen in controls was absent in glioma cases.
Alteration of mutant allele frequency in visceral metastases of melanoma.
Authors: Viktória Doma, Orsolya Papp, Erzsébet Rásó, Tamás Barbai, Lilla Reiniger, Laura Vízkeleti, Jozsef Timar
Journal: Journal of Clinical Oncology (2018)

e21528 Background: Metastatic drivers in melanomas are in focus of translational research. Methods: 50 patients were collected with primary skin melanomas and 139 corresponding visceral metastases at autopsy. Oncogenic driver mutations were determined by Sanger- and pyrosequencing. Mutant variant allele frequencies (MAF) were re-calculated compensating for tumor/normal cell ratio. Chromosome Analysis Suite 3.3. was used for cytognetic analysis underlying BRAF/NRAS MAF alterations. Results: BRAF, NRAS and KIT mutations were found at 64%, 24% and 0%, respectively. In case of BRAFmut/NRASmut tumors CNS was the most frequent metastases, followed by lung in BRAFmut and liver in NRASmut tumors. MAF increased significantly in metastases compared to primaries in BRAFmut tumors exclusively which was due to significant increase in lung- and less common metastases. Based on MAF values mutant alleles were classified as heterozygous-monoclonal ( > 40%), polyclonal (15-40%) or subclonal ( < 15%). Interestingly, both oncogenic drivers MAF values were < 50% in the majority of the primary tumors (41/44 = 93,2%). Stability of the MAF value is characteristic of NRASmut melanoma (6/12 = 50%) unlike in BRAFmut tumors (10/32 = 31.3%) where increase in MAF is the most frequent genetic event (18/32 = 56.3%). Almost third of primary melanomas (14/44 = 31,8%) contains one subclonal driver mutation. Increased MAF in metastases of BRAFmut tumors was most frequently accompanied by single copy increase of BRAF (polysomy). In lung metastases true BRAF gene amplification were detected. In NRASmut tumors the most frequent genetic alteration is LOH of various chromosomal regions, especially in liver metastasis. NRAS gene was diploid in primaries and metastases. Conclusions: MAF can change unpredictably in metastases. Decrease in MAF is a rare event during visceral metastatic progression and is independent from oncogenic drivers. We suggest to characterize driver status of metastases rather than primaries before clinical decision making. It is clinically relevant to provide MAF values in the molecular report. This work is supported by NKFI-K-112371, NVKP-16-1-2016-0004, NAPB/KTIA13-0021 and ÚNKP-17-3-III-SE-7.
Quantitative assessment of learning behaviors for oncology providers.
Authors: Marie Wood, Thomas J. George, Rami Manochakian, Maura Polansky, Allyson Baer, Anne Grupe, Yu Shyr, Cathy Wang, Leora Horn
Journal: Journal of Clinical Oncology (2018)

11004 Background: Understanding how different types of providers choose topics and activities for learning is key to meeting their needs. We sought to identify these needs in a diverse group of oncology providers. Methods: An online focus group study was conducted between November 2015 and August 2016. Participants were ASCO members and chosen by convenience and stratified random sampling. Participants included international, domestic, academic, and private practice providers as well as physicians and advanced practitioners (AP). Providers were asked monthly to journal their learning needs and explain how they identified that need. They were then asked what learning activity they chose to meet that need and what informed their choice. Results: 201 journal entries from 32 providers were reviewed; 47% from academic settings, 9% APs, and 41% international. Individuals provided an average 6 entries (range 1 to 17). Learning needs were associated with practice setting and professional role, with a significant association between practice setting and a making a choice based on a self-identified knowledge gap (p = .005). Colleague recommendation impacted learning needs for APs (p < .001), and patient cases drove > 50% of identified learning needs across groups. Preference for learning activity type, formal versus informal, was associated with practice setting (p = .02). The choice of learning activity was associated with practice setting, professional role, and geographic location, with international providers more likely to consider cost (p = .001) and provider reputation (p = .03) when selecting activities. Colleague recommendation was important for APs (p = .011). Over 75% of learner responses identify convenience and quality of content as factors in choosing an activity. Conclusions: To our knowledge, this study represents the first quantitative assessment of learning behaviors for oncology providers and shows that identification of learning needs and activity selection differ among them. Our cohort was small and may limit the generalizability of our findings. Future research should focus on educational needs of different members of the oncology care team and rank priorities for learning.
Management of common adverse effects of antipsychotic medications
Authors: T. Scott Stroup, Neil Gray
Journal: World Psychiatry (2018)

The benefits of antipsychotic medications are sometimes obscured by their adverse effects. These effects range from relatively minor tolerability issues (e.g., mild sedation or dry mouth) to very unpleasant (e.g., constipation, akathisia, sexual dysfunction) to painful (e.g., acute dystonias) to disfiguring (e.g., weight gain, tardive dyskinesia) to life‐threatening (e.g., myocarditis, agranulocytosis). Importantly, adverse effect profiles are specific to each antipsychotic medication and do not neatly fit into first‐ and second‐generation classifications. This paper reviews management strategies for the most frequent side effects and identifies common principles intended to optimize net antipsychotic benefits. Only use antipsychotics if the indication is clear; only continue antipsychotics if a benefit is discernible. If an antipsychotic is providing substantial benefit, and the adverse effect is not life‐threatening, then the first management choice is to lower the dose or adjust the dosing schedule. The next option is to change the antipsychotic; this is often reasonable unless the risk of relapse is high. In some instances, behavioral interventions can be tried. Finally, concomitant medications, though generally not desirable, are necessary in many instances and can provide considerable relief. Among concomitant medication strategies, anticholinergic medications for dystonias and parkinsonism are often effective; beta‐blockers and anticholinergic medications are useful for akathisia; and metformin may lead to slight to moderate weight loss. Anticholinergic drops applied sublingually reduce sialorrhea. Usual medications are effective for constipation or dyslipidemias. The clinical utility of recently approved treatments for tardive dyskinesia, valbenazine and deutetrabenazine, is unclear.
TCT-291 Impact of chronic kidney disease on left main coronary artery disease undergoing percutaneous coronary intervention (IRIS-MAIN registry)
Authors: Dae-Won Kim, Keepyung Hong, Sung-Mi Kim, Kyun Young Kim, Dong-Bin Kim, Sung-Ho Her, Hawook Park, Mahn Won Park, Gyung-Min Park, Jee Hyuk Kim, Byung-Hee Hwang
Journal: Journal of the American College of Cardiology (2018)
Characteristics of individuals self-reporting a higher-than-average risk of cancer.
Authors: Sebastien Couraud, Jerome Viguier, François Eisinger, Morgan Roupret, Chantal Touboul, Christine Lhomel, Laurent Greillier, Thibault De La Motte Rouge, Jean F. Morere
Journal: Journal of Clinical Oncology (2018)

e13555 Background: Many factors affect decisions regarding cancer screening. Risk perception depends on individual behavior but also on emotional, social and cultural issues. We studied individuals self-reporting a higher-than-average risk of cancer, and sought to distinguish between actual risk and possible misconceptions. Methods: The French nationwide observational survey, EDIFICE 6, was conducted online (26 June-28 July 2017) on a core sample of 12 046 individuals (age, 18-69 years). Representativeness was ensured by quota sampling on age, gender, profession, and stratification by geographical area/type of urban district. Multivariate stepwise logistic regression analysis was used to identify pointers of higher-than-average self-risk-assessment for breast (BC), cervical (CC), colorectal (CRC) and lung cancer (LC). Results: In all, 11 307 individuals (5776 women) were questioned about self-perceived higher-than-average risk. Thirty eight (N = 2220; BC) and 25% (N = 1476; CC) of women assessed their own risk as higher than average; 25% (N = 2806; CRC) and 31% (N = 3544; LC) of the total population self-assessed their individual risk as higher than average. Features associated with this perception were: for BC, accompanying someone close during cancer treatment (OR = 1.34, 95% CI = [1.14-1.57]), current smoker (OR = 1.28, [1.12-1.45]) and alcohol consumption (OR = 1.15, [1.02-1.28]). For CC: manual work (OR = 1.57, [1.12-2.18]), social vulnerability (OR = 1.31, [1.15-1.49]). For CRC: male (OR = 1.58, [1.44-1.73]), social vulnerability (OR = 1.37, [1.25-1.51]). For LC: current smoker (OR = 7.89, [7.13-8.74]), ceased tobacco ≥age 45 (OR = 2.65, [2.21-3.18]), current e-cigarette use (OR = 1.82, [1.55-2.15]). Being close to someone with cancer was a common feature of individuals assessing their own risk as higher than average: BC (OR = 1.71, [1.45-2.02]), CC (OR = 1.40, [1.23-1.59]) and CRC (OR = 1.51, [1.38-1.65]). Conclusions: Genuinely at-risk individuals identify with well-known risk factors e.g., tobacco for LC. Being close to a person with cancer raises awareness but can lead to needless overestimation of risk. Socioeconomic features observed hint at inadequate knowledge of cancer or difficulties in healthcare access.
Identification of Aurora-A and C-Met as recurrence predictor and therapeutic target for nasopharyngeal carcinoma.
Authors: XinJuan Fan, XiangBo Wan, Yikan Cheng
Journal: Journal of Clinical Oncology (2016)

e23171 Background: Among patients with locally advanced nasopharyngeal carcinoma (NPC) in endemic Southern China area, 30.0%-50.0% subset would develop recurrence or metastasis within 5 years after treatment. Identification recurrence related molecules might allow for timely identification of recurrence and target therapy for NPC. Methods: To identify candidate recurrence related molecules, we profiled global gene expression in NPC with a patient survival dataset. On the basis of The Cancer Genome Atlas (TCGA) analysis, we further selected the molecules with high risk for NPC recurrence. Moreover, xenograft animal model and 130 locally advanced NPC patients samples were used to validate the potential to target the selected molecules to prevent NPC recurrence. Results: Based on TCGA analysis and our previously constructed database, we selected 30 molecules that might be contributed to NPC recurrence: Cyclin D1, 14-3-3σ, Aurora-A, CENP-H, Stathmin, P21, CDC2, P27, ERK, p-ERK, Ki-67, E-Cadherin, β-Catenin, N-Cadherin, Snail, Twist, C-Met, nm23-H1, HIF-1α, COX2, MMP-2, MMP-9, TIMP-2, Bax, Bcl-2, Survivin, AKT 1, Beclin 1, EZH2, and LMP 1. Univariate and multivariate analyses confirmed that Aurora-A, MMP-9 and C-Met were independent prognostic biomarker to predict NPC recurrence (with all P < 0.05). For CNE-1 and CNE-2 NPC cells, VX-680, an Aurora-A specific inhibitor, and SU11274, a specific C-Met inhibitor, combined treatment significantly increased NPC cell sensitivity to radiation. Moreover, the similar results were also observed in NPC nude mice xenograft mode. We had construct the Aurora-A/C-met high expressed and Aurora-A/C-met low expressed PDX SCID mice, the combined therapeutic effect to radiation are ongoing testing. Conclusions: Based on this nonbiased method, we identified Aurora-A, C-Met and MMP-9 were the potential prognostic biomarker to predict NPC recurrence. Target Aurora-a and C-met with their specific inhibitor sensitized the NPC cell and tumor xenograft mice model to radiation, suggesting a promising way to upregulate radiosensitivity and abate radioresistant residue induced recurrence for nasopharyngeal carcinoma.
A novel acetylated derivative of vitexin improves the immunogenic profile of breast cancer through tuning miR-20a/MICA Axis
Authors: A.R. Awad, R.A. Youness, M. Ibrahim, A.A. Abdelmotaal, R.A. Assal, M.Z. Gad
Journal: Annals of Oncology (2018)

Background: The activating immune ligand, MICA, acts as a "kill me" signal through the NKG2D receptor expressed on natural killer (NK) cells that are key players in the fight against breast cancer (BC). Shedding of MICA during BC progression acts as a formidable barrier against NK cells' immune-surveillance. Recently, miR-20a was found to mediate immune escape through repressing MICA levels on BC cells. However, targeting miR-20a/MICA using natural compounds has seldomly been investigated. Vitexin, a flavone C-glycoside, showed potent anticancer properties. It was reported that acetylation of glycosides increases their cytotoxic activity, with an unknown impact on immunogenicity. Our group has successfully isolated 3'-O-acetylvitexin from Ocimum basilicum which showed potent cytotoxic effects against colon cancer cells but has never been investigated in BC. Our aim is to unravel the role of the immunogenic miR-20a/MICA axis in BC patients and its regulation by vitexin and 3'-O-acetylvitexin. Methods: Breast tissues were collected from 26 BC patients. ER, PR and HER2 expression was quantified using immunohistochemistry. MDA-MB-231 TNBC cells and MCF-7 HR+ BC cells were treated with serial dilutions of vitexin and 3'-O-acetylvitexin. Their cytotoxic activities were assessed using MTT, colony forming and migration assays. Total RNA was extracted, reverse transcribed, then MICA and miR-20a were quantified using qRT-PCR. Results: miR-20a is upregulated in BC patients, while MICA was downregulated in MDA-MB-231 compared to MCF7 cells. Vitexin decreased MDA-MB-231 cellular viability and migration capacity. 3'-O-acetylvitexin resulted in a more pronounced dose-dependent repression of TNBC cellular viability, colonogenicity and migration capacity. Treatment with vitexin didn't show any alteration in miR-20a but showed only 2 folds increase in MICA. However, 3'-O-acetylvitexin markedly decreased miR-20a with a concomitant increase in MICA by 12 folds. Conclusions: 3'-O-acetylvitexin displays more pronounced anticancer properties against TNBC through halting their progression and immune suppressive nature by modulating miR-20a/MICA axis. This highlights miR-20a/MICA axis as a potential therapeutic target in BC. Legal entity responsible for the study: German University in Cairo (GUC). Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Pooled analysis of venous thromboembolism (VTE) from four trials of necitumumab and chemotherapy for stage IV non-small cell lung cancer (NSCLC).
Authors: Kelvin Young, Luis G. Paz-Ares, Nick Thatcher, David R. Spigel, Javad Shahidi, Victoria Soldatenkova, Gerrit Grau, Raffael Kurek, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2016)

e20534 Background: Metastatic NSCLC is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance in patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC. Methods: Four trials of 1st-line treatment for Stage IV NSCLC were included in this analysis. SQUIRE (N = 1079) and INSPIRE (N = 616) were randomized phase 3 studies of cisplatin/gemcitabine +/- neci in squamous NSCLC and cisplatin/pemetrexed +/- neci in non-squamous NSCLC, respectively. JFCL (N = 161) was a randomized phase 2 study of carboplatin/paclitaxel +/- neci in squamous NSCLC. JFCK (N = 61) was a single arm study of cisplatin/gemcitabine+neci in squamous NSCLC. VTE risk was explored in each study in univariate analyses. A Cox proportional hazards model with treatment as a fixed covariate and any VTE (prior Hx and/or on-treatment) as a time-dependent covariate was used for survival (OS) analyses. Results: On-treatment VTE across studies ranged from 3.6-8.3% for chemo alone and 3.8-13.2% for neci+chemo. Neci+chemo was associated with increased VTE risk in SQUIRE (Relative Risk [RR] 1.699; CI 1.09-2.65), INSPIRE (RR 1.58; CI 0.99-2.52), and JFCL (RR 1.04; CI 0.20-5.49) compared to chemotherapy alone. Previous Hx of VTE was the strongest predictor of VTE in SQUIRE (RR 2.63; CI 1.296-5.34) and INSPIRE (RR 1.62; CI 0.79-3.33). In SQUIRE, other baseline risk factors with RR > 1.00 included age > 65, Hb < 10 g/dL, BMI > 35 kg/m2, and current smoking. Occurrence of VTE at any time was not associated with shorter OS in randomised trials: HR 1.06; CI 0.85-1.33 (SQUIRE), HR 0.99; CI 0.76-1.27 (INSPIRE), HR 1.16; CI 0.56-2.41 (JFCL). Conclusions: VTE was more frequent in patients on neci+chemo vs chemo alone, but was not associated with shorter OS. Hx of VTE was the most significant risk factor for VTE occurrence. A pooled analysis of all 4 trials is pending.