tbuckley/cabot-search huggingface dataset:
ABC trial (A011502): A randomized phase III double blinded placebo controlled trial of aspirin as adjuvant therapy for node positive breast cancer.
Authors: Wendy Y. Chen, Eric P. Winer, William Thomas Barry, Clifford A. Hudis, Thomas H. Openshaw, Kala Visvanathan, Banu Symington, Carol Matyka, Michelle D. Holmes
Journal: Journal of Clinical Oncology (2017)

TPS586 Background: In-vitro and in-vivo evidence suggest that aspirin, an inexpensive and widely available drug may have anti-tumor activity via effects on multiple pathways. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Furthermore, pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users, especially metastatic adenocarcinoma (RR 0.52 (95% CI 0.35-0.75). In order for aspirin to be considered standard of care, the exact benefits and risks for breast cancer survivors need to be confirmed in a randomized trial. Methods: The primary objective is to compare the effect of aspirin versus placebo upon invasive disease-free survival (iDFS) in stage II-III node-positive HER2 negative breast cancer patients. Secondary objectives include effects on overall survival and cardiovascular disease and to collect toxicity and adherence. A biospecimen repository will be created for future correlative analyses including tumor collection at baseline and blood and urine samples at baseline and 2 years. Questionnaires assessing lifestyle factors associated with inflammation (pain, sleep, stress, and depression) will also be collected at baseline and 2 years. Study design: Subjects will be randomized (1:1) to aspirin 300 mg vs placebo daily for 5 years in a double-blinded fashion. Stratification factors include hormone receptor status (positive vs negative), body mass index ( &lt; or ≥ 30 kg/m2), and stage (II vs III).Subjects will be followed every 6 six months while on study drug and then annually until 10 years from registration. 2936 patients will be enrolled with 80% power to detect HR 0.75. Eligibility: Eligible subjects include patients aged 18-70 diagnosed with a primary invasive stage II or III node positive HER2 negative breast cancer in the past year. Patients who currently use any oral or injectable anticoagulant or those with a prior history of GI bleeding, atrial fibrillation, myocardial infarction, or grade IV hypertension will be excluded. Patients who regular used aspirin over the past year will be excluded. Clinical trial information: NCT02927249.
ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells
Authors: Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis, Claude Haan
Journal: Molecular Cancer (2017)

Most melanoma patients with BRAFV600E positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAFV600E has been shown to affect the metabolism.Time course experiments and a series of western blots were performed in a panel of BRAFV600E and BRAFWT/NRASmut human melanoma cells, which were incubated with BRAF and MEK1 kinase inhibitors. siRNA approaches were used to investigate the metabolic players involved. Reactive oxygen species (ROS) were measured by confocal microscopy and AZD7545, an inhibitor targeting PDKs (pyruvate dehydrogenase kinase) was tested.We show that inhibition of the RAS/RAF/MEK/ERK pathway induces phosphorylation of the pyruvate dehydrogenase PDH-E1α subunit in BRAFV600E and in BRAFWT/NRASmut harboring cells. Inhibition of BRAF, MEK1 and siRNA knock-down of ERK1/2 mediated phosphorylation of PDH. siRNA-mediated knock-down of all PDKs or the use of DCA (a pan-PDK inhibitor) abolished PDH-E1α phosphorylation. BRAF inhibitor treatment also induced the upregulation of ROS, concomitantly with the induction of PDH phosphorylation. Suppression of ROS by MitoQ suppressed PDH-E1α phosphorylation, strongly suggesting that ROS mediate the activation of PDKs. Interestingly, the inhibition of PDK1 with AZD7545 specifically suppressed growth of BRAF-mutant and BRAF inhibitor resistant melanoma cells.In BRAFV600E and BRAFWT/NRASmut melanoma cells, the increased production of ROS upon inhibition of the RAS/RAF/MEK/ERK pathway, is responsible for activating PDKs, which in turn phosphorylate and inactivate PDH. As part of a possible salvage pathway, the tricarboxylic acid cycle is inhibited leading to reduced oxidative metabolism and reduced ROS levels. We show that inhibition of PDKs by AZD7545 leads to growth suppression of BRAF-mutated and -inhibitor resistant melanoma cells. Thus small molecule PDK inhibitors such as AZD7545, might be promising drugs for combination treatment in melanoma patients with activating RAS/RAF/MEK/ERK pathway mutations (50% BRAF, 25% NRASmut, 11.9% NF1mut).
Preferred lifestyle upon advanced cancer diagnosis: Comparison of perspectives of advanced cancer patients, family members, and physicians in Japan.
Authors: Mioko Ikushima, Jiichiro Sasaki, Seigo Nakamura, Naomi Sakurai, Michiko Oki, Yuhiko Nogi, Yosuke Uchitomi
Journal: Journal of Clinical Oncology (2014)

e20559 Background: In many societies including Japan, not only cancer patients and physicians, but families also play a prominent role when making treatment decisions. Opinions of each party do not necessarily coincide however and the gaps can cause conflicts at times. This study compares the perspectives of each party to explore similarities and differences. Methods: The study was conducted in Dec. 2012 via internet using market research firm panels. 1,477 completed the self-administered questionnaire, but data from 523 participants (104 advanced cancer (AC) patients/ 119 family members of AC patients/ 300 physicians) is analyzed here. To explore the lifestyle they would prefer upon cancer diagnosis, participants made multiple choices on 34 QOL related criteria, created referring to FACT-G and survey supervisors' opinions. Results: Families had significantly higher (P<0.05) percentage of
Erratum: Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia
Authors: N I Noguera, E Ammatuna, D Zangrilli, S Lavorgna, M Divona, F Buccisano, S Amadori, C Mecucci, B Falini, F Lo-Coco
Journal: Leukemia (2007)
High body mass index and the risk of hepatocellular carcinoma
Authors: Zheng Wang, Han Zhang, Jun Han, Meng-Chao Wu, Tian Yang
Journal: Gut (2017)

We read with great interest the recent article by Hagstrom et al, 1 in which they used register data from more than 1.2 million Swedish men enlisted for conscription between 1969 and 1996 in order to investigate the relationship between body mass index (BMI) in late adolescence and future liver diseases. During a follow-up of more than 34 million person-years, 251 cases of hepatocellular carcinoma (HCC) were identified from the Swedish Cancer Register (SCR). In this study, the authors used a sample survey …
The effect of proteolytic enzyme-containing gargling agents on severe stomatitis caused by therapy for head and neck cancer.
Authors: Masatoshi Ohmae, Norifumi Moriasa, Naoki Nakagwa, Yusei Fujia, Itsuro Kato, Mitsuhiro Nakazawa, Makoto Tahara
Journal: Journal of Clinical Oncology (2014)

6079 Background: Severe stomatitis is one of the most frequent and undesirable side effects of chemotherapy (CT) and chemoradiation therapy (CRT) for the treatment of head and neck cancer. It remarkably limits patients’ quality of life, and in some cases, it becomes a dose-limiting factor. Such stomatitis is usually treated with oral care, anti-inflammatory agents, and analgesics. As for gargling agents, sodium gualenate hydrate, aspirin, and glycerin are widely used for oral care; however, they typically offer insufficient pain relief. Objective: To devise gargling agents to relieve pain and other related symptoms induced by CT or CRT for head and neck cancer. Methods: We focused on the necrotic tissue covering the inflammatory mucosa as an exacerbating factor for stomatitis, and we empirically applied a proteolytic enzyme to remove the necrotic coating and relieve the pain. We used 2 proteolytic enzymes, bromelain and pronase, as topical oral antiphlogistics, which are easily available as oral medicines, and established 3 gargling agent treatment groups: G, gualenate hydrate + glycerin; GB, G + bromelain; and GBP, GB + pronase. Bromelain is a general name for a family of sulfhydryl proteolytic enzymes. Thirty patients were included in this study and received CT or CRT. When they developed stomatitis during the course of CT or CRT, they were randomly assigned into 1 of the 3 above groups. Pain intensity was measured with a 100-mm visual analog scale (VAS) and degree of discomfort was estimated using the face scale (FS) at day 0 (just prior to treatment initiation) and at day 7. The effects of the gargling agents were evaluated by changes in the VAS and FS scores Results: The changes in the VAS score for groups G, GB, and GBP were −18, −20, and −42, respectively. The FS score for each group decreased by 1.5, 1.2, and 2.7 points, respectively. Conclusions: Proteolytic enzyme-containing gargling agents are beneficial for the treatment of severe stomatitis related to cancer therapy for the head and neck region.
Co-administration of NO-Aspirin (NCX-4016) and Aspirin prevents platelet and monocyte activation and protects against damage induced by aspirin in humans.
Authors: S. Fiorucci, A. Mencarelli, A. Meneguzzi, A. Lechi, B. Renga, Del . Soldato P, A. Morelli, P. Minuz
Journal: Journal of the American College of Cardiology (2004)
Differential expression analysis at the individual level reveals a lncRNA prognostic signature for lung adenocarcinoma
Authors: Fuduan Peng, Ruiping Wang, Yuanyuan Zhang, Zhangxiang Zhao, Wenbin Zhou, Zhiqiang Chang, Haihai Liang, Wenyuan Zhao, Lishuang Qi, Zheng Guo, Yunyan Gu
Journal: Molecular Cancer (2017)

Deregulations of long non-coding RNAs (lncRNAs) have been implicated in cancer initiation and progression. Current methods can only capture differential expression of lncRNAs at the population level and ignore the heterogeneous expression of lncRNAs in individual patients.We propose a method (LncRIndiv) to identify differentially expressed (DE) lncRNAs in individual cancer patients by exploiting the disrupted ordering of expression levels of lncRNAs in each disease sample in comparison with stable normal ordering. LncRIndiv was applied to lncRNA expression profiles of lung adenocarcinoma (LUAD). Based on the expression profile of LUAD individual-level DE lncRNAs, we used a forward selection procedure to identify prognostic signature for stage I-II LUAD patients without adjuvant therapy.In both simulated data and real pair-wise cancer and normal sample data, LncRIndiv method showed good performance. Based on the individual-level DE lncRNAs, we developed a robust prognostic signature consisting of two lncRNA (C1orf132 and TMPO-AS1) for stage I-II LUAD patients without adjuvant therapy (P = 3.06 × 10-6, log-rank test), which was confirmed in two independent datasets of GSE50081 (P = 1.82 × 10-2, log-rank test) and GSE31210 (P = 7.43 × 10-4, log-rank test) after adjusting other clinical factors such as smoking status and stages. Pathway analysis showed that TMPO-AS1 and C1orf132 could affect the prognosis of LUAD patients through regulating cell cycle and cell adhesion.LncRIndiv can successfully detect DE lncRNAs in individuals and be applied to identify prognostic signature for LUAD patients.
Mastectomy rates in relation to adoption of a margin guideline.
Authors: Monica Morrow, Steven J. Katz, Reshma Jagsi
Journal: Journal of Clinical Oncology (2017)

508 Background: Surgery after initial lumpectomy to obtain a bigger negative margin is common and may lead to mastectomy. The impact of a 2014 consensus statement endorsing a minimal negative margin for invasive breast cancer on surgeon attitudes, re-excision rates, and final surgical procedure is uncertain. Methods: Women with stage I and II breast cancer diagnosed between 7/13–8/15 and reported to the Los Angeles and Detroit SEER registries were surveyed about 2 months post diagnosis, and 70% responded; 3729 comprise the analytic sample. All attending surgeons identified by the patients (n=489) were sent a questionnaire at the end of the patient survey period, and 376 (77%) responded. Pathology reports were reviewed for margin status. Multinomial regression models were used to assess trends. Results: The 67% initial lumpectomy rate was unchanged during the study. The final lumpectomy rate increased by 13% (to 65% from 52%) from 2013–2015, accompanied by a decrease in unilateral (to 18% from 27%) and bilateral (to 16% from 21%) mastectomy (p=0.002). Surgery after lumpectomy, both re-excision and mastectomy, declined by 16% (p&lt;0.001). Pathology review showed no association between date of treatment and positive margins. Patient report of surgeon-recommended mastectomy after initial lumpectomy declined to 8% from 20% (p&lt;0.001). 69% of surgeons endorsed a margin of no ink on tumor to avoid re-excision in ER+PR+ cancer and 63% for ER-PR- cancer. Surgeons treating &gt;50 breast cancers annually were more likely to accept this margin than those treating &lt;20 cases (p&lt;0.001). Conclusions: Additional surgery after initial lumpectomy markedly decreased between 2013‒2015 after publication of a margin guideline endorsinga minimal negative margin. This resulted in a substantial increase in lumpectomy as the definitive surgical procedure, which illustrates that guidelines can be an effective, low-cost approach to addressing clinical controversies.
Pivanex inhibits histone deacetylase activity in non small cell lung cancer patients
Authors: Uwe F. Wirtz, Gilbert Carrizales, Elzbieta Izbicka, Anish Bhatnagar, Louis Bucalo, Sunil Sreedharan
Journal: Cancer Research (2004)

4016  Pivanex™ (pivaloyloxymethyl butyrate) is a histone deacetylase (HDAC) inhibitor that distributes rapidly into tissues and induces cell differentiation, leading to apoptosis in a wide range of tumor cells examined. Pivanex is very well tolerated, and has demonstrated phase II single-agent activity in non-small cell lung cancer (NSCLC) patients with refractory or relapsed disease. It is currently in a phase IIb randomized, controlled study in combination with docetaxel (Taxotere™) in second line treatment of NSCLC. Using the NCI-H23 human NSCLC cell line as a model for Pivanex’s activity, we examined HDAC inhibition at various time points following a single in vitro addition of Pivanex. Hyperacetylation of histones 3 and 4 were quantified by Western blot analysis, and HDAC activity was determined with a fluorescent-substrate based enzyme activity assay (Biomol, Inc.). HDAC activity was then evaluated in NSCLC patient peripheral blood mononuclear cells (PBMCs) before and after treatment with Pivanex. Pivanex was administered by 6-hr infusions on 3 consecutive days at a dose of 2.5 g/m2. Blood samples were collected just before starting Pivanex treatment (day 1) and the day after a course of Pivanex infusion (day 4). PBMCs were isolated with sodium citrate Vacutainer-CPT tubes (Becton Dickinson) and frozen until analysis. PBMC pellets were lysed in osmotic lysing buffer containing 1% protease and phosphatase inhibitor cocktails (Sigma) with or without 0.3% SDS, respectively, for Western blot and HDAC activity assays. The total protein concentration was determined with BCA reagent (Pierce) and equal amounts of total protein were analyzed. Results: For NCI-H23 NSCLC cells, a single treatment with Pivanex resulted in the hyperacetylation of histone 3 at 1, 3, 7, 24 and 48 hours. HDAC enzyme activity was found to be inhibited at all time points examined: 1, 3, 5, 7, 24, 48, and 72 hours; with maximum inhibition to 25% at 72 hours. Pivanex-treatment in the clinic also resulted in the hyperacetylation of histones 3 and 4 in patient-derived PBMCs, one day after initial infusion. In addition, HDAC activity from patient PBMCs on day 4 was also strongly inhibited after Pivanex treatment. Conclusion: Pivanex treatment in the clinic results in the inhibition of HDAC enzyme activity leading to the hyperacetylation of histones as previously demonstrated in in vitro experiments. PBMCs from patients undergoing Pivanex therapy can thus be monitored for the activity of this potent HDAC inhibitor.
64Cu-DOTA-trastuzumab PET/CT to predict response to ado-trastuzumab emtansine (TDM1) in HER2-positive metastatic breast cancer.
Authors: Joanne E. Mortimer, James R. Bading, Paul Henry Frankel, Rita Gidwaney, John Park, Lusine Tumyan, Maria Parayno, Kofi Poku, David Colcher
Journal: Journal of Clinical Oncology (2017)

e12525 Background: Having demonstrated that 64 Cu-DOTA trastuzumab is an effective PET imaging agent for HER2 positive (HER2+) breast cancer, we now evaluate the methodology for prediction of response and benefit from TDM1 in women with metastatic disease. Methods: Patients eligible to receive TDM1 as therapy were chosen on the basis of biopsy confirmed HER2+ disease, and at least 1 site of metastasis ≥ 2.0 cm outside the biopsy site. Pretreatment staging included 18 F-FDG PET/CT. Prior to injection of 64 Cu-DOTA-trastuzumab, patients received 45 mg of cold trastuzumab to reduce liver uptake. PET-CT scans were obtained at 16-28 h (Day1) and 39-49 h (Day 2) over fields of view chosen in reference to the 18 F-FDG scans. TDM1 (3.6 mg/kg) was administered every 3 weeks. Restaging 18 F-FDG PET/CT was performed every 2 cycles, and response to therapy was determined by PERCIST (solid tumor) criteria. Radiolabel uptake was measured in terms of maximum voxel, standardized uptake value (SUV max ). Results: Ten women between the ages of 48-83 years old (median 55 years) qualified for study, and have been evaluated for response; 4 continue on TDM1 with treatment durations of 3-27 months.Three were trastuzumab-naïve, while 7 had received trastuzumab-containing chemotherapy 3 wks to 55 mo prior to study entry. HER2 was positive by ImmunoHistoChemistry, IHC (3+) in 5 patients, and by FISH testing in the other 5 (3 were 2+ by IHC; 1 was 1+, and 1 was indeterminate). Complete or partial metabolic response was observed in 5 patients. Median Day 2 SUV max for 64 Cu-DOTA trastuzumab was 9.3 g/ml in responding patients, and 4.6 g/ml in non-responders ( P= 0.03). Progression-free survival was longer for patients with higher SUV max , with a hazard ratio of 0.73 (95% confidence interval 0.46-1.16) for each 1 unit increase in SUV max . This was not statistically significant, although we can select a threshold SUV max for which the effect is significant even for this small study. Further data is required to confirm such a threshold effect. Conclusions: 64 Cu-DOTA-trastuzumab PET imaging predicts benefit from TDM1 in women with biopsy-confirmed HER2+ metastatic disease. Supported by NCI Clinical trial information: NCT02827877.
S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression
Authors: Daniel Prieto, Natalia Sotelo, Noé Seija, Sandra Sernbo, Cecilia Abreu, Rosario Durán, Magdalena Gil, Estefanía Sicco, Victoria Irigoin, Carolina Oliver, Ana Inés Landoni, Raúl Gabus, Guillermo Dighiero, Pablo Oppezzo
Journal: Blood (2017)
The Fat but Fit paradox: what we know and don’t know about it
Authors: Francisco B Ortega, Jonatan R Ruiz, Idoia Labayen, Carl J Lavie, Steven N Blair
Journal: British Journal of Sports Medicine (2017)

In the late 1980s, one of us (SNB) published a study that demonstrated that individuals with a low (below first quintile=20th percentile) cardiorespiratory fitness level had a higher risk of mortality 8 years later, when compared with those who were at least moderately fit.1 Since then, many longitudinal studies have consistently confirmed this notion in men and women, as well as in healthy and diseased individuals, for all-cause mortality, as well as for cardiovascular disease (CVD) mortality.2 

Obesity is related to multiple physical and mental comorbidities and it is an incontrovertible risk factor for all-cause and CVD mortality.3 It has been suggested, however, that being fit might attenuate some of the adverse consequences of obesity, independently of some key potential confounders. In this context, in the late 1990s, some studies provided first evidence for what was later known as the Fat but Fit paradox (see review by Ortega et al .3). These studies demonstrated that all-cause and CVD mortality risk in obese individuals, as defined by body mass index (BMI), body fat percentage or waist circumference, who are fit (ie, cardiorespiratory fitness level above the age-specific and sex-specific 20th percentile) is not significantly different from their normal-weight and fit counterparts (ie, the theoretically healthiest group possible) (figure 1).



Figure 1 
Illustration of the Fat but Fit paradox in relation with cardiovascular disease (CVD) mortality and all-cause mortality in …
The time is right for an international PCD disease registry: insight and ongoing research activities
Authors: Myrofora Goutaki, Florian S. Halbeisen, Claudia E. Kuehni
Journal: European Respiratory Journal (2017)

We read the editorial entitled “The time is right for an international primary ciliary dyskinesia disease registry” with interest [1]. In it, Haver [1] discussed our recent article on the International Primary Ciliary Dyskinesia Cohort (iPCD Cohort) [2] and stressed three aims important to primary ciliary dyskinesia (PCD) research: the development of a prospective international PCD registry, the standardisation of data collection and the achievement of an international diagnostic consensus. We support these aims and here highlight ongoing activities that support them. It is important to use all available data for PCD research while we strengthen efforts to reach diagnostic consensus <http://ow.ly/N7SP30btbVY> We want to thank all the patients in the iPCD Cohort and their families, and we are grateful to the PCD patient organisations who collaborated closely with us. We thank all the researchers who collaborate with us in the iPCD Cohort and other BEAT-PCD projects. We also thank Christopher Owen Ritter from the Institute of Social and Preventive Medicine at the University of Bern, Bern, Switzerland, for his editorial suggestions.