tbuckley/cabot-search huggingface dataset:
PS-010-24-nor-ursodeoxycholic acid ameliorates inflammation by reshaping mTOR proteome and immunometabolism sensing programs in CD8 T-cells
Authors: Ci Zhu, Nicole Boucheron, André Müller, Peter Májek, Claudia D. Fuchs, Hatoon Baazim, Emina Halilbasic, Tatjana Stojakovic, Andreas Bergthaler, Wilfried Ellmeier, Michael Trauner
Journal: Journal of Hepatology (2019)
Dynamics of steroid and thyroid hormones in blood serum of rats with experimental liver metastases.
Authors: Irina Viktorovna Kapliyeva, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Evgeniy N. Kolesnikov, Lidia K. Trepitaki, Irina Igorevna Gorina, Yulia A. Pogorelova
Journal: Journal of Clinical Oncology (2015)

e22001 Background: Liver metastases are found in 1 million patients annually all over the world. In most cases, this pathology is diagnosed when it is too late to help the patient. The purpose of this study was to analyze pathogenetic significance of changes in hormonogenesis in liver metastases in order to develop new methods for its prevention and treatment. Methods: The study included 30 male rats (Wistàr) with liver metastases. Dynamics of thyroid-stimulating hormone (TSH), luteinizing hormone (LH), prolactin (PRL), estrone, estradiol, corticosterone (Crt), dehydroepiandrosterone (DHEA), free T4 (FT4), free T3 (FT3) and antibodies to tPO in blood serum was analyzed in development of liver metastasis. Levels of TSH, LH, PRL, Crt, FT4, FT3 and antibodies to tPO were determined with radioimmunoassay using standard reagents, and levels of estrone, estradiol, DHEA – with ELISA using standard reagents. Results: Increase in concentration of PRL by 2 times, LH – by 2.3 times, Crt - by 3 times, DHEA - by 2.7 times, TSH - by 3.3 times and antibodies to tPO – by 1.5 times was found in blood serum of rats with liver metastases, as well as decrease in concentration of follicle-stimulating hormone (FSG) by 3.4 times, estrone by 5.9 times and estradiol by 1.5 times. Conclusions: Liver metastasis is accompanied by development of latent hypothyroidism caused by autoimmune thyroiditis, increased levels of luteinizing hormone and prolactin and decreased levels of FSG, estradiol and estrone and activation of the adrenal glands with equal increase in concentration of the stress hormone corticosterone and its antagonist DHEA in blood serum.
Feasibility of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for treatment monitoring of brain metastases in lung cancer patients
Authors: D.S. Abdulla, M. Ruge, M. Scheffler, L. Nogova, S. Koleczko, T. Persigehl, S. Grau, A. Drzezga, C. Kobe, R. Buettner, N. Galldiks, J. Wolf
Journal: Annals of Oncology (2019)

Background: Brain metastases (BMs) occur frequently in patients with advanced lung cancer. So far, intracranial efficacy of systemic lung cancer treatment is nearly unpredictable. Contrast-enhanced magnetic resonance imaging (MRI) is considered gold standard for response assessment but lacks potential to discriminate between malignant or active tumor lesions from benign or postinflammatory signal alterations. O-(2- [18F]fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) has shown additional diagnostic value over standard MRI in glioma patients. We set out this analysis to determine the feasibility of FET PET in lung cancer patients. Methods: FET with a mean activity of 200 MBq was produced and FET PET performed 20-40 minutes post injectionem at Research Center Juelich (Forschungszentrum Jülich). Patients with cerebral metastasized lung cancer underwent at least one tomography, and tumor volume and activity were assessed by both standard uptake values (SUVs) or tumor-to-brain ratios. A lesion-brain ratio in the standard uptake value (SUV) of more than 2 was considered pathological. Results: From 2015 to 2018, 48 patients received at least one FET PET, whereof 11 patients (22.9%) underwent two scans and one patient three serial FET PETs. All scans could be analyzed for the assessment of tumor activity. The patients did not suffer of adverse events related to the tracer or the procedure. In most cases, FET PET was performed to discriminate between scar tissue and new tumor activity in singular metastases treated stereotactically. In a smaller number of patients, FET PET was used to assess treatment response in systematically treated patients. Conclusions: FET PET is feasible in patients with brain metastases of lung cancer and might provide additional information to MRI for treatment decisions in these patients. Validation of the results and the reproducibility is ongoing. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
<i>RAS</i> mutation acquisition at transformation from myelodysplastic syndrome to acute myeloid leukemia to predict poor outcome.
Authors: Talha Badar, Jorge E. Cortes, Elias Jabbour, Gautam Borthakur, Marina Konopleva, Tapan M. Kadia, Zach Bohannan, Sherry Pierce, Farhad Ravandi, Keyur Patel, Rajyalakshmi Luthra, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2015)

7052 Background: Although RAS mutation (m) in de novo MDS has not shown to influence outcome but it does have prognostic value when acquire later in disease course (Takahashi et al. Leukemia. 2013; 27 (10): 2081-3). We sought to further characterize the acquisition of RASm at the time of transformation to AML in a large group of MDS patients and assessed its prognostic impact. Methods: We retrospectively analyzed 289 MDS patients who had wild type (wt) RAS at the time of MDS diagnosis and were referred to our institution between 2002 and 2013. Ninety eight (34%) patients had repeat mutation testing at the time of transformation to AML, and we evaluated these patients for the frequency of RASm acquisition and its clinical implications. Results: Twenty two (22%) patients acquired RASm at the time of transformation to AML. At the time of diagnosis of MDS, the median age was 65 years (range 26-83). Five percent, 14%, 22%, 25%, and 32% patients had R-IPSS very low, low, intermediate, high, and very high-risk disease, respectively. The median number of therapies patients received for MDS was 1 (range 0-4), and 8 patients had stem cell transplants (SCT). At the time of transformation to AML, the median age was 59 years (range, 27-86). In 22 (22%) patients who had poor-risk cytogenetics (complex, -7/7q-, -5/5q-, or inv 3), 14 (14%) acquired RASm versus 8 (8%) who had wt RAS (p = 0.33). Most patients received either cytarabine- or hypomethylating agent-based induction regimens. Overall, 25% (12% with RASm and 13% with wt RAS) achieved CR/CRi (p = 0.17), and 15 (15%) patients had SCT. The median survival after leukemia transformation in RASm patients was 3.6 months compared to 7.5 months in RAS wt patients (p = 0.0002). When we excluded patients with poor risk cytogenetics, median survival was 3.9 months for RASm patients versus 9.3 months for RASwt (p < 0.001). In a multivariate analysis, RASm (hazard ratio [HR] = 2.9, p < 0.0001) and t-MDS/AML (HR = 2.0, p < 0.01) were associated with poor prognosis, and SCT was associated with a favorable outcome (HR = 0.30, p < 0.001). Conclusions: Acquisition of RASm at the time of transformation to AML is associated with poor outcome and it may provide opportunities for targeted therapy.
THU-433-Availability of information in drug labels for appropriate prescribing in patients with hepatic impairment
Authors: Rianne A. Weersink, Lotte Timmermans, Margje H. Monster-Simons, Peter G.M. Mol, Herold J. Metselaar, Sander D. Borgsteede, Katja Taxis
Journal: Journal of Hepatology (2019)
Comparative Analysis of Nonalcoholic Steatohepatitis– Versus Viral Hepatitis– and Alcohol-Related Liver Disease–Related Hepatocellular Carcinoma
Authors: Caitlin A. Hester, Nicole E. Rich, Amit G. Singal, Adam C. Yopp
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Despite an increasing burden of nonalcoholic steatohepatitis (NASH), limited data are available comparing outcomes of NASH-related hepatocellular carcinoma (HCC) versus other etiologies. Methods: Patient demographic and tumor characteristics were collected for 1,051 patients diagnosed with NASH-, alcohol-related liver disease (ALD)–, hepatitis C virus (HCV)–, and hepatitis B virus (HBV)–related HCC at 2 large health systems from January 2008 through December 2016. Patient demographics, clinical characteristics, and survival were compared. Risk-adjusted treatment receipt and overall survival (OS) were examined using multivariable analysis. Results: A total of 92 patients with NASH-related HCC were compared with 153 patients with ALD-, 719 with HCV-, and 87 with HBV-related HCC. Patients with NASH were older, more likely female, and more likely Hispanic white. Patients with NASH and HBV had more compensated liver disease than those with ALD or HCV, including significantly higher proportions having noncirrhotic HCC. Despite similar surveillance receipt and Barcelona Clinic Liver Cancer (BCLC) tumor stage at diagnosis, patients with NASH had higher rates of curative-intent therapy than those with other diseases. Unadjusted median OS was 16 months for NASH, 15 months for ALD, 14 months for HCV, and 8 months for HBV. In multivariable analysis, NASH was associated with worse OS compared with ALD (hazard ratio, 1.92; 95% CI, 1.3–2.5), but there was no difference between NASH- and HCV- or HBV-related HCC. Conclusions: Patients with NASH-related HCC present with more preserved liver function, including a higher proportion having noncirrhotic HCC, than other diseases. Despite patients having similar tumor stage at diagnosis, NASH is independently associated with worse survival compared with ALD, but similar survival compared with HCV and HBV.
PS-078-A phase 1b evaluation of HepTcell HBV-specific immunotherapy in nuc-controlled, eAg negative chronic HBV infection
Authors: Young-Suk Lim, David Mutimer, Jeong Heo, Won Young Tak, William Rosenberg, Byoung KukJang, YoonJun Kim, Dan Forton, Sybil Tasker, Bertrand Georges
Journal: Journal of Hepatology (2019)
GS-14-ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients
Authors: Manisha Balwani, Laurent Gouya, David Rees, Penelope Stein, Ulrich Stölzel, Paula Aguilera, D Montgomery Bissell, Herbert Bonkovsky, Sioban Keel, Charles Parker, John Phillips, Samuel Silver, Jerzy Windyga, Delia D’avola, Gayle Ross, Peter Stewart, Bruce Ritchie, Jeeyoung Oh, Pauline Harper, Jiaan-Der Wang, Janneke Langendonk, Aneta Ivanova, Yutaka Horie, Karl Anderson, Paolo Ventura, Amy Chan, Craig Penz, Amy Simon, Quinn Dinh, Gary Liu, Eliane Sardh
Journal: Journal of Hepatology (2019)
REDOXI-miRNA of Keap1/Nrf2 axis in lung tumors
Authors: F.P. Fabrizio, A. Sparaneo, S. Castellana, T. Mazza, D. Trombetta, P. Graziano, A. Rossi, V.M. Fazio, L.A. Muscarella
Journal: Annals of Oncology (2019)

Background: Oxidative and electrophilic changes in cellular redox balance are mainly coordinated by the Keap1/Nrf2 axis and is strongly related to tumor progression, chemo- and radio-therapy resistance of cancer cells. In lung tumors this system is constitutively activated mainly by the loss of Keap1 or gain of Nrf2 functions due to point mutations in the key interacting domains of these two proteins. Beside of genetic lesions, Keap1/Nrf2 epigenetic abnormalities, as aberrant Keap1 promoter methylation and regulation by microRNAs were reported as emerging mechanisms of deregulation. Here we investigated the contribution of miRNA machinery on the modulations of Keap1/Nrf2 activity in lung tumors by analyzing panels of NSCLC and SCLC cell lines. Methods: We searched for candidate miRNAs interacting with Nrf2 and Keap1 by using a combination of published data and in silico analyses performed by multiple bioinformatics tools (miRTarBase for known miRNAmRNA interactions; TargetScan, MiRanda, microRNA.org, miRBase also for predicted interactions). After this preliminary analysis we selected a list of 11 miRNAs that are experimentally validated in other tumors and/or predicted to be associated to NRF2 or KEAP1 and profiled their expression levels by real-time PCR in lung cancer cell lines and tissues. Results: miR-27 family (miR-27a and miR-27b) was found to be significantly downregulated in NSCLC and SCLC cell lines. Conversely, miR-200 family (miR-200a and miR-141) was found to be significantly upregulated. Afterward, the expression data for miR-27 family and miR-200a was validated on an available training set of 29 tumor/normal paired tissues from NSCLC patients. As expected, miR- 200a was significantly up-regulated (p < 0,01, t-test), whereas miR27a and miR-27b significantly downregulated (p < 0,001, t-test) in tumors compared to normal tissues. Conclusions: Since the obtained results refer to currently un-investigated miRNAs related to Keap1/Nrf2 axis in lung cancer, we plan to extend our analysis and confirm their role and impact on KEAP1/NRF2 modulation by in vitro studies. Our preliminary results suggest that redoxi-miRNA in lung cancer should add a new order of complexity to the regulation of the Nrf2/ARE pathway and will need to be more deeply explored in the future. Legal entity responsible for the study: The authors. Funding: AIRC. Disclosure: All authors have declared no conflicts of interest.
A method for comprehensive genomic analysis of cell-free DNA.
Authors: Sonya Parpart-Li, Samuel V. Angiuoli, Bryan Chesnick, Kevin Galens, Siân Jones, Maura Kadan, Lisa Kann, Karli Lytle, Derek M Murphy, Monica Nesselbush, Jillian Phallen, David Riley, Manish Shukla, Theresa Zhang, Hatim Husain, Victor E Velculescu, Luis A. Diaz, Mark Sausen
Journal: Journal of Clinical Oncology (2015)

e22070 Background: Liquid biopsies of circulating tumor DNA (ctDNA) offer a considerable advantage as they may eliminate the need for invasive tissue biopsies and allow for the detection of alterations in multiple metastatic lesions throughout the course of therapy. However, the fraction of ctDNA obtained from a blood sample is often very low ( < 1.0%) and can be difficult to detect. Additionally, most methods to evaluate ctDNA interrogate single hot spot mutations or only a few genetic alterations. Methods: To address these issues, we have developed a ctDNA approach, PlasmaSelect, to detect somatic sequence mutations and translocations at low allele frequencies in the circulation of cancer patients. Utilizing digital genomic approaches, PlasmaSelect achieves high sensitivity and specificity while interrogating > 250,000 nucleotides spanning 63 well-established cancer genes. In addition to evaluation of exons in genes that are frequently mutated in cancer, PlasmaSelect also performs a structural alteration analysis of translocations in 10 genes and the full coding regions of 18 genes significant in cancer tumorigenesis. Results: To evaluate PlasmaSelect, we performed dilution series using tumor-derived DNA, containing well-characterized somatic mutations, in the presence of wild-type DNA. PlasmaSelect was able to detect genetic alterations at low levels ( > 0.10%) with high specificity. Further analyses in late-stage cancer patients demonstrated high concordance between the somatic sequence mutations and translocations identified in the tumor sample and those identified directly in the plasma, including alterations in both driver genes as well as those related to acquired resistance to targeted therapies. Conclusions: PlasmaSelect provides a non-invasive platform to enable liquid biopsy detection of clinically relevant genetic alterations across a large number of genomic loci.
Implications for UK practice of the use of durvalumab in stage III NSCLC
Authors: M.S. Iqbal, P. Atherton, C. Macgregor, A. Wieczorek, J. Singer, J. Walther, F. Little, S. Harden, C. Peedell, A. Cyriac, S. Chowdhury, M. Bayne, K. Yip, A. Britten, C. Powell, J. Brock, S. Datta, T. Sevitt, A. Mehta, A. Greystoke
Journal: Annals of Oncology (2019)

Background: The PACIFIC trial showed a survival benefit in patients receiving Durvalumab after concurrent chemoradiotherapy (CRT) in stage III Non-Small Cell Lung Cancer (NSCLC). Key inclusion criteria were platinum doublet chemotherapy with no chemotherapy delivered after concurrent phase. Dose delivered was 54 - 66Gy and treatment started within 42 days of completing radiotherapy. European licence is restricted to patients with PDL1 positive tumours. Previous UK audits have shown a number of CRT regimens in routine use. We assessed the implications to UK practice of adding durvalumab after CRT. Methods: A 9 point questionnaire was sent by email to all 50 radiotherapy centres delivering chemoradiotherapy for NSCLC in the UK. Results: 21 responses were received (42%) at the time of submission. Rates of concurrent treatment ranged from 10 - 90% (median 40%, IQR 25-60%) with median surgery rates for N2 disease of 10%. Doses delivered ranged from 55 to 66 Gy (median 60, IQR 55 – 64 Gy) in a median of 30 fractions (IQR 20 to 32). 10 centres used hypofractionated regimens. The most common chemotherapy back-bone was cisplatin and vinorelbine (1 centre used carboplatin and 1 etoposide routinely). 11 centres prescribe chemotherapy post concurrent treatment. Currently only 3 centres scan within the 6 week window after completion of treatment. The majority of centres are now planning to avoid giving consolidative chemo after concurrent CRT and will scan early after CRT. 13 centres are already testing PDL1 in this context. Durvalumb will be supervised in 16 centres by a clinical oncologist, in 2 by medical oncologist with the remaining 3 undecided. Conclusions: The implementation of consolidative Durvalumab in stage III NSCLC post concurrent CRT will require changes in practice in the majority of UK centres. Most centres have already implemented some changes but more work needs to be done to standardise practice and ensure equality of access for patients. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
CK19 in peripheral blood to indicate the status of non-sentinel lymph nodes: An independent predicative factor.
Authors: Xingfei Yu, Maio lu Lu, Hongjian Yang
Journal: Journal of Clinical Oncology (2015)

e12047 Background: CK19 mRNA level of lymph node tissue detected by RT-PCR has been used in sentinel lymph node biopsy (SLNB) in breast cancer. This study was designed to figure out whether CK19 expression could indicate non-sentinel lymph nodes (nSLNs) metastasis and prove its predicative value. Methods: We identified breast cancer cases diagnosed with clinical stage I, II and cT3N1M0. We tested the CK19 mRNA level of peripheral blood before operation by RT-PCR (test box of PrimeScript). During the surgery, the patients underwent SLNB with blue dye, if SLNB was proved metastasis, and then underwent an axillary lymph node dissection for identifying the status of nSLNs; if SLNB was negative then the nSLNs were also identified negative. We evaluated the clinical characteristics and nSLNs metastasis associated with CK19 level using chi-square tests and logistic regression, and used ROC curve proving its predicative value. Results: We identified 124 breast cancer cases in the study，because of 4 cases failed in SLNB, finally 120 cases were included in the analysis. 60 cases were SLN negative and 60 cases were positive. In latter ones, there were 38 cases with nSLNs positive. Patients with nSLNs metastasis had larger size, higher grade of tumor, more positive vessel carcinoma embolus and high level of CK19 mRNA than those with negative nSLNs (p < 0.05). Subgroup analysis showed that in the SLN positive patients, only CK19 got a significant difference between nSLNs negative and positive groups. The Logistic regression model indicated that vessel carcinoma embolus and CK19 had significant influences on predicating the status of nSLNs (P < 0.05). The result of testing the predictive value of CK19 on the status of nSLNs showed that the area under ROC curve was 0.81 (p < 0.05). Conclusions: High level of CK19 in peripheral blood can have a great predicative value on metastasis of non-sentinel lymph nodes as an independent factor.
Dual-modality optical diagnosis for precise <i>in vivo</i> identification of tumors in neurosurgery
Authors: Mingyu Zhu, Wei Chang, Linkai Jing, Yingwei Fan, Ping Liang, Xinran Zhang, Guihuai Wang, Hongen Liao
Journal: Theranostics (2019)

In neurosurgery, the precise diagnosis and treatment of tumor diseases are challenging to realize. Current clinical diagnoses lack fast and accurate intraoperative information. Therefore, the development of new methods and techniques to assist neurosurgeons intraoperatively is necessary. Optical diagnosis is a promising method to provide accurate information about biological tissues in a short time. Therefore, in this study, we proposed a dual-modality optical diagnostic method through point-to-face registration fusion in the optical system. We incorporated quantitative autofluorescence spectroscopy and optical coherence tomography (OCT) and evaluated our methods in an animal model. Methods: A mouse model consisting of 16 nude mice was built by injecting the mouse brains with human glioma cells. Preoperative bioluminescence imaging was used to evaluate the growth states of tumors and locate the tumor sites. Quantitative autofluorescence spectroscopy, which provided local biochemical information with single-point detection, and OCT, which provided relatively global structural information with en face mapping scanning, were combined using the point-to-face registration fusion method to provide precise diagnostic information for identifying the brain tumors. Postoperative pathology was performed to evaluate the sensitivity and specificity of optical diagnosis. Results: Ex vivo quantitative autofluorescence spectroscopy and OCT imaging were first performed in eight mice to acquire the optimal measuring parameters for tumor staging and identification. We then performed in vivo quantitative autofluorescence spectroscopy and OCT imaging. The results showed that tumor staging could be realized through quantitative autofluorescence spectroscopy, and fusion images could be used to precisely identify tumors. The autofluorescence spectral map, OCT en face map, and fused diagnostic map had average sensitivities of 91.7%, 86.1%, and 95.9% and specificities of 93.2%, 96.0%, and 88.7%, respectively, for tumor identification. Conclusion: The dual-modality optical point-to-face registration fusion method and system we proposed could provide both biochemical information and structural information. The in vivo experimental results validated that the sensitivity (95.9%) of the fused map was higher than that of either single diagnostic modality (86.1% or 91.7%). Tumor staging was realized through quantitative autofluorescence spectroscopy. The proposed method will be applicable to future intelligent theranostic systems and improve many clinical neurosurgeries.
THU-334-PNPLA3 rs738409 C &gt;G variant predicts liver-related events and death in non-alcoholic fatty liver
Authors: Stefania Grimaudo, Grazia Pennisi, Rosaria Maria Pipitone, Calogero Camma, Vito Di Marco, Roberta Boemi, Aurora Giannetti, Federica Spatola, Giulio Marchesini Reggiani, Antonio Craxi, Salvatore Petta
Journal: Journal of Hepatology (2019)