tbuckley/cabot-search huggingface dataset:
Abstract P134: Genome-wide Association Study of Heart Rate Response to Mental Stress
Authors: Yunfeng Huang, Qin Hui, Muhammad Hammadah, Pratik M Pimple, Ibhar Al Mheid, Kobina Wilmot, Ronnie Ramadan, Amit J Shah, Brad Pearce, Ernest V Garcia, Michael Kutner, J. Douglas Bremner, Fabio Esteves, Paolo Raggi, David S Sheps, Viola Vaccarino, Arshed A Quyyumi, Yan Sun
Journal: Circulation (2018)

Ischemia results from an imbalance between myocardial oxygen supply and demand. Ischemia associated with mental stress (MS) has been associated with adverse outcomes in patients with coronary artery diseases (CAD). Higher heart rate (HR) and blood pressure responses to MS are associated with a greater likelihood of MS-induced ischemia. Although multiple genetic loci have been associated with baseline HR, genetic associations for HR responses to MS remain unknown. We aimed to discover the genetic determinants of HR response to MS in a bi-ethnic population. A sample of 499 Caucasian and 271 African American patients with CAD were recruited into the Mental Stress Ischemia Prognosis (MIPS) study. Race was defined using genetic ancestry. Genome-wide SNP data were genotyped using Illumina’s Multi-Ethnic Genotyping (MEG) chip and then imputed to the 1000 Genome Project phase 3 panel. Cardiovascular risk factors, demographic, behavioral, and medication history data were obtained by questionnaires and chart reviews. MS was induced by a public speaking task and the HR response to MS was measured as post-stress HR minus pre-stress HR. We conducted genome-wide association analysis of HR response to MS using multiple linear regression adjusted for age, sex, beta-blocker use, the pre-stress HR and ethnicity. A meta-analysis was performed across the two ethnicities. After multiple-testing correction, no significant associations with HR response to MS were identified among Whites .However, fourteen SNPs located in gene ITGA1 with a mean minor allele frequency of 36.5% (range: 36.3% - 37.1%) were significantly associated with the HR response to MS in Blacks (meta-analysis p&lt;5х10 -8 ). The minor alleles of all 14 variants were associated with a higher HR response. On average heterozygotic and homozygotic Blacks of the minor allele in any of these SNPs have a 4.558 beat/min (range: 4.514 – 4.659 beat/min) and 9.116 beat/min (range: 9.028 – 9.318 beat/min) increase in HR response to MS, correspondingly. The ITGA1 gene encodes the alpha-1 subunit of integrin receptors. This protein heterodimerizes with the beta-1 subunit to form a cell-surface receptor for collagen and laminin. The heterodimeric receptor is involved in cell-cell adhesion and may play a role in inflammation and fibrosis. Further functional studies to follow up these genetic loci may provide insight into regulatory mechanisms of HR response to mental stress that may be prognostically informative for CAD patients.
NHS England’s “hierarchy of goals” can be used to argue for service expansion
Authors: Daniel J Short
Journal: BMJ (2018)

Robinson’s article about NHS England’s recommendations on restricting access to some currently routine interventions is reminiscent of the situation surrounding an intervention that has repeatedly faced rationing—in vitro fertilisation (IVF).1 IVF services continually come under fire from clinical commissioning groups looking to save money in times of financial difficulty. Recent investigations have shown that only 11.5% …
Treatment patterns and survival for hepatocellular carcinoma in USA and Taiwan.
Authors: Shi-Yi Wang, Yih-Jyh Lin, Chia-Ni Lin, Tannaz Sedghi, Sylvia H. Hsu, Hyun S Kim, Tsung-Ching Chou, Yen-Cheng Chiu, Cary Philip Gross, Jung-Der Wang
Journal: Journal of Clinical Oncology (2018)

e16120 Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality in the United States. Due to the high prevalence of hepatitis B/C infection, HCC ranks second in cancer mortality in Taiwan. To date, little is known about whether treatment patterns and corresponding outcomes differed between USA and Taiwan. Methods: This international collaboration applied a uniform methodology, but analyzed data independently. We identified patients with newly diagnosed HCC from 2004 through 2011, aged 66 years or older from the Surveillance, Epidemiology, and End Results-Medicare database and the interlinkages of Taiwan Cancer Registry, National Health Insurance, and National Mortality Registry. All patients were followed through 2013. We stratified patients by AJCC stage, and identified the treatment received (including resection/transplant, radiofrequency ablation, ethanol injection, transarterial chemoembolization, and chemotherapy) within 6 months of HCC diagnosis. We calculated stage-specific survival overall and by receiving any treatment vs. no treatment. Results: Our sample consisted of 7,003 patients in the USA and 32,987 patients in Taiwan. Compared with patients in Taiwan, patients in the USA were more likely to have stage IV (14% vs 8%), ≥3 comorbidities (49% vs 31%), and cirrhosis (54% vs 20%), and were less likely to receive treatment (stage I: 56% vs 75%; stage II: 65% vs 74%; stage III: 40% vs 43%; stage IV: 16% vs 22%, p < .001 for all). The 2-year cumulative mortality was higher across all stages in the USA compared to Taiwan (stage I: 59.8% vs 32.6%; stage II: 60.4% vs 41.2%; stage III: 85.9% vs 81.6%; stage IV: 96.5% vs 94.6%, p < .001 except p = .015 for stage IV). Across all stages and for both countries, patients who received treatments had a better survival than those who did not receive any treatment. For example, the mean survival for patients with stage I HCC in the USA was 43.2 months if receiving treatment and 16.0 months if not receiving any treatment (p < .001). Conclusions: Treatment patterns for HCC differed substantially between the USA and Taiwan; this differential access to treatment contributed to significant survival differences between countries.
Abstract 16716: Intravascular Injection of Sendai Virus Vector Carrying Continuously cGMP Producing Mutant of Type B Natriuretic Peptide Receptor Can Ameliorate Pulmonary Arterial Hypertension
Authors: Nobutoshi Nawa, hidekazu Ishida, Shinichi Katuragi, Hiroki Baden, Kunihiko Takahashi, Sigetoyo Kogaki, Ryota Higeno, Fumiko Torigoe, Seiko Mihara, Jun Narita, Koji Miura, Keiichi Ozono
Journal: Circulation (2015)

Introduction: Type B natriuretic peptide receptor (NPR-B) is one of the transmembrane guanylyl cyclases and synthesizes cGMP on C-type natriuretic peptide binding. We have found a novel constitutively active mutation in the NPR-B gene in a family case showing overgrowth and bone anomalies. Previously, we constructed adenovirus vectors carrying this mutant NPR-B and administered to Sugen PAH rats intratracheally to investigate its therapeutic effect. However, the use of adenovirus vectors actually caused inflammatory host response in the lung. Objective: Sendai virus vector (SeV) is well known for its high transduction efficiency as well as the low toxicity. Recently, the results of a Phase I/IIa clinical study of SeV in human peripheral arterial disease have been reported. The objective of this study was to investigate the therapeutic effect of SeV carrying constitutively active mutant of NPR-B for PAH in rats. Methods and Results: We constructed SeV carrying wild-type (WT), and mutant (Mut) NPR-B. Control SeV carrying Azami-Green was purchased from MBL (Medical &amp; Biological laboratories, Nagoya, Japan). The overexpression of the mutant in human pulmonary artery smooth muscle cells by SeV induced significant increase in cGMP levels (control, 0.193±0.115 pmol/mL; WT-NPR-B, 38.3±29.6 pmol/mL; Mut-NPR-B, 2460±577 pmol/mL; n=3; p&lt;0.01), and suppressed proliferation as assessed by 5-ethynyl-2′-deoxyuridine (EdU) incorporation (EdU positive ratio: control, 0.18±0.017; WT, 0.12±0.023; Mut, 0.085±0.010; n=6; P &lt; 0.05). In Sugen PAH rats, intravascular administration of SeV carrying Mut-NPR-B significantly decreased right ventricular systolic pressure (Control, 61.4±8.4 mmHg; WT, 61.5±5.4 mmHg; Mut, 46.9±4.9mmHg; n=6; p&lt;0.01) and the ratio of right ventricular/left ventricular pressure (Control, 0.67±0.05; WT, 0.70±0.03; Mut, 0.53±0.09; n=6; p&lt;0.01). Furthermore, the proportion of occluded arteries was lower in Mut transduced rats than in control or WT transduced rats histologically. Conclusions: The CNP/NPR-B signaling pathway is an additional therapeutic target for the treatment of PAH. The enhancement of CNP/NPR-B pathway could ameliorate both intimal and medial remodeling of pulmonary artery in PAH.
The impact of social contagion on physician adoption of breast cancer imaging.
Authors: Craig Evan Pollack, Pamela R. Soulos, Jeph Herrin, Xiao Xu, Nicholas Christakis, Howard Forman, James B. Yu, Brigid K. Killelea, Shi-Yi Wang, Cary Philip Gross
Journal: Journal of Clinical Oncology (2016)

6534 Background: Advanced imaging tests (AIT) such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans were adopted rapidly into breast cancer practice despite unproven benefits. We sought to examine the extent to which social contagion among physicians explains the adoption of AIT. Methods: We used SEER-Medicare data to construct physician patient-sharing networks during T1 (2004-2006) and determined the potential impact of these networks on the adoption of AIT during T2 (2007-2009). Our T1 patient-sharing networks included all surgeons, radiation oncologists, radiologists, and primary care providers who cared for women with breast cancer during the 3 months prior to diagnosis through 9 months after. We then generated peer groups consisting of physicians who most frequently shared patients with one another using the Girvan-Newman method. Finally, for surgeons whose patients did not receive AIT during T1, we used hierarchical logistic regression to examine the subsequent use of AIT among their patients diagnosed in T2 (N = 3,219 patients). Our key explanatory variable was use of AIT in the corresponding surgeon’s peer group in T1; we controlled for patient sociodemographic and clinical characteristics and included random effects for the surgeon, peer group, and hospital referral region. Results: Overall, 16.4% of patients received AIT during T1, increasing to 34.6% in T2. Of the 735 surgeons who did not have patients who received AIT during T1, over half (52%) had patients who received AIT during T2. Patients whose surgeons’ T1 peer groups had the highest use of AIT ( ≥ 25% of patients received AIT in T1) were more likely to receive AIT compared to patients whose surgeons were in a peer group where no patients received AIT during T1 (36.1% vs 21.8%, adjusted Odds Ratio 2.92, 95% Confidence Interval 1.53,5.60). T1 peer group explained 4.7% of the variation in T2 AIT use, compared to 15.9% for the surgeon and 3.3% for hospital referral region. The patterns were stronger for MRI than PET when modeled separately. Conclusions: Physician patient-sharing networks and the phenomenon of social contagion may offer important opportunities to better understand—and potentially intervene upon—the adoption of cancer technologies.
P04.92 Silencing Lis1 gene enhances the radiosensitivity and chemosensitivity of U87 glioblastoma cells grown in vitro
Authors: F M Brehar, V G Trusca, A V Gafencu, G E D Petrescu, A M Sandu, M Amaireh, M R Gorgan
Journal: Neuro-Oncology (2018)

Our previous results showed that Lis1 gene is preferentially expressed in CD133+ glioblastoma cells and suggested a role of Lis1 in maintaining the CD133+ glioblastoma cell population. It is also known that CD133+ cells are resistant against radiation therapy and chemotherapy. Therefore, we tested if the Lis1 gene silencing could increase in vitro the radiosensitivity and chemosensitivity of U87 glioblastoma cells. Lis1 gene expression was silenced in U87 cells by stable transfection using specific shRNA plasmids. U87 cells having Lis1 gene silenced (shLis1 U87 cells) and control U87 cells were irradiated with a 25 Gy X-ray dose. U87 control and shLis U87 irradiated or non-irradiated cells, treated or not with 50 nM temozolomide were followed for their proliferative capacity for 100 hours in xCelligence RTCA instrument. Our results demonstrate that irradiated U87 cells have a higher proliferative capacity than irradiated shLis-U87 cells. Using the xCELLigence system, we showed that the proliferation rate of the control cell is significantly higher as compared to shLis1 U87 cells, and the biggest difference is obtained at 100 hours after exposure to 25 Gy (a cell index of approximately three times less for shLis1 U87 compared with control U87). The chemosensitivity experiments demonstrated important differences between control U87 cells and shLis1 U87 cells proliferation rate when cells were exposed to 50 nM temozolomide. The cell index of shLis1 U87 cells at 100 h was four times diminished as compared with control U87 cells. The increased radiosensitivity and chemosensitivity of shLis1 U87 culture compared with control U87 cells is that the Lis 1 gene silencing lead to a smaller number of CD133+ cells which are resistant to irradiation and temozolomide chemotherapy. These results indicated that Lis1 gene silencing enhances the radiosensitivity and chemosensitivity of U87 cells glioblastoma cells in vitro. Our findings suggest that targeting Lis1 may become an important adjuvant therapy for standard radio- and chemotherapy in glioblastoma. Nevertheless, future in vitro and in vivo studies are necessary to confirm this hypothesis. This work was supported by a grant of the Romanian National Authority for Scientific Research, CNCS - UEFISCDI, project number PN-II-RU-TE-2012-3-0235 F.M.B., V.G.T. and A.V.G. contributed equally to the research done in this paper.
Epigenomics paves a new way to assess potential toxicity and chemotherapeutic response of breast tumours to 5-fluorouracil
Authors: V.V. Strelnikov, E.O. Ignatova, T.V. Kekeeva, E.V. Poddubskaya, M.V. Nemtsova, E.B. Kuznetsova, D.V. Zaletaev, A.S. Tanas
Journal: Annals of Oncology (2018)

Background: 5-fluorouracil (5-FU) is widely used in the therapy of solid tumors, including breast cancer (BC). Toxicity remains a major limitation in the clinical efficacy of 5-FU. Developed approximately 50 years ago, this competitive antagonist of uracil is still not exhaustively studied in terms of its mechanism of action, and the potential of molecular markers in predicting its efficacy and toxicity is not yet fully unravelled. Methods: A modified Reduced Representation Bisulfite Sequencing genome-wide DNA methylation analysis assay, XmaI-RRBS, was applied to 170 BC samples obtained before chemotherapy, and to 10 normal breast tissue samples. Unsupervised hierarchical cluster analysis was used to discern intrinsic DNA methylation BC subtypes; clustering uncertainty was assessed with pvclust R package using bootstrap permutation approach. Results: In a DNA methylation BC subtype enriched in triple-negative breast cancer samples we have identified statistically significant enrichment with the samples non-methylated at the promoter region of the NME1 gene, compared to all other DNA methylation BC subtypes. Another finding was abnormal methylation of the DPYS gene in a DNA methylation BC subtype enriched in HER2 positive tumors. Conclusions: Most studies of 5-FU resistance have focused on germline status of thymidylate synthase TYMS and DPYD genes, and 5-FU Toxicity and Chemotherapeutic Response Panels for the detection of germline variants in these genes are now widely available. It has also been shown that increased expression in tumor cells of some enzymes from the 5-FU metabolic pathway such as DPYD is correlated with resistance to 5-FU. Here we demonstrate differential methylation of the 5-FU drug pathway mediator genes DPYS and NME1 between the DNA methylation BC subtypes. DNA methylation is easily detected by methylation sensitive PCR and does not require RNA extraction. Thus, we suggest that the existing germline DNA tests may be supplemented with the tumour biopsy DNA methylation analysis in order to provide better prediction of 5-FU response and toxicity. Legal entity responsible for the study: Research Centre for Medical Genetics. Funding: Russian Science Foundation (project No.18-15-00430). Disclosure: All authors have declared no conflicts of interest.
A budget impact model of third-line or later trifluridine/tipiracil treatment of metastatic colorectal cancer.
Authors: Cheryl Ferrufino, Fred Wiseman, Tim D Wert, Victoria Barghout
Journal: Journal of Clinical Oncology (2017)

e15070 Background: Trifluridine/tipiracil (FTD/TPI) was recently approved for the treatment of third-line or later (3L+) metastatic colorectal cancer (mCRC). The objective of this study was to develop a payer-perspective budget impact model to estimate the 1-year budgetary consequences of adding FTD/TPI to a health plan’s formulary when a portion of the eligible mCRC patients who are currently treated with regorafenib are treated with FTD/TPI. Methods: The baseline annual budget for treating 3L+ mCRC patients, including pharmacy, administration, monitoring, and adverse-event (AE) costs, and excluding FTD/TPI, was estimated. Pharmacy costs were calculated using wholesale acquisition costs, and all other costs, AE rates, dosing administration, and monitoring guidelines were obtained from publically available sources. The model assumes that all treatment costs were incurred over 1 year, all AEs were mutually exclusive, and 30% of serious AEs (grades 3 and 4) were treated on an inpatient basis. Medication costs associated with outpatient AE management were not included. Using a regorafenib replacement strategy which pulls FTD/TPI market share from regorafenib, the projected annual budget was calculated assuming 30.5% adoption by FTD/TPI. Results: Of the hypothetical population of 1 million, approximately 107 were mCRC patients eligible for receiving 3L+ treatment. A net saving of $230,949 (−6.3%) in total costs was achieved when FTD/TPI therapy was included on total costs of $3,412,713, with the greatest savings in medication (−7.7%) and AE management costs (−0.3%). The reduction in cost per treated patient per year was $2150.12, and the net budget impact was −$0.02 (−6.3%) per member per month. Conclusions: Inclusion of FTD/TPI therapy in the model resulted in net savings in medication, AE management, and total costs, and costs per treated patient per year. These data suggest potential savings if FTD/TPI is added to a health plan formulary for the 3L+ treatment of mCRC patients. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion.
Extraordinary survivorship after colorectal liver metastasis resection to identify a distinct molecular profile associated with survival in an independent cohort of 965 patients.
Authors: Jesse Joshua Smith, Cyriac Kandoth, John Christopher McAuliffe, Efsevia Vakiani, Timothy Frankel, Isaac Wasserman, Walid Chatila, Marla Lipsyc, Vinod P. Balachandran, Peter J. Allen, Ronald P. DeMatteo, T. Peter Kingham, William R. Jarnagin, Nikolaus Schultz, Nancy E. Kemeny, Julio Garcia-Aguilar, Barry S. Taylor, David B. Solit, Rona Yaeger, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2017)

3581 Background: Half of patients diagnosed with colorectal cancer (CRC) develop metastases and most are CRC liver metastasis (CRLM). A mere 20% of these patients undergo complete resection of their liver disease and 5-year overall survival (OS) is only 50%. We hypothesized that we could identify a specific molecular profile associated with extraordinary survivorship in CRLM patients that would more precisely inform underlying tumor biology beyond standard clinical and pathologic features. Methods: Tumor samples were identified from patients who underwent curative resection. Patients with disease-specific survival (DSS) ≥10 years following resection were compared to those with ≤2-year survival (10yr vs. 2yr). Evaluable DNA was obtained from 36 cases (2yr, n = 17; 10yr, n = 19) then sequenced and analyzed with MSK-IMPACT (MSK-I), a hybridization capture, next generation sequencing platform. Differentially altered genes in 10yr vs. 2yr cohorts were identified (Fisher’s exact). Findings in the extraordinary survivors group were validated using MSK-I in an independent cohort of 965 metastatic CRCs (metCRCs). Kaplan-Meier estimates and log-rank test were used. Results: In the 2yr group, we noted higher clinical risk scores and more complex chemotherapy regimens vs. the 10yr group. Molecularly, mutually exclusive KRAS and TP53 mutations were noted in the 10yr group, whereas significant co-occurrence of KRAS and TP53 mutations was seen in the 2yr group. Further, we noted significant enrichment of VEGF copy number gains in the 2yr group vs. the 10yr group. APC mutation was equally common. In the validation cohort, KRAS mut /TP53 wt and TP53 mut /KRAS wt patients (median OS of 10 and 15 years respectively) had significantly better OS than the co-occurring KRAS mut / TP53 mut patients (median OS of 4.9 years; (P = 0.0001)). Conclusions: Single mutation of either KRAS or TP53 is associated with better outcomes than co-occurring KRAS/TP53 mutations in metCRC. These data demonstrate use of an extraordinary survivor cohort to identify a molecular profile associated with significant survival differences in an independent cohort of metCRC patients.
The effect of yoga interventions on cancer-related fatigue for breast cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Meagan O'Neill, Daniel Santa Mina, Catherine Sabiston, George A. Tomlinson, Dominic Samaroo, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2016)

e21578 Background: Cancer-related fatigue (CRF) is a common, long-lasting, and debilitating symptom that women with breast cancer (BC) can experience. Rest has previously been recommended to manage CRF; however this is not evidence-based whereas exercise has been shown to reduce the effects of CRF. Yoga, as a form of exercise, incorporates multiple features such as physical poses and meditation. However the effects of yoga on CRF are not consistent in the literature. The objective of this meta-analysis is to evaluate the role of yoga intervention on CRF for women with BC. Methods: An electronic search was performed using 3 databases: Medline, Embase and Cochrane using a search strategy developed with an experienced librarian. We identified all full text randomized controlled trials (RCTs) involving women with BC at any stage and treatment published in English. Inclusion criteria included: RCT, yoga intervention compared to a control, exercise group, or other, and reporting on CRF. Relevant data were extracted using a customized data extraction form. A meta-analysis was performed using the standardized mean difference (SMD) and heterogeneity was assessed with the I2 statistic. Results: Of 325 initial citations, 21 full-length articles were reviewed and 14 RCTs were included. Study sample sizes ranged from 18 to 128 participants with mean ages ranging from 47 to 63. Eight different yoga interventions were used within the 14 studies. Comparison arms included waitlist control, usual care, health education, supportive therapy and aerobic training. The meta-analysis analyzed 9 of the 14 RCTs comparing yoga to a non-exercise control. There was substantial heterogeneity within the 9 RCTs (I2= 74%). The meta-analysis found no indication that yoga reduced fatigue over the control group (SMD effect estimate – 0.42 (-0.23, 1.07), z = 1.27, p = 0.20). Conclusions: Our meta-analysis found no significant difference between yoga and non-exercise controls for CRF in women with BC. However, heterogeneity and considerable uncertainty around our effect estimate suggest further trials of yoga in women with BC are warranted.