tbuckley/cabot-search huggingface dataset:
Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial.
Authors: Sean Kehoe, Jane Hook, Matthew Nankivell, Gordon C. Jayson, Henry Charles Kitchener, Tito Lopes, David Luesley, Timothy Perren, Selina Bannoo, Monica Mascarenhas, Stephen Dobbs, Sharadah Essapen, Jeremy Twigg, Jonathan Herod, W. Glenn McCluggage, Mahesh Parmar, Ann Marie Swart
Journal: Journal of Clinical Oncology (2013)

5500 Background: First line treatment of advanced ovarian cancer (OC) is accepted to be primary surgery (PS) followed by adjuvant platinum-based chemotherapy (P-CT). However, the EORTC55971 trial suggested neoadjuvant chemotherapy (NACT) is an alternative, showing increased optimal debulking rates and reduced surgical complications without detriment to survival. CHORUS (CRUK 07/009) is the 2nd phase III randomized controlled trial to investigate timing of initial surgery in OC. Methods: Patients (pts) with clinical FIGO stage III-IV OC (pelvic mass, extrapelvic metastases and CA125/CEA ratio &gt;25) were randomized to standard treatment (PS followed by 6 cycles P-CT) or NACT (3 cycles P-CT either side of surgery). CHORUS was designed to demonstrate non-inferiority of NACT, excluding a 6% absolute detriment in 3yr survival from 50% expected with PS (1-sided alpha 10%). Primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), toxicity and quality of life. Results: 550 women (276 PS, 274 NACT) were randomized from 74 centres (72 UK, 2 NZ) between Mar 2004 and Aug 2010. Baseline characteristics were well balanced: median age 65yrs, median tumor size 80mm, 25% FIGO stage IV, 19% WHO PS 2. Median follow-up was 3yrs, 410 pts have died. Treatment data are summarized in the Table. 3yr survival in the control arm was 32%. Intention to treat analysis showed a median OS of 22.8 months for PS vs 24.5 months for NACT (hazard ratio (HR) 0.87 in favor of NACT, 80% CI 0.76 – 0.98) and median PFS of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). OS results represent a 5% absolute benefit in 3yr survival for NACT to 37% and the upper 80% CI allows us to exclude a survival benefit for PS. Conclusions: NACT was associated with increased optimal debulking, less early mortality and similar survival in this poor prognosis group. CHORUS results are consistent with EORTC55971 and strengthen evidence that NACT is a viable alternative to PS. Clinical trial information: ISRCTN74802813. [Table: see text]
Haploidentical versus Matched-Sibling Transplant in Adults with Philadelphia-Negative High-Risk Acute Lymphoblastic Leukemia: A Biologically Phase III Randomized Study
Authors: Yu Wang, Qi-Fa Liu, Lan-Ping Xu, Kai-Yan Liu, Xiao-Hui Zhang, Xiao Ma, Mei-Qing Wu, De-Pei Wu, Xiao-Jun Huang
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Although matched-sibling donor (MSD) hematopoietic stem-cell transplantation (HSCT) has an established role in the management of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), the effect of haploidentical donor (HID) HSCT as post-remission treatment for this portion of patients is not defined. Experimental Design: Transplantation outcomes from HIDs or MSDs were compared in a disease-specific, biologically phase III randomized, multicenter study. Between July 2010 and December 2013, 210 patients with Philadelphia-negative high-risk ALL in CR1 were assigned to undergo unmanipulated HIDs (121 patients) or MSDs HSCT (89 patients) according to donor availability on an intent-to-treat (ITT) basis. Results: Overall, 24 of the 210 patients had lost transplant eligibility. Therefore, 186 of 210 (88%) patients were finally transplanted from MSD (n = 83) or HID (n = 103). Based on the ITT principle, the 3-year disease-free survival (DFS) did not differ between HID and MSD groups [61%, 95% confidence interval (CI), 52%–70%; vs. 60%, CI, 49%–71%; P = 0.91] from CR, neither did DFS differ between the two groups (68%, CI, 58%–78%; vs. 64%, CI, 52%–76%; P = 0.56) from time of the graft, with cumulative incidence of nonrelapse mortality of 13% (CI, 7%–19%) and 11% (CI, 4%–18%; P = 0.84) and relapse rates of 18% (CI, 10%–26%) and 24% (CI, 14%–34%; P = 0.30), respectively. Conclusions: Haploidentical HSCT achieves outcomes similar to those of MSD-HSCT for Philadelphia-negative high-risk ALL patients in CR1. Such transplantation could be a valid alternative as post-remission treatment for high-risk ALL patients in CR1 lacking an identical donor. Clin Cancer Res; 22(14); 3467–76. ©2016 AACR.
Results of new cases of APL treatment by arsenic trioxide and long-term follow-up: Is it time for using arsenic trioxide in first-line treatment?
Authors: A. Ghavamzadeh, K. Alimoghaddam, S. Ghaffari, S. Rostami, M. Jahani, M. Iravani, S. Mousavi, M. Jalili, N. Alizadeh, A. Khodabandeh
Journal: Journal of Clinical Oncology (2010)

6545 Background: Arsenic trioxide approved for treatment of APL patients who relapsed after first-line treatment failure by ATRA and chemotherapy. Its efficacy as first-line treatment studied in at least three trials (including our center reports) previously. Here we are studying its efficacy, safety and long-term follow-up of new cases of APL. Methods: it is an intention to treat trial.between 1999 and 2009 we treated 190 new cases of APL by Arsenic Trioxide ( 0.15 mg/kg/day till CR). Presence of t(15,17) confirmed in all cases by cytogenetic study and/or RT-PCR. In patients who achieved to CR we applied 4 more courses of daily ATO with the same dose for 28 days. Patients followed every 3 months by physical exam, hemogram and RT-PCR on peripheral blood for detection of relapse. Results: Median age of our patients was 29 years. Remission rate was 84.7% and median time to achieve to CR was 30 days. Median follow-up was 38 months (maximum 105 months) and for patients entered to trial, DFS was 72.5%. Also chance of 3 and 5 years DFS were 72.5% and 66.5% Also OS for 3 and 5 years were 83.45 and 70.8% respectively. For patients who don't experience relapse till 5 years after first remission chance of relapse is very low (2.8%). Also we couldn't find any significant correlation between DFS or OS and WBC count. Conclusions: Arsenic trioxide is first-line treatment. Its long-term results is comparable with conventional treatment of APL. According to results of this trial and similar trials it seems that guidelines can move arsenic trioxide to first-line treatment of APL especially for high-risk patients. No significant financial relationships to disclose.
The number of segregating sites in expanding human populations, with implications for estimates of demographic parameters.
Authors: G Bertorelle, M Slatkin
Journal: Molecular Biology and Evolution (1995)

The frequency distribution of pairwise differences between sequences of mtDNA has recently been used to estimate the size of human populations before and after a hypothetical episode of rapid population growth and the time at which the population grew. To test the internal consistency of this method, we used three different sets of human mtDNA data and the corresponding demographic parameters estimated from the distribution of pairwise differences to determine by simulation the expected number of segregating sites, S, and its empirical distribution. The results indicate that the observed values of S are significantly lower than expected in two of three cases under the assumption of the infinite-sites model. Further simulations in which mutations were allowed to occur more than once at the same site and in which there was variation in mutation rate among sites show that the expected number of segregating sites can be much lower than under the infinite-site assumption. Nevertheless, the observed value of S is still significantly different from the value expected under the expansion hypothesis in two of three cases.
E-cigarettes help up to 22 000 smokers in England quit each year
Authors: Jacqui Wise
Journal: BMJ (2016)

Electronic cigarettes helped between 16 000 and 22 000 more people quit smoking in England in 2014, researchers said in the journal Addiction .1

The researchers, from University College London, tracked the use of e-cigarettes from 2011 using monthly household surveys. Each month involved a new representative sample of 1800 respondents, 450 of whom were smokers. They estimated that at the start of 2014 there were approximately 8.46 million adult smokers in England, 19% of the adult population.

The percentage of smokers in 2014 who reported that they had tried to …
A Japanese Post-Marketing Surveillance of Regorafenib in Colorectal Cancer Patients: Interim Report
Authors: Taroh Satoh, Naoya Yamazaki, Hajime Takikawa, Hideyuki Ito, Yuichiro Ito, Toshiaki Sakaguchi, Takashi Yamada, Kei Muro, Kenichi Sugihara
Journal: Annals of Oncology (2014)
Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants
Authors: Ravi M. Patel, Andrea Knezevic, Neeta Shenvi, Michael Hinkes, Sarah Keene, John D. Roback, Kirk A. Easley, Cassandra D. Josephson
Journal: JAMA (2016)

<h3>Importance</h3> Data regarding the contribution of red blood cell (RBC) transfusion and anemia to necrotizing enterocolitis (NEC) are conflicting. These associations have not been prospectively evaluated, accounting for repeated, time-varying exposures. <h3>Objective</h3> To determine the relationship between RBC transfusion, severe anemia, and NEC. <h3>Design, Setting, and Participants</h3> In a secondary, prospective, multicenter observational cohort study from January 2010 to February 2014, very low-birth-weight (VLBW, ≤1500 g) infants, within 5 days of birth, were enrolled at 3 level III neonatal intensive care units in Atlanta, Georgia. Two hospitals were academically affiliated and 1 was a community hospital. Infants received follow-up until 90 days, hospital discharge, transfer to a non–study-affiliated hospital, or death (whichever came first). Multivariable competing-risks Cox regression was used, including adjustment for birth weight, center, breastfeeding, illness severity, and duration of initial antibiotic treatment, to evaluate the association between RBC transfusion, severe anemia, and NEC. <h3>Exposures</h3> The primary exposure was RBC transfusion. The secondary exposure was severe anemia, defined a priori as a hemoglobin level of 8 g/dL or less. Both exposures were evaluated as time-varying covariates at weekly intervals. <h3>Main Outcomes and Measures</h3> Necrotizing enterocolitis, defined as Bell stage 2 or greater by preplanned adjudication. Mortality was evaluated as a competing risk. <h3>Results</h3> Of 600 VLBW infants enrolled, 598 were evaluated. Forty-four (7.4%) infants developed NEC. Thirty-two (5.4%) infants died (all cause). Fifty-three percent of infants (319) received a total of 1430 RBC transfusion exposures. The unadjusted cumulative incidence of NEC at week 8 among RBC transfusion-exposed infants was 9.9% (95% CI, 6.9%-14.2%) vs 4.6% (95% CI, 2.6%-8.0%) among those who were unexposed. In multivariable analysis, RBC transfusion in a given week was not significantly related to the rate of NEC (adjusted cause-specific hazard ratio, 0.44 [95% CI, 0.17-1.12];<i>P</i> = .09). Based on evaluation of 4565 longitudinal measurements of hemoglobin (median, 7 per infant), the rate of NEC was significantly increased among VLBW infants with severe anemia in a given week compared with those who did not have severe anemia (adjusted cause-specific hazard ratio, 5.99 [95% CI, 2.00-18.0];<i>P</i> = .001). <h3>Conclusions and Relevance</h3> Among VLBW infants, severe anemia, but not RBC transfusion, was associated with an increased risk of NEC. Further studies are needed to evaluate whether preventing severe anemia is more important than minimizing RBC transfusion.
Annals On Being a Doctor Story Slam - Lessons From the Home Front
Authors: Alan D. Haber
Journal: Annals of Internal Medicine (2016)

Web Exclusives19 January 2016Annals On Being a Doctor Story Slam - Lessons From the Home FrontFREEAlan D. Haber, MDAlan D. Haber, MDFrom the Fox Chase Cancer Center, Philadelphia, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/V15-0019 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals On Being a Doctor Story Slam - Lessons From the Home Front This story, "Lessons From the Home Front," by Dr. Alan D. Haber, is from the Annals On Being a Doctor Story Slam held on 18 November 2015 in Philadelphia, with support from the Josiah Macy Jr. Foundation. (Duration 5:23)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.Attendees of the 18 November 2015 Annals On Being a Doctor Story Slam voted this story as one of their 3 favorites.For more videos from and information on Annals On Being a Doctor Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From the Fox Chase Cancer Center, Philadelphia, Pennsylvania.Note: This story is from the Annals On Being a Doctor Story Slam held on 18 November 2015 in Philadelphia, with support from the Josiah Macy Jr. Foundation. Attendees voted this story as one of their 3 favorites.Corresponding Author: Alan D. Haber, MD, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111; e-mail, alan.[email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 January 2016Volume 164, Issue 2Page: SS8 ePublished: 19 January 2016 Issue Published: 19 January 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.Loading ...
Abstract 302: Neuregulin-1β Inhibits TGFβ-induced Cardiofibroblast to Myofibroblast Transition
Authors: Cristi L Galindo, Linh Truc-Tran, Sergey Ryzhov, Igor Feoktistov, Douglas Sawyer
Journal: Circulation Research (2013)

Neuregulin (NRG) is a growth and survival factor critical for cardiac development and repair. Our laboratory recently demonstrated decreased fibrosis with NRG treatment in post-infarcted swine. We subsequently hypothesized that NRG inhibits transition of fibroblasts to myofibroblasts (myoFbs), the cells primarily responsible for collagen deposition after cardiac injury. Immunohistochemistry of post-infarcted swine hearts confirmed reduced presence of myoFbs in NRG-treated pig ventricles, compared to untreated animals. Further investigation revealed that NRG acts directly upon primary cultures of rat cardiac fibroblasts, with subsequent phosphorylation of both AKT and p38. Based on quantitative RT-PCR, primary fibroblasts isolated from both rats and mice express ErbB2 and ErbB3, which are known to form heterodimers and thereby transduce the NRG signal. NRG treatment also reduced myoFb percentages by ~40% in primary rat and mouse cardiac cultures, compared to untreated cells, as demonstrated by immunohistochemistry, Western blot, and flow cytometric analyses of the myoFb marker, alpha smooth muscle actin. NRG pre-treatment of cardiac fibroblasts likewise inhibited TGFβ-induced fibroblast-to-myoFb transition, including suppression of SMAD3 phosphorylation and reduction of the down-stream pro-fibrotic proteins, collagen I and periostin. Considered together, these data strongly support the hypothesis that NRG modulates fibroblast signaling directly. These results demonstrate that NRG inhibits the activation of pro-fibrotic cells and suggests a novel mechanism by which NRG treatment might improve cardiac remodeling.
Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection
Authors: Graham R. Foster, Nezam Afdhal, Stuart K. Roberts, Norbert Bräu, Edward J. Gane, Stephen Pianko, Eric Lawitz, Alex Thompson, Mitchell L. Shiffman, Curtis Cooper, William J. Towner, Brian Conway, Peter Ruane, Marc Bourlière, Tarik Asselah, Thomas Berg, Stefan Zeuzem, William Rosenberg, Kosh Agarwal, Catherine A.M. Stedman, Hongmei Mo, Hadas Dvory-Sobol, Lingling Han, Jing Wang, John McNally, Anu Osinusi, Diana M. Brainard, John G. McHutchison, Francesco Mazzotta, Tram T. Tran, Stuart C. Gordon, Keyur Patel, Nancy Reau, Alessandra Mangia, Mark Sulkowski
Journal: New England Journal of Medicine (2015)

In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3.We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy.Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia.Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).
Inhibition of <i>FoxM1</i>-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis
Authors: Subapriya Rajamanickam, Subbarayalu Panneerdoss, Aparna Gorthi, Santosh Timilsina, Benjamin Onyeagucha, Dmytro Kovalskyy, Dmitri Ivanov, Martha A. Hanes, Ratna K. Vadlamudi, Yidong Chen, Alexander J. Bishop, Jack L. Arbiser, Manjeet K. Rao
Journal: Clinical Cancer Research (2016)

The approaches aimed at inhibiting the ability of cancer cells to repair DNA strand breaks have emerged as promising targets for treating cancers. Here, we assessed the potential of imipramine blue (IB), a novel analogue of antidepressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination (HR).The effect of IB on breast cancer growth and metastasis was assessed in vitro as well as in preclinical mouse models. Besides, the therapeutic efficacy and safety of IB was determined in ex vivo explants from breast cancer patients. The mechanism of action of IB was evaluated by performing gene-expression, drug-protein interaction, cell-cycle, and DNA repair studies.We show that the systemic delivery of IB using nanoparticle-based delivery approach suppressed breast cancer growth and metastasis without inducing toxicity in preclinical mouse models. Using ex vivo explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cells. Furthermore, our mechanistic studies revealed that IB may interact and inhibit the activity of proto-oncogene FoxM1 and associated signaling that play critical roles in HR-mediated DNA repair.These findings highlight the potential of IB to be applied as a safe regimen for treating breast cancer patients. Given that FoxM1 is an established therapeutic target for several cancers, the identification of a compound that inhibits FoxM1- and FoxM1-mediated DNA repair has immense translational potential for treating many aggressive cancers. Clin Cancer Res; 22(14); 3524-36. ©2016 AACR.
Effect of the Retinoic Acid Analog Ro 11-1430 on Proteoglycans of Swarm Rat Chondrosarcoma<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>
Authors: T R Oegema, S M Parzych
Journal: JNCI Journal of the National Cancer Institute (1981)

When treated with a retinoic acid analog (Ro 11-1430), the Swarm rat chondrosarcoma regressed (t½ = 11–12 days) with a rapid removal of tumor proteoglycan, histologic evidence of mineralization, and cartilage proteoglycan synthesis was suppressed down to a value of 1% of the control. During the first 3 weeks of treatment, the newly synthesized proteoglycan was similar both in aggregation and size to the proteoglycan present in the control. However, after 5 weeks of treatment synthesis shifted to a small nonaggregating proteoglycan with longer glycosaminoglycan chains now containing dermatan sulfate, possibly representing a switch in proteoglycan synthesized. Heparan sulfate was also detected. Unlabeled proteoglycan released from the tissue during Ro 11-1430 treatment was large (Kav = 0.25 on Sepharose CL-2B) but incapable of aggregation, suggesting the initial proteolytic cleavage was in or near the hyaluronic acid-binding region of the proteoglycan. Degradative enzyme activity varied during the period of treatment. Since other tissues remained histologically normal during the treatment with Ro 11-1430, this drug may have possible therapeutic value.