tbuckley/cabot-search huggingface dataset:
Cognitive Impairment Among Older Patients With Hematologic Cancers
Authors: Tetsuya Tanimoto, Tomohiro Morita, Kenji Tsuda
Journal: JAMA Oncology (2018)

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Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Asim Amin, Elizabeth R. Plimack, Jeffrey R. Infante, Marc S. Ernstoff, Brian I. Rini, David F. McDermott, Jennifer J. Knox, Sumanta Kumar Pal, Martin Henner Voss, Padmanee Sharma, Christian K. Kollmannsberger, Daniel Yick Chin Heng, Jennifer L. Spratlin, Yun Shen, John F. Kurland, Paul Gagnier, Hans J. Hammers
Journal: Journal of Clinical Oncology (2014)

5010 Background: Antiangiogenic agents sunitinib (S) and pazopanib (P) are SOC for mRCC, but new therapies are needed as pts advance through therapy with limited survival benefit. We report preliminary results of a phase I trial of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, in combination with S or P in pts with mRCC. Methods: mRCC patients (≥1 prior systemic therapy) received nivolumab in combination with S (50 mg, 4 wks on, 2 wks off; arm S) or P (800 mg daily; arm P), until progression/unacceptable toxicity. Starting dose of nivolumab was 2 mg/kg IV Q3W (N2), with planned escalation to 5mg/kg IV Q3W (N5). Based on tolerability, arm S N5 cohort was expanded to treatment-naïve pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity (objective response rate [ORR] and duration of response [DOR]). Results: 7 pts were assigned to each of arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached thus N5 was expanded with 19 additional pts (total n=33). Arm P enrolled 20 pts at N2; 4 DLTs (elevated ALT/AST [n=3], fatigue [n=1]) were observed, leading to closure of this arm. Grade 3–4 related AEs were observed in 24/33 pts (73%) in arm S and 12/20 pts (60%) in arm P. Most common related grade 3–4 AEs included elevated ALT (18%), hypertension and hyponatremia (15% each) in arm S and elevated ALT/ AST (20% each) and fatigue (15%) in arm P. Hepatotoxicities were manageable using treatment algorithms. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3–4 related AEs led to therapy discontinuation in 8/33 pts (24%; 1 N2, 7 N5) in arm S and 4/20 pts (20%) in arm P. ORR was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wks) in 41% (arm S) and 56% (arm P) of responding pts and were durable (range: arm S: 12.1+ to 54 wks; arm P: 12.1 to 69.1+ wks). Stable disease rate was 33% (n=11) in arm S and 35% (n=7) in arm P. PFS rate at 24 wks was 78% for arm S and 55% for arm P. Conclusions: Nivolumab plus S or P showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Additional follow up will be presented. Clinical trial information: NCT01472081.
Single-dose versus 7-day-dose metronidazole for the treatment of trichomoniasis in women: an open-label, randomised controlled trial
Authors: Patricia Kissinger, Christina A Muzny, Leandro A Mena, Rebecca A Lillis, Jane R Schwebke, Laura Beauchamps, Stephanie N Taylor, Norine Schmidt, Leann Myers, Peter Augostini, William E Secor, Martina Bradic, Jane M Carlton, David H Martin
Journal: The Lancet Infectious Diseases (2018)
Gene copy number gains are associated with prognosis in a comprehensive molecular profile of non-small cell lung cancer
Authors: Patrick Micke, Karolina Edlund, Hanna Goransson, Simon Ekman, Michael Bergqvist, Lena Scheibenflug, Kristina Lamberg, Elisabeth Stahle, Anders Berglund, Mats Lambe, Fredrik Nyberg, Andrew Thomas, Anders Isaksson, Lars Holmberg, Johan Botling
Journal: Journal of Thoracic Oncology (2009)
Nanoparticle albumin-bound (nab) rapamycin as an anticancer agent
Authors: Tapas De, Vuong Trieu, Zachary Yim, Jon Cordia, Andrew Yang, Bridget Beals, Sherry Ci, Leslie Louie, Neil Desai
Journal: Cancer Research (2007)

4719  Background: The mammalian target of rapamycin (mTOR) is involved in the control of cellular growth and proliferation. Abnormal activation of signaling pathways both proximal and distal to this kinase occurs frequently in human cancer, making mTOR an attractive target for antineoplastic therapies. Due to insolubility and poor bioavailability of rapamycin, water soluble analogs, such as CCI-779, RAD001 and AP23573 are in development, which have demonstrated potent antitumor activity in vitro and in xenograft models. Here we report on rapamycin albumin-bound nanoparticles using nanoparticle albumin-bound (nab) technology, which allows the direct administration of the drug at high dose.  Methods: Overall toxicity of nab-rapamycin was determined in a dose-ranging study in Sprague-Dawley rats. The dose levels of nab-rapamycin used were 0, 15, 30, 45, 90, and 180 mg/kg with a q4dx3 schedule. Pharmacokinetics (PK) of nab-rapamycin was investigated in Sprague-Dawley rats at dose levels of 1, 15, 30, and 45 mg/kg. Antitumor activity of nab-rapamycin was examined using three tumor models in athymic mice (MX-1, breast, N=5; HCT-116, colon, N=10; and HT29, colon, N=8) at a dose level of 40 mg/kg with a 3x wkly/4wks schedule. Tumor growth data were analyzed by ANOVA.  Results: nab-Rapamycin was nontoxic at the highest dose of 180 mg/kg on a q4dx3 schedule. No changes in blood chemistry,CBC, hypercholesterolemia, or hypertriglyceridemia were observed. nab-Rapamycin exhibited linear PK with respect to dose and rapid extravascular distribution as demonstrated by large Vss and Vz, and typical for nab technology, e.g. nab-paclitaxel and nab-docetaxel. nab-Rapamycin was highly effective against all tumor models tested, achieving a tumor growth inhibition (TGI) of 80.7% against HT29 xenograft (p  Conclusion: nab-Rapamycin was well tolerated, showed linear PK, and was highly effective against a number of tumor models in vivo.
A randomized phase III study in advanced esophageal cancer (OC) to compare the quality of life (QoL) and palliation of dysphagia in patients treated with radiotherapy (RT) or chemoradiotherapy (CRT) TROG 03.01 NCIC CTG ES.2.
Authors: Michael Gordon Penniment, Jennifer A Harvey, Rebecca Wong, Sonya Stephens, Heather-Jane Au, Christopher J. O'Callaghan, Andrew Kneebone, Sam Ngan, Iain G. Ward, Rajarshi Roy, Thomas Richard Sullivan, Tirath Nijjar, James Joseph Biagi, Liam A Mulroy
Journal: Journal of Clinical Oncology (2014)

4009 Background: RT is known to relieve dysphagia of advanced oesophageal cancer, there is no data from randomised phase III trials determining response, toxicity, or role of palliative CRT. Aims 1) to establish effective and least toxic treatment for symptom relief of advanced OC 2) determine effects of common cancer treatments on QoL and end of life care 3) establish an evidence base for patient decision making regarding the optimal management for incurable OC. Methods: 220 patients were randomised to receive a course of palliative RT [35 Gy in 15 fractions, (n=115) or 30 Gy in 10 fractions (n=105) in Canada and UK], or concomitant CRT with Cisplatin and 5FU (D1-4) (n=111). Dysphagia was measured using the Mellow score, toxicity using CTCAE v2, and QoL using EORTC QLQ30 and oesophagus module (OES-18). The primary end point was the proportion of patients with improved dysphagia as measured at week 9 and maintained until week 13. Results: The patients receiving radiotherapy alone showed a dysphagia response (at any point) of 67.89% compared to chemotherapy response in 73.87%, this was not a significant difference (p=0.343). There was increased toxicity in patients receiving CRT, with worse bowel conditions (nausea (p=0.0019) and vomiting (p=0.0072)). The median survival was 210 days for CRT and 203 days for RT alone. The baseline parameters of both groups were well matched at randomisation and although the results of the trial showed equally poor survival prognosis in both arms, there were some patients (n=21) still alive at 2 years post treatment. Conclusions: Although the CRT group had slightly better dysphagia response and median survival, the bowel toxicity was worse. Further analysis of QoL, toxicity and durable palliative response will be published. This multicentre trial, conducted in the UK, Canada, Australia and New Zealand reflects practice in several countries RT alone remains an excellent tool for palliation of patients with advanced OC and should remain the standard of care. Clinical trial information: NCT00193882.
Abstract 20011: Novel Genetic Variants Associated With Circulating Soluble Glycoprotein 130 Levels in The IMPROVE Study
Authors: Alice Bonomi, Fabrizio Veglia, Damiano Baldassarre, Zahra Golabkesh, Rona Strawbridge, Anders Hamsten, Elena Tremoli, Ulf de Faire, Bruna Gigante
Journal: Circulation (2017)

Introduction: Genetic variants regulating soluble glycoprotein (sgp130), a natural antagonist of the pro-inflammatory/pro-atherogenic IL6/sIL6R complex, are largely unknown. Recently, a single nucl...
Breaking news: DNA damage and repair pathways in COPD and implications for pathogenesis and treatment
Authors: Ian M. Adcock, Sharon Mumby, Gaetano Caramori
Journal: European Respiratory Journal (2018)

Cigarette smoke exposure is the major driver of chronic obstructive pulmonary disease (COPD) and lung cancer in the developed world [1]. COPD affects over 450 million people worldwide whilst lung cancer is the biggest cause of death in people with cancer [2, 3]. Cigarette smoke-mediated DNA damage causes apoptosis, cellular senescence, inflammation and mutagenesis, which have all been implicated in the pathogenesis of COPD [4, 5]. Reduced components of DNA damage and repair pathways have previously been reported in COPD lung tissues (with or without associated pulmonary emphysema) and blood (including stem cells), and airway epithelium and lung fibroblast primary cells [6–10]. A failure to correctly repair cigarette smoke-induced DNA damage has also been reported in COPD [8] and a genetic link to COPD susceptibility noted [9, 11]. Evidence has also implicated DNA damage and repair mechanisms with lung cancer and response to therapy [12, 13]. However, the precise mechanisms of DNA damage and repair that are associated with these diseases are unclear. Defective DNA damage and repair processes are important in COPD <http://ow.ly/edRb30lTF2J>
CaFLe: A novel naming test for use during awake craniotomy for tumour resection
Authors: Ms Casidhe Edwards, Ms Kate Wade-Brown, Prof Rosaleen McCarthy
Journal: Neuro-Oncology (2018)

Confrontation naming tests are widely used techniques for assessing language function in people with dominant hemisphere pathology. Tests that vary in difficulty allow the assessment to be matched to the educational and intellectual level of the patient. For example, somebody with an extensive premorbid vocabulary and mild injury to the language areas of the brain will easily retrieve common words – their word finding impairment only becomes apparent with less common items. Conversely, somebody with limited educational attainment may need to be assessed using a range of common items to avoid falsely identifying pathology rather than pre-morbid limitations. This study aimed to assess the validity and utility of a novel naming test, the CaFLe, for use during awake craniotomy for tumour resection. Our surgical protocol involved pre-assessing patients with the CaFLe alongside other neuropsychological tests. Items that could be named at baseline were incorporated into the intraoperative assessment Better performance on the CaFLe at baseline was found to be associated with better performance on the Graded Naming Test (r (29) = .61, p < .001, r2 = .37), showing the novel CaFLe has convergent validity with an established graded difficulty naming test. The CaFLe was deployed during direct electrical stimulation and repeatedly throughout the course of resection. Surgeons were immediately notified of word finding difficulty if and when it became apparent. As shown in our poster, use of the CaFLe pre- and intraoperatively demonstrates that it is sensitive to relatively subtle language deficit and can be predictive of focal seizures.
Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group
Authors: Frédéric E Lecouvet, Daniela E Oprea-Lager, Yan Liu, Piet Ost, Luc Bidaut, Laurence Collette, Christophe M Deroose, Karolien Goffin, Ken Herrmann, Otto S Hoekstra, Gem Kramer, Yolande Lievens, Egesta Lopci, David Pasquier, Lars J Petersen, Jean-Noël Talbot, Helle Zacho, Bertrand Tombal, Nandita M deSouza
Journal: The Lancet Oncology (2018)
Tapered versus constant drug exposure to anti-EGFR monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI).
Authors: Alexandre Bozec, Patricia Formento, jean-louis fischel, Marie-Christine Etienne-Grimaldi, Gerard Milano
Journal: Cancer Research (2008)

1343   Tumor re-growth is clinically observed at the time of arrest of anti-EGFR therapies. The aim of the present study was to compare, for a similar dose exposure to anti-EGFR therapies, a constant schedule with a tapered schedule (i.e. progressive dose reduction). Both the mAb cetuximab (i.p. administration) and the TKI gefitinib (p.o. administration) were tested. A human head and neck cancer cell line exhibiting high EGFR levels (CAL33) was subcutaneously implanted in the flank of nude mice (15 mice per condition). Constant schedule consisted in 7 days cetuximab (1.14 mg/kg/d) or gefitinib (68.4 mg/kg/d) administration. Tapered schedule consisted in 7 days cetuximab (1 mg/kg/d) or gefitinib (60 mg/kg/d) followed by 7 days administration at decreased doses (divided by 2 every day). Equal total doses were given for both schedules. Five mice in each treatment group were sacrificed at the 3 following times (day 0 = start of treatment): day 7, day 14, and at the end of observation when mean tumor volume in the group reached 2000 mm 3 . Tumor volume and time to reach a mean tumor volume of 1000 mm 3  (TRV) were measured. At each time, tumor EGFR expression along with the EGFR-signalling proteins p-Erk, p-Akt, apoptosis-related factors Bax/Bcl2 and % cleaved Parp (Western blot analyses) were analyzed.  Of note, tumor growth with gefitinib at the constant schedule did not differ from controls, whereas gefitinib at the tapered schedule significantly slowed down tumor re-growth (difference in TRV between schedules = 7 days). Cetuximab treatment was effective with both schedules, with a stronger growth inhibition and lasting effect with the tapered schedule as compared to the constant schedule (difference in TRV between schedules = 10 days). For both drugs, these effects were paralleled by a significant down-regulation of EGFR expression relative to controls (on day 7 and day 14). The EGFR down-regulation observed with gefitinib lasted longer with the tapered schedule than with the constant schedule, whereas that observed with cetuximab was similar with both schedules. Significant effects on EGFR signalling proteins were only observed with cetuximab at the constant schedule, with decreases in p-Akt and p-Erk expression (both at the end of observation) and parallel increases in the apoptosis markers Bax/Bcl2 (on day 7 and day 14) and cleaved Parp (at the end of observation).  The present data clearly show that for both anti-EGFR monoclonal antibody and TKI, a tapered schedule more efficiently slowed down the tumor re-growth as compared to a constant schedule given at the same total drug exposure. This new drug schedule, unexplored so far in the clinical setting, could be of interest in the management of anti-EGFR-based therapies, in particular for TKIs.
Abstract #3239: Enhanced in vitro and in vivo activity of trastuzumab-DM1 antibody-drug conjugate combined with GDC-0941, a small molecule inhibitor of PI3 kinase
Authors: Carter Fields, Guangmin Li, Wei Wei Prior, Kathryn Parsons, Deepak Sampath, Gail Lewis Phillips
Journal: Cancer Research (2009)

Molecularly targeted therapeutics continue to offer great promise in the treatment of human cancers. The receptor tyrosine kinase, HER2/ErbB2, is a validated clinical target for HER2-amplified breast cancer, as evidenced by the U.S.F.D.A approval of the humanized HER2 antibody trastuzumab (Herceptin®) and the dual HER2/EGFR small molecule tyrosine kinase inhibitor lapatinib (Tykerb®). Although many patients respond to trastuzumab, innate resistance or acquired resistance upon prolonged treatment also occur. Mechanisms of resistance to trastuzumab include upregulation of compensatory signaling pathways through activation of receptor tyrosine kinases such as EGFR, IGF-1R and met, or through mutational activation of the PI3 kinase (PI3K) pathway. An alternative approach for targeting HER2 is the direct covalent coupling of a cytotoxic drug to trastuzumab. We have previously reported the potent in vitro and in vivo efficacy of trastuzumab linked to the microtubule polymerization inhibitor mertansine (trastuzumab-DM1) in trastuzumab-sensitive and -refractory breast tumor models. Inhibition of signaling through PI3K, which is hyperactivated in HER2-amplified breast cancer due to constitutive activity of overexpressed HER2 and/or through mutation of the p110-\#945; subunit of PI3K, offers an additional therapeutic approach. We describe here the enhanced anti-tumor activity of trastuzumab-DM1 combined with the PI3K inhibitor GDC-0941, in HER2-amplified breast cancer lines with mutated PI3K: BT474 (K111N), MDA-361.1 (E545K), and KPL4 (H1047R). Combination treatment in vitro resulted in additive or synergistic inhibition of cell proliferation, as well as increased apoptosis. Similarly, in vivo efficacy was augmented with combined drug treatment compared to single agent activityin the MDA-MB-361.1 and Fo5 HER2-amplified xenograft models. Biochemical analyses of biomarkers for each agent showed inhibition of phospho-Akt and phospho-ERK by both trastuzumab-DM1 and GDC-0941, decreased phosphorylation of Rb and PRAS40 by GDC-0941, and increased levels of the mitotic markers phospho-histone H3 and cyclin B1 after treatment with trastuzumab-DM1. In addition, trastuzumab-DM1 treatment resulted in apoptosis in these breast cancer models as determined by appearance of the 23 kDa PARP-cleavage fragment, decreased levels of Bcl-XL, as well as activation of capases 3 and 7. Addition of GDC-0941 to trastuzumab-DM1 further enhanced apoptosis induction. These studies provide evidence for the use of rational drug combinations in HER2-amplified breast cancer and offer additional therapeutic approaches for patients whose disease progresses on trastuzumab or lapatinib-based therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3239.
Abstract 15585: Using Genetics To Explore Whether The Cholesterol-lowering Drug Ezetimibe May Cause An Increased Risk Of Cancer
Authors: Bo K Lauridsen, Stefan Stender, Ruth Frikke-Schmidt, Børge G Nordestgaard, Anne Tybjærg-Hansen
Journal: Circulation (2015)

Introduction: Ezetimibe reduces plasma levels of low-density lipoprotein(LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1(NPC1L1). However, results from a randomized trial have raised concern that ezetimibe might increase the risk of cancer. Hypothesis: We tested the hypothesis that genetic variation in NPC1L1 , mimicking treatment with ezetimibe, was associated with an increased risk of cancer. Methods: We included 67,257 individuals from the Danish general population. Of these, 8,333 developed cancer and 2,057 died of cancer during follow-up from 1968 to 2011. To mimic the effect of ezetimibe, we calculated a weighted genotype score (from &lt;2.0 to ≥5.0) using four NPC1L1 variants. The score was based on the LDL cholesterol-lowering (=inhibitory) effect of each variant, and has previously shown to associate with a stepwise reduction in risk of ischemic vascular disease (=positive control). Variants were also grouped by a simple allele score. Finally, we tested the association between genotype score and allele score with risk of any cancer, death from any cancer, risk of death after a cancer diagnosis, and risk of 28 cancer subtypes. Results: The cumulative incidence by age of any cancer or cancer death was not associated with genotype score(P-trend across genotype scores: 0.42 and 0.98, respectively). Hazard ratios(HRs) for genotype scores ≥5.0 versus &lt;2.0 were 1.04(95% confidence interval: 0.92-1.19) for any cancer, 1.11(0.85-1.45) for cancer death, and 0.91(0-73-1.14) for death after a cancer diagnosis (P-trend across genotype scores: 0.42, 0.81, 0.98, respectively). In contrast, the corresponding HR for ischemic vascular disease was 0.82(0.71-0.95) (P-trend=0.002). Finally, genotype score did not associate with risk of cancer subtypes (all adjusted P-values≥0.28). Results were similar using allele scores. Conclusions: Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer, cancer death, death after a cancer diagnosis, or risk of specific cancer subtypes. These results suggest that long-term treatment with ezetimibe does not increase the risk of cancer.