tbuckley/cabot-search huggingface dataset:
Relationship between young age at diagnosis and disease free survival in premenopausal patients according to breast cancer subtypes.
Authors: Shuangshuang Lu, Li Zhu, Jiayi Wu
Journal: Journal of Clinical Oncology (2018)

e12557 Background: Previous studies have shown that young women are at high risk of recurrence and death. We aim to explore the roles of the clinic-pathological characteristics and treatment in disease free survival for premenopausal breast cancer patients. Methods: We extracted information of operable premenopausal early breast cancer patients from January 2009 to December 2013 in the database of Comprehensive Breast Health Center in Ruijin Hospital, Shanghai, China. Chi-Square test, Kaplan-Meier analysis, and Multivariable Cox Proportional Hazards Models were adopted in the analysis. Results: A total of 1259 premenopausal women with stage I to III breast cancer were eligible for analysis. Among them 316 (25.1%) were <40 years old at diagnosis, and compared with older patients, they developed a higher proportion of grade 3 tumors (45.9% vs 33.8%, p=0.001), tumors with Ki-67 >20% (57.6% vs 43.6%, p<0.001), ER negative tumors (34.8% vs 28.1, p=0.024), and triple negative and HER-2 positive breast cancer (21.5% vs 17.8%, 11.7 vs 9.1%, p<0.001). Furthermore, patients <40 years old were more likely to receive chemotherapy (88.6% vs 76.1%, p<0.001) and radiotherapy (59.2% vs 49.2%, p<0.001). Median follow-up time was 64 months, and median age was 44. In the multivariable cox regression analysis, after adjustment for adjuvant treatment, age was an independent prognostic factor for disease free survival. Women <40 years old at diagnosis showed distinctly inferior DFS compared with their counterparts (HR, 1.5; 95% CI, 1.1 to 2.2), and the inferiority was most remarkable in patients with luminal-subtype breast cancer (HR, 2.0; 95%CI, 1.2 to 3.2). Conclusions: Young age, which is less than 40 years old at diagnosis, predicts worse survival predominantly in premenopausal patients with luminal subtype breast cancer.
Disconnect between physical activity guidelines and ground reality: A real world analysis of physical activity profile of cancer survivors.
Authors: Amit Mohan Algotar, Kalpana Algotar, Alyssa Berkowitz, Tara Beth Sanft
Journal: Journal of Clinical Oncology (2018)

105 Background: Physical activity recommendations are often made through survivorship care plans and survivorship guidelines. However, recommendations may not translate into actions and hence it is important to understand the ground reality of cancer survivors and determine how much physical activity they are able to do in their daily life. Methods: Data were obtained from a self-reported survey of patients attending survivorship clinic at a comprehensive cancer center. Participants were asked what kind of physical activity they were engaging in, how many times a week and how many minutes per session. A composite variable was created by multiplying the number of times by number of visits and adding all the activity types patients reported engagement in. This number was compared against the current recommendations of 150minutes of physical activity weekly as recommended National Comprehensive Cancer Network (NCCN) guidelines. Data were stratified by age, gender and cancer type. Results: A total of 729 survivors filled out the survey. Only 26.3% of participants reported meeting the NCCN guideline for physical activity and this did not differ by gender (26.6% female vs 23.9% male). Percent of survivors meeting the guidelines reduced with increasing age (32% &lt; 40 years, 26.5% 40-60 years, and 24% &gt; 60years). Participants with lymphoma reported the highest level of physical activity (113.15 minutes per week) where as those with prostate cancer reported low levels of physical activity (0 minutes per week). Conclusions: This real world analysis demonstrates disconnect between current physical activity guidelines and ground reality of cancer survivors. Not only is research needed to understand barriers of cancer survivors towards achieving physical activity guidelines but attention also needs to be paid to determine if guidelines need to be modified as they may be setting the bar too high.
<i>EGFR</i> Amplification as a Target in Gastroesophageal Adenocarcinoma: Do Anti-EGFR Therapies Deserve a Second Chance?
Authors: John H. Strickler
Journal: Cancer Discovery (2018)

Abstract Summary: Anti-EGFR therapies have failed to improve survival for unselected patients with metastatic gastroesophageal cancer, but in a subset of patients, EGFR amplification may predict treatment benefit. Maron and colleagues report the clinical activity of anti-EGFR therapies in a cohort of patients with EGFR-amplified metastatic gastroesophageal cancer and utilize serial blood and tumor tissue collection to identify molecular drivers of treatment sensitivity and resistance. Their insights offer a path to overcome technical limitations associated with EGFR amplification and facilitate molecularly targeted therapeutic strategies. Cancer Discov; 8(6); 679–81. ©2018 AACR. See related article by Maron et al., p. 696.
Predicting drug permeability through skin using molecular dynamics simulation
Authors: Magnus Lundborg, Christian L. Wennberg, Ali Narangifard, Erik Lindahl, Lars Norlén
Journal: Journal of Controlled Release (2018)

Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
Upgrades from a previous device compared to <i>de novo</i> cardiac resynchronization therapy in the European Society of Cardiology CRT Survey II
Authors: Cecilia M. Linde, Camilla Normand, Nigussie Bogale, Angelo Auricchio, Maciej Sterlinski, Germanas Marinskis, Christian Sticherling, Alan Bulava, Óscar Cano Pérez, Alexander H. Maass, Klaus K. Witte, Roin Rekvava, Salima Abdelali, Kenneth Dickstein
Journal: European Journal of Heart Failure (2018)
Critically appraising the evidence to help our patients with overload syndromes: should we prioritise knowledge from observational studies and focus on ‘the essentials’?
Authors: Marinus Winters
Journal: British Journal of Sports Medicine (2018)

Sarah enjoys 10K runs on Saturdays and Sundays. After the summer, she decided to prepare for the London Marathon. Within 1 week, she increased her loading to 35K in the weekends and added 8K on Wednesdays. Today, she presents with shin pain. She has continued running for 3 months with deteriorating pain. History and physical examination reveal that Sarah has bilateral medial tibial stress syndrome (MTSS).1 The marathon is only 4 months away; how can we help Sarah best?

Evidence-based practice (EBP) ‘…is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’.2 Systematic reviews and randomised controlled trials (RCTs) form the highest levels of evidence to inform clinical practice. A key aspect of EBP is to critically appraise the evidence. To this end, there are four considerations to inform the care for your patient with an overload syndrome:

### Is the evidence trustworthy?

Most RCT outcomes are at high risk of bias , meaning that we cannot …
Long‐ versus short‐interval follow‐up after resection of hepatocellular carcinoma: a retrospective cohort study
Authors: Wei He, Yun Zheng, Ruhai Zou, Jingxian Shen, Junping Yang, Jiliang Qiu, Qiang Tao, Wenwu Liu, Zhiwen Yang, Yuanping Zhang, Binkui Li, Yunfei Yuan
Journal: Cancer Communications (2018)

Abstract Background Average postoperative follow‐up intervals vary in patients undergoing hepatocellular carcinoma (HCC) resection because of limited evidence regarding the optimal interval. We aimed to compare the associations of long‐versus short‐interval follow‐up with survival and recurrence in risk‐stratified HCC patients. Methods We performed a retrospective cohort study between 2007 and 2014. In total, 1227 patients treated by curative resection of Barcelona Clinic Liver Cancer stage A or B HCC were stratified as having a low (n = 865) or high (n = 362) risk of early recurrence (within the first 2 years after resection) based on prognostic factors identified by the least absolute shrinkage and selection operation algorithm. Patients were further classified into long‐interval (every 4–6 months) and short‐interval (every 2–4 months) follow‐up subgroups based on follow‐up within 2 years after resection (low risk, long vs. short: n = 390 vs. n = 475; high‐risk, long vs. short: n = 149 vs. n = 213). Results The short‐interval follow‐up did not prolong overall survival in either the low‐risk (hazard ratio [HR] = 1.152; 95% confidence interval [CI] 0.720–1.843) or high‐risk (HR = 1.213; 95% CI 0.702–2.094) patients. Early recurrence occurred in 401 patients. For high‐risk patients, the short‐interval follow‐up subgroup exhibited smaller intrahepatic recurrence than did the long‐interval group (2.6 vs. 3.5 cm, respectively, P = 0.045). However, no significant difference in the rate of Barcelona Clinic Liver Cancer stage 0/A recurrence was found between the long‐ and short‐interval follow‐up groups in either low‐ or high‐risk patients (63.1% vs. 68.2%, respectively, P = 0.580; 31.3% vs. 41.5%, respectively, P = 0.280). The rate of curative intent treatment for recurrence (34.5% vs. 39.7%, respectively, P = 0.430; 14.6% vs. 20.3%, respectively, P = 0.388) was also similar between the follow‐up groups for low‐ and high‐risk patients. Conclusions Shortening the postoperative follow‐up interval from every 4–6 months to every 2–4 months within the first 2 years after resection did not increase the rate of curative intent treatment or prolong the overall survival of patients with Barcelona Clinic Liver Cancer stage A or B HCC.
Effect Of Nintedanib On Disease Progression In The Inpulsis (R) Trials In Patients With Idiopathic Pulmonary Fibrosis (ipf)
Authors: G. Raghu, Y. Inoue, J. Behr, V. Cottin, S. Stowasser, W. Stansen, T. M. Maher
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Abstract 17279: Kcnk3 Dysfunction Contributes to the Development of Pulmonary Arterial Hypertension - Characterization of Kcnk3 Deficient Rats
Authors: Fabrice Antigny, Mélanie Lambert, Aurélie Hautefort, Boris Manoury, Philippe Jourdon, Catherine Rucker-Martin, Barbara Girerd, Gérald Simonnneau, David Montani, Marc Humbert, Frédéric Perros
Journal: Circulation (2016)

Background:  Inactivating mutations in the  KCNK3  gene (K +  channel) have been identified in heritable forms of pulmonary arterial hypertension (PAH). We discovered that KCNK3 dysfunction contributes actually to the development of both heritable and non-heritable PAH, and to experimental pulmonary hypertension (PH) ( Antigny et al. Circulation 2016 ).   Methods and results:  We generated  Kcnk3  deficient rats using CRISPR-Cas9 technology and characterized at electrophysiological, hemodynamics, morphological and molecular levels the first genetically modified rat model linked to  kcnk3  mutation:  Kcnk3  Δ94Ex1/+  (94pb deletion in exon 1 of  Kcnk3  gene). Using a patch-clamp technique in freshly isolated pulmonary artery smooth muscle cells (PASMCs), we found that KCNK3-current is absent in heterozygous and homozygous  Kcnk3  mutated rats and that isolated PASMC are significantly depolarized compared to WT rats.  Kcnk3  mutation induced distal neomuscularization, abnormal pulmonary arteries vasoreactivity, elevated mean right ventricular systolic pressures and upregulation of MAP kinase signaling pathways. Heterozygous  Kcnk3 -mutated rats developed more severe pulmonary hypertension than WT littermate under hypoxic condition.   Conclusions:  In this study we established the first  Kcnk3  deficient rat model. We demonstrated that a genetic inactivation of KCNK3 in rats promoted the early signs of pulmonary hypertension, confirming that KCNK3 loss of function is a key event in PAH pathogenesis. The development and characterization of the first  Kcnk3  deficient PH-rats model open new opportunities for testing relevant therapeutics molecules in context of heritable PH.
The MTOR inhibitor, rapamycin, inhibits growth of Ewing’s sarcoma in vitro and in vivo
Authors: E. Anders Kolb, Alexander J. Chou, W. E. Zhang, Peter G. Steinherz, Richard G. Gorlick, Paul A. Meyers
Journal: Cancer Research (2005)

4714   While conventional therapies have lead to significant improvement in overall survival for patients with Ewing’s sarcoma, patients with metastatic disease and relapsed disease remain largely incurable with even the most intensive therapy. There is an ongoing need for new agents with activity in Ewing’s sarcoma (ES). Maintenance of a neoplastic phenotype in tumor cells often requires signaling through the mammalian target of rapamycin (MTOR), which functions as a sensor of mitogen, energy and nutrient levels, and a gatekeeper for cell cycle progression from G 1  to S. A recent report by Mateo-Lozano, et. al. (Oncogene. 2003;22:9282-7) demonstrates that rapamycin leads to decreased proliferation of ES cells, down-regulation of EWS-FLI-1 levels, and a restoration of TGF-β type-2 receptor, which is repressed by EWS-FLI-1. Inhibition of MTOR may be an effective anti-neoplastic strategy in the treatment Ewing’s sarcoma. The cytotoxicity of rapamycin in ES was evaluated in a panel of Ewing’s sarcoma cell lines. Cells were incubated in the presence of drug at various concentrations for 3 to 7 days. The IC50 in all lines tested is in the range of 1-10ng/ml. In vivo response was determined in SCID xenograft models of ES implanted heterotopically. Treatment groups consisted of 5 to 8 mice. Each animal received either rapamycin (7mg/kg) or normal saline orally for 2 weeks starting when tumors reached a volume of 1cm 3 . There was complete inhibition of tumor growth in the rapamycin-treated mice with no tumor re-growth for the duration of therapy. At day 14 of treatment the mean tumor volume for the rapamycin treated group was 115mm 3  and for the control group 3155 mm 3  (p
Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial
Authors: Noel Clarke, Pawel Wiechno, Boris Alekseev, Nuria Sala, Robert Jones, Ivo Kocak, Vincenzo Emanuele Chiuri, Jacek Jassem, Aude Fléchon, Charles Redfern, Carsten Goessl, Joseph Burgents, Robert Kozarski, Darren Hodgson, Maria Learoyd, Fred Saad
Journal: The Lancet Oncology (2018)
Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins
Authors: Rachel Blau, Yana Epshtein, Evgeni Pisarevsky, Galia Tiram, Sahar Israeli Dangoor, Eilam Yeini, Adva Krivitsky, Anat Eldar-Boock, Dikla Ben-Shushan, Hadas Gibori, Anna Scomparin, Ori Green, Yael Ben-Nun, Emmanuelle Merquiol, Hila Doron, Galia Blum, Neta Erez, Rachel Grossman, Zvi Ram, Doron Shabat, Ronit Satchi-Fainaro
Journal: Theranostics (2018)

Complete tumor removal during surgery has a great impact on patient survival.To that end, the surgeon should detect the tumor, remove it and validate that there are no residual cancer cells left behind.Residual cells at the incision margin of the tissue removed during surgery are associated with tumor recurrence and poor prognosis for the patient.In order to remove the tumor tissue completely with minimal collateral damage to healthy tissue, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings.Methods: We designed, synthesized and characterized three novel polymeric Turn-ON probes that will be activated at the tumor site by cysteine cathepsins that are highly expressed in multiple tumor types.Utilizing orthotopic breast cancer and melanoma models, which spontaneously metastasize to the brain, we studied the kinetics of our polymeric Turn-ON nano-probes.Results: To date, numerous low molecular weight cathepsin-sensitive substrates have been reported, however, most of them suffer from rapid clearance and reduced signal shortly after administration.Here, we show an improved tumor-to-background ratio upon activation of our Turn-ON probes by cathepsins.The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling accurate resection.Conclusions: Our findings show that the control groups of tumor-bearing mice, which underwent either standard surgery under white light only or under the fluorescence guidance of the commercially-available imaging agents ProSense® 680 or 5-aminolevulinic acid (5-ALA), survived for less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes.Our "smart" polymeric probes can potentially assist surgeons' decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome.
Marijuana/tobacco use and patient-reported outcomes (PROs) in adult survivors of childhood cancer.
Authors: I-Chan Huang, James L. Klosky, Nickhill Bhakta, Melissa M. Hudson, Leslie L. Robison
Journal: Journal of Clinical Oncology (2018)

175 Background: In 2017, the National Academy of Medicine reported adverse physical and psychosocial outcomes associated with marijuana use, and an increased risk of marijuana use among those who use tobacco. However, the association of marijuana and/or tobacco use with PROs has not been well-studied in survivors of childhood cancer. Methods: A random sample (stratified on self-reported smoking status) of 287 adult survivors of childhood cancer was selected from the St. Jude Lifetime Cohort Study. Chemotherapy and radiotherapy were abstracted from medical records. Marijuana use was self-reported and classified as past/current vs. never use. Current tobacco use was determined using serum cotinine concentrations by liquid chromatography tandem mass spectrometry. PROs were evaluated by physical and mental component summary (PCS and MCS) scores from the Medical Outcomes Study SF-36. Linear regression was used to evaluate associations of marijuana and tobacco use with PROs after adjusting for covariates, and the results were stratified by treatment modality. Results: Survivors’ mean age at study participation was 33.6 years (SD = 9.1), mean years from diagnosis was 24.2 (SD = 6.2). 61.3% used marijuana and 39.4% were current tobacco users. 79.3% of the tobacco users had marijuana use. Marijuana and tobacco were independently associated with lower PCS (βs = -3.1 and -2.9, respectively, p’s &lt; 0.05) and MCS (βs = -3.3 and -3.2, respectively, p’s &lt; 0.01). Among survivors who received chemotherapy, marijuana and tobacco were associated with lower PCS (β = -4.3, p &lt; 0.01; β = -2.8, p &lt; 0.05, respectively) and MCS (βs = -4.8 and -3.1, respectively, p’s &lt; 0.05). In survivors who received radiotherapy, marijuana, but not tobacco, use was associated with lower PCS (β = -3.6, p &lt; 0.05) and MCS (β = -4.6, p &lt; 0.05). Among those who received neither chemotherapy nor radiotherapy, each substance was independently associated, but not significantly, with lower PCS and MCS. Conclusions: Among adult survivors of childhood cancer, marijuana users likely co-used tobacco, and both substances were independently associated with lower PROs. When associations with treatment exposures were assessed, different profiles of PRO scores were identified.
The Canonical Wnt Pathway Drives Macropinocytosis in Cancer
Authors: Gil Redelman-Sidi, Anna Binyamin, Isabella Gaeta, Wilhelm Palm, Craig B. Thompson, Paul B. Romesser, Scott W. Lowe, Mukta Bagul, John G. Doench, David E. Root, Michael S. Glickman
Journal: Cancer Research (2018)

Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the β-catenin-dependent canonical Wnt pathway, was PAK1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via