tbuckley/cabot-search huggingface dataset:
P17.38 * THE EFFECT OF TIMING OF RADIOTHERAPY (RT) IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) RECEIVING TEMOZOLOMIDE (TMZ): AN ANALYSIS BASED ON THE UCSF EXPERIENCE
Authors: S. J. Han, W. C. Rutledge, A. M. Molinaro, S. Chang, J. L. Clarke, M. D. Prados, M. S. Berger, N. A. Butowski
Journal: Neuro-Oncology (2014)

BACKGROUND: The effect of timing of initiation of radiotherapy (RT) after surgery on the outcome of patients with glioblastoma (GBM) remains controversial. Most neurosurgeons and neuro-oncologists believe that early initiation of RT may result in clinical benefits. However, certain reports suggested that delayed RT may be positively associated with survival for GBM patients. To further explore this issue, we analyzed three clinical trials for newly diagnosed GBM patients receiving temozolomide (TMZ) conducted at UCSF. METHODS: From 2004 through 2010, 207 adult patients with supratentorial GBM were enrolled into 3 clinical trials which consisted of RT plus TMZ and an experimental agent. Timing of RT was defined as the time interval between definitive surgery and commencement of RT, which was intended to be within 6 weeks per protocol eligibility. Overall survival (OS) and Progression-free survival (PFS), measured from study registration, were estimated using the Kaplan-Meier method. Analysis by classification and regression trees was used to determine the cut-off values for timing of RT at which there was a significant difference in OS and PFS. Cox proportional hazards model was used to assess the effect of RT timing (in days) on clinical outcomes, adjusting for treatment protocol, age, KPS, and extent of resection. RESULTS: The median wait time between surgery and RT was 29.5 days (range: 7-89 days). There was no significant difference in timing of RT with respect to baseline variables, except for resection extent: patients who were given RT earlier were more likely to have undergone a biopsy than more extensive surgery. Unexpectedly, a short delay in RT administration (at 30-34 days) was predictive of prolonged OS (HR = 0.58, p < 0.02) as well as prolonged PFS (HR = 0.55, p < 0.001), compared to early initiation of RT (<29 days), after adjusting for protocol and baseline prognostic variables, including extent of resection. Interestingly, a longer delay of RT initiation past 34 days was not associated with improved OS or PFS compared to early initiation (HR = 0.89, p = 0.54, HR = 0.76, p = 0.14, respectively). CONCLUSIONS: We conclude that there may be an optimal window in which a short delay in start of RT may be associated with prolonged OS and PFS. Caution should be exercised in interpreting these results since it is well known that secondary analyses may be influenced by unknown confounding factors.
Abstract LB-16: Breast cancer risk in association with occupational exposure to organic solvents.
Authors: Christine Ekenga, Christine G. Parks, Aimee A. D'Aloisio, Lisa A. DeRoo, Dale P. Sandler
Journal: Cancer Research (2013)

Abstract Background: Organic solvents are widely used in occupational settings as adhesives, degreasing agents and cleaning products, and in the production of plastics and textiles. Several solvents have been recognized as human carcinogens; however, there is limited data on solvent exposure and the risk of breast cancer. The objective of this study was to examine the relationship between occupational exposure to organic solvents and breast cancer among women enrolled in the Sister Study. Methods: The Sister Study is a prospective cohort of over 50,000 US and Puerto Rican women aged 35-74 with a family history of breast cancer; enrollment and completion of baseline questionnaires occurred between 2004 and 2009. This analysis includes 47,763 women who reported working outside the home. We categorized occupational solvent exposure using baseline data on self-reported use of solvents on each job held for 12 months or longer. Women were followed for breast cancer incidence through 2012. Cox regression analyses were performed, adjusting for established breast cancer risk factors, including parity and age at first birth. Preliminary Results: A total of 1,596 women were diagnosed with invasive or in situ breast cancer during follow-up. Overall, there was no increased risk of breast cancer associated with lifetime use or duration of exposure to solvents (HR: 0.93, 95%CI: 0.79-1.09, p trend = 0.26). Among parous women, those who worked with solvents for five or more years prior to their first birth had an increased risk of breast cancer compared to women who never worked with solvents (HR: 2.12, 95%CI: 0.94-4.80, p trend = 0.02). Among all women, an increased risk was seen for solvent-exposed assemblers and fabricators (HR: 2.28, 95%CI: 1.13-4.57), and non-significantly elevated risks were noted among solvent-exposed cooks and nurses. Conclusions: These findings suggest that occupational exposure to organic solvents prior to first birth, a critical period of breast tissue differentiation, may result in increased vulnerability for breast cancer. Our results also give some indication of increased risks for solvent-exposed women in production, service and healthcare occupations. Future studies on solvent-related breast cancer risk should focus on exposure time window and types of organic solvents used across different occupational settings. Citation Format: Christine Ekenga, Christine G. Parks, Aimee A. D'Aloisio, Lisa A. DeRoo, Dale P. Sandler. Breast cancer risk in association with occupational exposure to organic solvents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-16. doi:10.1158/1538-7445.AM2013-LB-16
AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment
Authors: Natalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth, Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder, Ian A. Blair, Constantinos Koumenis
Journal: Cancer Research (2016)

Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER)-positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacologic and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMP-activated protein kinase (AMPK) signaling pathway in vitro and in vivo AMPK in turn promotes glycolysis and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKα1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents that concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells, which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER(+) breast cancer. Cancer Res; 76(11); 3295-306. ©2016 AACR.
RELATIONSHIP BETWEEN MAJOR ADVERSE CARDIOVASCULAR EVENTS AND ACHIEVED LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL
Authors: Christopher P. Cannon, Henry Ginsberg, Kausik Ray, Michael Davidson, Robert Pordy, Laurence Bessac, Pascal Minini, Robert Eckel
Journal: Journal of the American College of Cardiology (2016)
Abstract 273: Transcriptional regulation of L1CAM in endometrial cancer
Authors: Uwe Schirmer
Journal: Cancer Research (2012)

Abstract The L1 cell adhesion molecule (L1CAM, CD171) was initially described as a cell surface protein in the developing nervous system involved in neural outgrowth and axon guidance. During the last years it became evident that high expression levels of L1CAM are observed in many human carcinomas and are linked to tumor progression. L1CAM expression in tumors can augment cell motility and invasive potential and lead to constitutive NFκB activation. We showed before that in endometrial cancer (EC) the expression of L1CAM was correlated with poor prognosis. ECs can be subdivided in two types; a less aggressive type I and a highly aggressive type II. We showed that L1CAM expression was absent in type I ECs, whereas all cases of type II tumors (n=272) were L1CAM positive. We also provided evidence that in L1CAM-negative EC cell lines L1CAM expression can be upregulated by TGF-b1 treatment involving the transcription factor SLUG. In the present study, we have investigated additional mechanisms that can affect L1CAM expression. These mechanisms involve the modification of histone proteins and their packaging to the DNA as well as the direct modification of the DNA by DNA-methyltransferases (DNMTs). We show that the treatment of EC cell lines with Histon-deacetylase-Inhibitors (HDACIs) and/or DNMT inhibitors lead to increased L1CAM expression at the mRNA and protein level. Furthermore, we observed that the methylation pattern of the L1CAM-promoter differed between L1CAM positive and negative cell lines. The RE-1 silencing transcription factor (REST) complex seems to be responsible for the silencing of the L1CAM expression in non-neuronal tissues. The REST complex is associated with chromatin-remodeling complexes, the recruitment of HDACs as well as DNMTs and thereby leads to the silencing of the respective promoter element. We observed that the knockdown of REST in L1CAM negative EC cell lines leads to a dramatic increase in L1CAM expression. Likewise the overexpression of REST in L1CAM positive EC cell lines diminished L1CAM expression. We conclude that the loss or reduced expression of REST in concert with epigenetic elements could represent an additional and novel mechanism to cause aberrant L1CAM expression in ECs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 273. doi:1538-7445.AM2012-273
P5-16-01: Are We Going To Be Able To Train Future Surgeons How To Perform Axillary Lymph Node Dissection?
Authors: N Betambeau, C Chan
Journal: Cancer Research (2011)

Abstract Background: Axillary lymph node dissection (ALND) has been performed regularly by surgeons for several decades. The sentinel lymph node era has led to a reduction in ALND procedures as node negative women are now spared further surgery and morbidity. Following the publication of the ACOSOG Z0011 trial, it is conceivable that completion ALND (cALND) may be rendered unnecessary for many women who have breast conserving surgery and have 1 to 2 positive sentinel lymph node disease. If there is a substantial drop in ALND procedures, this may impact on our ability to train surgeons in the future. Material and Methods: We retrospectively reviewed the breast cancer practice for 2 consultant surgeons in a busy UK centre. In this centre all patients with a positive diagnosis of invasive breast cancer had preoperative axillary ultrasound scanning (USS) and needle biopsy (fine needle aspiration or core biopsy) if enlarged or suspicious axillary lymph nodes were seen. Hence sentinel lymph node biopsy (SLNB) was only performed on patients with both clinically and radiologically negative axillary lymph nodes. Results: In 2009 and 2010 the 2 consultants treated a total of 255 patients with invasive breast cancer. Thirty one patients (12.2%) had positive axillary lymph disease identified by USS and axillary needle biopsy; these women were treated with ALND. The remaining 224 patients had clinically and radiologically negative axillary lymph nodes and proceeded to SLNB. Of these, 58 patients had at least one positive sentinel lymph node (25.9%) and proceeded to cALND; 39 women had breast conserving surgery and 19 women had mastectomy. If our centre were to adopt a policy of observation only in those women having breast conserving surgery and whom had no more than 2 positive sentinel lymph nodes (as per ACOSOG Z0011 trial), then 33 fewer ALND would have been performed. This would leave a new total of 56 ALND procedures being performed over a 2 year period in women with pre-operatively identified positive axillary lymph nodes, those undergoing mastectomy and those women with 3 or greater positive sentinel lymph nodes on SLNB. On our service we have 2 residents which would result in a maximum number of 14 ALND procedures per year that each resident may be trained to perform. It is likely that the actual number will be less due to commitments away from the elective operating room, such as emergency duties and annual leave etc. Is this an adequate number of ALND procedures for a resident to gain competence in the technique? Discussion: The training of surgical residents is competence based and if our centre is representative of most centres treating breast cancers in the UK, will the teaching of ALND procedures be limited to specialist, ultra-high volume centres if the ACOSOG Z0011 trial findings are to be adopted? Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-16-01.
OP0089 Genetic studies on DICKKOPF-1, sclerostin and the severity of joint destruction in rheumatoid arthritis
Authors: D. de Rooy, N. Yeremenko, R. Knevel, E. Brouwer, G. Wilson, E. Lindqvist, T. Saxne, A. Krabben, M. Leijsma, R. Tsonaka, N. Daha, S. Zhernakova, J. Houwing-Duistermaat, T. Huizinga, D. Baeten, R. Toes, A. van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Abstract</h3> Information processing in the brain is mediated through a complex functional network architecture whose comprising nodes integrate and segregate themselves on different timescales. To gain an understanding of the network function it is imperative to identify and understand the network structure with respect to the underlying anatomical connectivity and the topographic organization. Here we show that the previously described resting-state network for the somatosensory area 3b comprises of distinct networks that are characteristic for different topographic representations. Seed-based resting-state functional connectivity analysis in macaque monkeys and humans using BOLD-fMRI signals from the face, the hand and rest of the medial somatosensory representations of area 3b revealed different correlation patterns. Both monkeys and humans have many similarities in the connectivity networks, although the networks are more complex in humans with many more nodes. In both the species face area network has the highest ipsilateral and contralateral connectivity, which included areas 3b and 4, and ventral premotor area. The area 3b hand network included ipsilateral hand representation in area 4. The emergent functional network structures largely reflect the known anatomical connectivity. Our results show that different body part representations in area 3b have independent functional networks perhaps reflecting differences in the behavioral use of different body parts. The results also show that large cortical areas if considered together, do not give a complete and accurate picture of the network architecture. <h3>Highlights</h3> Somatosensory resting-state functional network is not uniform across the entire area 3b. Different body part representations have different connectivity networks. These functional connectivity networks have many similarities in the two primate species, i.e. macaque monkeys and humans, although the human network is more complex. In both the species network of the face representation is most extensive, which includes ipsilateral face motor cortex and PMv in both hemispheres. The hand representation in area 3b has connectivity with ipsilateral hand motor cortex. Bilateral connectivity with homologous and nonhomologous area 3b representations was observed only in humans. The functional connectivity networks largely reflect the underlying anatomical connectivity.
SP-02 * PATTERNS OF END-OF-LIFE CARE FOR PATIENTS WITH GLIOBLASTOMA
Authors: P. L. Nghiemphu, A. Lai, T. Cloughesy
Journal: Neuro-Oncology (2014)

There is an increase in costs and frequencies of care for cancer patients toward the end-of-life, but few have reported on end-of-life care for patients with Glioblastoma (GBM). We retrospectively reviewed the medical records of patients with GBM followed regularly by the UCLA Neuro-Oncology clinic in the last 180 days before death (DBD) and recorded their patterns of care in the last 90 days of life. Between June 2012-May 2014, 72 patients were followed for active disease treatment and palliative care until death. The median age for this group was 61, with a median overall survival of 20.2 months. Within 60 DBD, 66.2% of patients still received treatment with bevacizumab (BV), but only 45.1% received another chemotherapy or radiotherapy, with or without BV. Only 15% of patients remained on active treatments within 30 DBD. In the last 90 DBD, 33.8% had at least 1 hospital visit (range 1-3), and most (83.3%) required an admission. We managed the hospice care of 61 (85.9%) patients. Hospice referral were made at a median of 23 (range 2-112) DBD, and patients were last seen in clinic at a median of 37 (range 10-156) DBD. 16 (22.5%) of the hospice referrals were made from an inpatient setting. 3 patients died in a hospital, 2 after discharged to a skilled-nursing facility, and the rest passed away at home. 4 patients had gastrostomy tube placement, and 1 was on a ventilator. Overall, the patterns of care for our patients reveal that GBM patients can have end-of-life care managed easily at home, and hospitalization toward the end-of-life can be limited if patients are followed regularly. We will also report on the costs of care within the last 90 days of life for this group.
Lamotrigine for Generalized Seizures Associated with the Lennox–Gastaut Syndrome
Authors: Edwin Trevathan, E. Lynette Mullens, Penelope Manasco
Journal: New England Journal of Medicine (1998)

Background The Lennox–Gastaut syndrome, a severe form of epilepsy that usually begins in early childhood, is difficult to treat. Dose-related drug toxicity is common. Methods We conducted a double-blind, placebo-controlled trial of the antiepileptic drug lamotrigine in patients with the Lennox–Gastaut syndrome. Eligible patients had more than one type of predominantly generalized seizure, including tonic–clonic, atonic, tonic, and major myoclonic, and had seizures on average at least every other day. After a 4-week base-line period in which all participants received placebo, we randomly assigned 169 patients (age range, 3 to 25 years) to 16 weeks of lamotrigine (n = 79) or placebo (n = 90) in addition to their other antiepileptic drugs. Results The median frequency of all major seizures changed from base-line levels of 16.4 and 13.5 per week in the lamotrigine and placebo groups, respectively, to 9.9 and 14.2 per week after 16 weeks of treatment (P = 0.002). Thirty-three percent of the patients in the lam...
“Brush recanalization” of a challenging biliary stricture after liver transplantation: a novel application for an old device
Authors: Gabriele Curcio, Antonino Granata, Neville Azzopardi, Patrizia Sanna, Luca Barresi, Ilaria Tarantino, Roberto Miraglia, Mario Traina
Journal: Endoscopy (2014)

A 34-year-old gentleman, who had undergone orthotopic liver transplantation (OLT) for idiopathic fulminant hepatic failure in November 2004, presented with jaundice and abnormal liver function tests. Magnetic resonance imaging (MRI) identified an anastomotic biliary stricture with dilated intrahepatic ducts, which were also confirmed at endoscopic retrograde cholangiopancreatography ([Fig. 1]).
FOXO3A MODULATES CARDIAC REMODELING VIA INHIBITION OF MYOFIBROBLAST DIFFERENTIATION IN ACUTE MYOCARDIAL INFARCTION
Authors: Luise Holzhauser, Alexander Jenke, Konstantinos Savvatis, Mathias Grueger, Robert Schur, Dirk Westermann, Diana Lindner, Wolfgang Poller, Heinz-Peter Schultheiss, Carsten Skurk, Charite Berlin, Campus Benjamin Franklin
Journal: Journal of the American College of Cardiology (2015)
Lateral Pharyngeal-Wall Motion as a Predictor of Surgical Success in Velopharyngeal Insufficiency
Authors: Charles A. Kelsey, Stanley J. Ewanowski, Andrew B. Crummy, Diane M. Bless
Journal: New England Journal of Medicine (1972)

Separation of the oral and nasal cavities is essential for normal speech. This separation is in part accomplished by sphincteric action of the lateral pharyngeal walls. A prospective study of 67 patients with velopharyngeal insufficiency carried out with radiographic and ultrasonic measurements of lateral pharyngeal-wall motion showed that patients with velopharyngeal insufficiency could be divided into three distinct groups based on ratings of lateral pharyngeal-wall motion. The preoperative and postoperative performance indexes of nasality, nasal emission, and speech intelligibility were compared in all three groups. The greatest improvement was in patients with normal or near normal motion of the lateral pharyngeal wall. Thus, rating of lateral pharyngeal-wall motion can be made reliably. These ratings should be a routine part of the assessment of velopharyngeal incompetency, and have predictive value in the determination of the success of velopharyngeal-flap surgery.
Abstract 4448: Rational design of a novel nanocarrier for doxorubicin delivery in cancer treatment
Authors: Juntao Luo, Kai Xiao, Joyce S. Lee, Yuanpei Li, Kit S. Lam
Journal: Cancer Research (2011)

Abstract Doxorubicin is a very important anti-cancer drug and is currently being used in the treatment of many hematologic malignancies and solid tumors. There is a great need to develope a more effective nanoformulation of doxorubicin that can overcome cardiotoxicity of doxorubicin, as well as the problems associated with Doxil (PEGylated liposomal doxorubicin): large particle size, therefore unable to penetrate deep into the tumor, foot and hand syndrome, and myelotoxicity. We have recently developed a novel biocompatible telodendrimer (PEG block dendritic oligomer of cholic acids), which can self-assemble into stable micelles (∼50 nm) in water when mixed with a hydrophobic drug, such as paclitaxel, with high loading capacity. However, the doxorubicin delivery using this formulation suffers from lower drug loading capacity, less stability and series hemolytic properties. We have optimized the structure of the telodendrimer via introducing the specific building blocks, which has strong interactions with doxorubicin through TT- TT interaction and the hydrogen bonding. The engineered telodendrimer showed better doxorubicin drug loading capacity (4 mg/mL) and greater physical stability (18 nm, stable &amp;gt;3 months) compared with the original formulation. Nanocarrier is nontoxic in cell culture even at &amp;gt;1 mg/mL concentration. The doxorubicin-loaded formulation exhibited the similar potency as the free doxorubicin and Doxil in killing of cancer cells in the cell culture. This engineered formulation after loaded with doxorubicin can completely avoid the hemolysis in the in vitro red blood cell incubation. The in vivo biodistribution and the in vivo antitumor efficacy of this novel DOX-nanotherapeutics will be further studied in the animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4448. doi:10.1158/1538-7445.AM2011-4448