tbuckley/cabot-search huggingface dataset:
ICD Implantation in Patients with Nonischemic Heart Failure
Authors: Gerhard Hindricks, Nikolaos Dagres, A John Camm
Journal: New England Journal of Medicine (2017)

To the Editor: The findings of the Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter-Defibrillators] in Patients with Nonischemic Systolic Heart Failure on Mortality (DANISH) (Sept.29 issue) 1 are important and raise doubts about the current strategy of defibrillator implantation for the primary prevention of sudden cardiac death.The results are not unexpected.Current recommendations are based mainly on the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) 2 and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).3 Since these trials were conducted, the treatment of patients with heart failure has changed dramatically, with the introduction of angiotensin receptor-neprilysin inhibitors; much wider use of mineralocorticoid antagonists, betablockers, and statins; and improved coronary revascularization in patients with ischemic cardiomyopathy.These treatments reduce not only total mortality but also specifically the rate of sudden cardiac death. 4,5We agree with the comment by McMurray in the accompanying editorial that trials involving patients at higher risk should be considered. 6
RARE-24. THE USE OF A PROGRAMMABLE SHUNT IN A PATIENT, TREATED WITH OPTUNE®: FEASIBILITY REPORT
Authors: Lutz Schreiber, Martin Wettig, Suzin Jung, Adrian Kinzel, Martin Scholz
Journal: Neuro-Oncology (2016)

Tumor Treating Fields (TTFields) are an established, non-invasive anti mitotic therapy for the treatment of patients with a newly diagnosed or a recurrent glioblastoma multiforme (GBM). TTFields are low intensity, intermediate frequency alternating electric fields, which are applied directly to the tumor in the brain via a system called Optune. Regarding the toxicity profile it seems to be well tolerated and the main side effect we saw in our treated patient population (in total N=14 patients) were mild to moderate skin irritations that usually didn’t cause a significant treatment break. Concerning the contraindications it is mentioned that Optune should not be used for patients with a programmable shunt, because it is unclear how the shunt itself will be affected by the electric field and if the shunt may affect treatment efficacy. In this report we focused on safety of using Optune in a patient with a programmable shunt (Codman®Hakim® Programmable Valve System). We performed an X-ray of the shunt valve prior to the treatment start, one day after the start and 14 days after the start of Optune to ensure that TTFields didn’t change the valve position. We also performed a CT Scan prior to the start and an MRI after the “14 days valve control” without observing any changes. Due to safety reasons we didn’t select a patient with a hydrocephalus for this first case feasibility report. This GBM patient received the shunt after a CSF fistula, which was also not influenced by TTFields. In this proof-of-concept report, we were able to demonstrate that TTFields did not lead to any programmable shunt dysfunction in a patient with glioblastoma. Further studies are needed elaborate on the safety and efficacy of Optune in patients with programmable shunts as well as in patients with a hydrocephalus.
Genomic analysis of translocation renal cell carcinoma: Association of frequent 3p loss and poor outcome.
Authors: Gabriel Malouf, Federico A. Monzon, Jerome Couturier, Vincent Molinie, Bernard J. Escudier, Philippe Camparo, Pheroze Tamboli, Christopher G. Wood, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2012)

360 Background: Translocation renal cell carcinoma (RCC) is a rare subtype of kidney cancer that is characterized by translocations involving TFEB or TFE3 genes. We recently reported that adults with translocation RCC have worse prognosis than pediatric and adolescent patients (Malouf et al, J Urol, 2011), however little is known about the genetic and epigenetic differences between these groups. Methods: Cytogenomic analysis was performed with 250K SNP microarrays (Affymetrix) on 19 tumor specimens of translocation RCC (Age &lt;18 (n=6); Age &gt;=18 (n=13) and 2 established cell lines (UOK109, UOK146). Changes in global DNA methylation levels were measured by using pyrosequencing of highly repetitive LINE-1 sequences on 27 tumor samples. Results were correlated with the patients’ clinical data. Results: 3p loss was observed in 8 patients (42%) and was associated with other chromosomal alterations frequently seen in clear-cell RCC such as 9p loss. Patients with 3p loss showed poor overall survival (OS) as compared to patients without 3p loss (Median OS 12.7 month vs. not reached) [p=0.03]. There was no association found between 3p loss and clinico-pathological variables such as AJCC stage, age and gender. The UOK146 cell line also showed 3p and 9p loss. Young patients (&lt;18 years) displayed fewer number of genetic abnormalities as compared to older patients (p=0.02). Moreover, Line-1 methylation was found to be lower in adult as compared to young patients (76.7% vs. 71.1%, p=0.02). Conclusions: Our results show that a subset of translocation RCC is characterized by a genetic profile similar to that of clear-cell RCC and these tumors seem to behave aggressively. Studies to determine the presence of VHL mutation in these tumors are underway. Adult patients display higher genetic abnormalities and lower Line-1 methylation as compared to young patients. These results might explain the different behavior of pediatric and adult translocation RCC.
Dose-ranging study of tesetaxel, a novel oral taxane, administered as second-line therapy at a flat dose to patients with advanced gastric cancer.
Authors: J. S. Baker, A. Qureshi, L. Itri, W. Sun, M. F. Mulcahy, J. A. Ajani
Journal: Journal of Clinical Oncology (2011)

4110 Background: Tesetaxel, a novel oral taxane, yielded a 20% major objective response rate in pretreated patients (pts) with advanced gastric cancer when administered at a dose of 27 mg/m2 Q3 wks. Relative to docetaxel, tesetaxel is not a substrate for P-gp, is associated with lower neurotoxicity, and does not cause hypersensitivity or require premedications. We have conducted a dose-ranging study of tesetaxel to determine whether “flat” (rather than weight-based) dosing of this new agent would be feasible for phase III testing. Methods: Pts with advanced gastric cancer who had failed 1 prior fluoropyrimidine/cisplatin regimen were accrued to 1 of 3 cohorts. Tesetaxel was administered to pts in Cohorts 1 and 2 once every 3 weeks at a flat starting dose of 40-45 mg and 50-60 mg, respectively. In Cohort 3, the starting dose was 27 mg/m2. For analysis, flat doses were converted to weight-based (body-surface area [BSA]) equivalents. Standard parameters of response and safety were compared. Results: Tesetaxel was well tolerated. No episodes of ≥ grade 3 neutropenia occurred in either flat-dose cohort. We found substantial BSA variability in both flat-dose cohorts (median BSA = 1.9 and 2.0 mg/m2, respectively), which resulted in substantial underdosing compared with the weight-based regimen. Weight-based doses as low as 19 and 20 mg/m2, respectively, were administered in the 2 flat-dose cohorts. Among 11 evaluable pts in Cohort 1, the lower flat-dose regimen yielded 1 unconfirmed partial response (uPR) and 1 stable disease (SD). Among 13 evaluable pts in Cohort 2, the higher flat-dose regimen yielded 1 uPR and 4 SD; it is too early to evaluate 3 pts. Pts are currently being accrued to the weight-based regimen. Conclusions: On the Q3 week schedule, flat dosing of tesetaxel results in substantial underdosing of pts due to high BSA variability in Western subjects. Safety and response to tesetaxel in pts with advanced gastric cancer appear to be dose-related. A randomized Phase 3 study will proceed using the Q3 week schedule supported in this trial. Our data suggest a starting dose of 27 mg/m2, with escalation to 35 mg/m2 depending on tolerance, appears optimal.
Characterization and Induced Cytokine Expression in PBMC of an Alternaria alternata Depigmented-Polymerized Extract
Authors: Victor Iraola, Maria Morales Esteban, Mayte Gallego, María Angeles López-Matas, Raquel Moya, Beatriz Rojas, Jerónimo Carnés
Journal: Journal of Allergy and Clinical Immunology (2017)
OS1.3 N-Myc downstream regulated gene 1 (NDRG1) influences the glioma tumor microenvironment
Authors: C. Thomé, J. Blaes, J. Sonner, K. Deumelandt, M. Osswald, M. Breckwoldt, P. Vajkoczy, F. Winkler, M. Platten, W. Wick
Journal: Neuro-Oncology (2016)
No Influence of Post-Transplant Anti-HLA Antibodies on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Mismatched Unrelated Donors
Authors: Anna Koclega, Miroslaw Markiewicz, Sylwia Mizia, Urszula Siekiera, Alicja Dobrowolska, Monika Dzierzak-Mietla, Krzysztof Bialas, Slawomira Kyrcz-Krzemien
Journal: Blood (2015)
BMET-31. DETECTION OF EGFR MUTATIONS IN THE CEREBRO-SPINAL FLUID OF NON-SMALL CELL LUNG CANCERS
Authors: Emilie Le Rhun, Valérie Grégoire, Edwina Girard, Anne Baranzelli, Simon Baldacci, Clotilde Descarpentries, Claude Alain Maurage, Alexis B Cortot, Fabienne Escande
Journal: Neuro-Oncology (2016)

Detection of Epidermal Growth Factor Receptor (EGFR) mutational status is required to determine optimal treatment of non-small cell lung cancer (NSCLC). In this retrospective cohort, we evaluated EGFR mutational status including the resistance mutation T790M using SNapShot technology in Cerebro-spinal fluid (CSF) in NSCLC patients presenting with leptomeningeal metastasis (LM) between 2012 and 2016. Among 16 patients with LM, 13 had an EGFR mutation (exon 19, n=7; exon 21, n=6), 1 had a KRAS mutation, 1 had an ALK rearrangement, and 1 a HER2 mutation at NSCLC diagnosis. LM were diagnosed after a median of 19 months (range, 0–115) after lung cancer diagnosis. CSF molecular analyses were performed at LM diagnosis (n=12) or for the evaluation of mutations during the management of a known LM (n=4). At the time of molecular CSF analysis, malignant cells were observed in the CSF of 15 patients. The known molecular alteration was found in CSF in all 13 initially EGFR mutated patients. A supplementary EGFR T790M mutation was detected in the CSF of one patient. In another patient, the EGFR mutation was detected whereas no malignant cells were observed using standard cytology. Initial treatments for EGFR-mutated LM included first- or second-generation tyrosine kinase inhibitors (TKI, n=9) systemic chemotherapy (n=5), immunotherapy (n=1) and intraCSF liposomal cytarabine combined with systemic treatment (n=8) or alone (n=1). Median overall was 4.7 months (range, 0.5-20) in the whole population whereas 5.7 months (range, 0.5-20) in the EGFR mutated population. CSF molecular analysis may identify EGFR mutations, including the T790M resistance mutation, even in the absence of malignant cells in the CSF with standard cytology. Specific therapeutic strategies may benefit to EGFR-mutated NSCLC patients with LM.
Correlation Between Alpha-1-Antitrypsin Levels and Bronchiectasis in Humoral Immunodeficiency Patients Receiving Gammaglobulin Infusions
Authors: Brian P. Peppers, John Frith, Chelsea Michaud, Priya Varma, Devi Jhaveri, Haig Tcheurekdjian, Robert Hostoffer
Journal: Journal of Allergy and Clinical Immunology (2017)
The influence of multidisciplinary rehabilitation on physical well-being and quality of life of breast cancer survivors.
Authors: Nele Adriaenssens, Christel Fontaine, Marian Vanhoeij, Jan Lamote, Jacques De Greve
Journal: Journal of Clinical Oncology (2016)

143 Background: Breast cancer treatment has adverse effects. The aim of this study was to examine the effects of a multidisciplinary oncologic rehabilitation program on health related quality of life (HRQoL), cancer related fatigue (CRF), muscle strength, physical fitness and anthropometrics in breast cancer survivors. Methods: This quasi-experimental study included 30 early breast cancer patients in the first year following treatment. Patients completed a 12-week exercise program for 4 hours a week combined with lifestyle guidance for 2 hours a week. The supervised training sessions consisted of aerobic exercises combined with muscular strengthening exercises. Measurements were carried out at baseline (T0), at the end of the intervention (T1) and at 12-weeks follow-up (T2). HRQoL (EORTC QLQ-C30 questionnaire) and CRF (FACIT-Fatigue questionnaire), were measured at T0, T1 and T2. Muscle strength (handgrip dynamometer) was measured at T0 and T1. Physical fitness and anthropometrics were assessed at T0 and T1 using spiro ergometrics, bioimpedance and waist- and hip circumference. Results: Significant positive changes in HRQoL were found, especially for physical functioning (p = 0.004) and dyspnea (p = 0,003) at T1, but HRQoL decreased at T2. Weight, BMI, waist - and hip circumference and fat free mass decreased significantly (respectively p = 0,030; p = 0,047; p = 0,020; p = 0,041 and p = 0,003). Body impedance increased significantly over time (p = 0,034). There was a significant improvement in CRF at T1 (p = 0.03), that was no longer significant at T2. No significant improvements were found in muscle strength at the affected side (p = 0.16) and the non-affected side (p = 0.95). Physical fitness increased significantly for VO 2 max at the maximal progressive cycle test (p = 0.005). Conclusions: This study reports significant improvements in HRQoL, anthropometric characteristics, CRF and physical fitness after a 12-week rehabilitation program. The declines between T1 and T2 may be explained by discontinuation of physical activity. Further research should use randomized clinical trials to examine the effectiveness of rehabilitation programs with different contents, duration and initiation.
AGS62P1, a Novel Anti-FLT3 Antibody Drug Conjugate, Employing Site Specific Conjugation, Demonstrates Preclinical Anti-Tumor Efficacy in AML Tumor and Patient Derived Xenografts
Authors: Nandini Rudra-Ganguly, Christine Lowe, Cyrus Virata, Monica Leavitt, Liqing Jin, Brian Mendelsohn, Josh Snyder, Hector Aviña, Chunying Zhang, Deanna L Russell, Michael Mattie, Peng Yang, Baljinder Randhawa, Gao Liu, Faisal Malik, Misty Vest, Joseph D Abad, Christopher C Kemball, René Hubert, Sher Karki, Banmeet Anand, Zili An, Jeanette Grant, John E. Dick, Fernando Doñate, Kendall Morrison, Pia Challita-Eid, Ingrid B Joseph, Daniel S. Pereira, David R. Stover
Journal: Blood (2015)
Antitumor activity of SNX-2112, a synthetic heat shock protein 90 inhibitor, in malignancies with amplification of the MET oncogene.
Authors: T. Bachleitner-Hofmann, M. Y. Sun, C. Chen, Z. Zeng, A. Viale, A. Olshen, J. G. Christensen, N. Rosen, D. B. Solit, M. R. Weiser
Journal: Journal of Clinical Oncology (2010)

e13561 Background: Heat shock protein 90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases (e.g. HER-2, EGFR, Raf-1, v-Src, AKT) for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase which is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. Methods: Aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. Results: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors which have acquired resistance to MET kinase inhibition. Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. No significant financial relationships to disclose.
David Oliver: Is the ward round dead?
Authors: David Oliver
Journal: BMJ (2017)

Has the ward round had its day? I recently enjoyed an animated conversation on Twitter with some junior doctors who had posed this question.1

My intuitive response? Absolutely not. Seeing and talking with each of our patients, reviewing their progress, treatment, and investigations, and planning their ongoing care or discharge, is what inpatient hospital doctors do. It’s often accompanied by a multidisciplinary team discussion of all patients—perhaps a better use of non-medical staff time than traipsing after a medical entourage.

This all sounded like a ward round to me, so what was the problem? Besides, earlier in …
PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase
Authors: Yok-Lam Kwong, Thomas S. Y. Chan, Daryl Tan, Seok Jin Kim, Li-Mei Poon, Benjamin Mow, Pek-Lan Khong, Florence Loong, Rex Au-Yeung, Jabed Iqbal, Colin Phipps, Eric Tse
Journal: Blood (2017)
Characterization of Myeloid and Plasmacytoid Dendritic Cells in Microbes, Allergy, Asthma and Pets (MAAP) Birth Cohort Infants
Authors: Stacey M. Bellemore, Alexandra Sitarik, Suzanne L. Havstad, Erik T. Mann, Albert M. Levin, Susan V. Lynch, Dennis R. Ownby, Christine C. Johnson, Nicholas W. Lukacs, Edward M. Zoratti, Kimberley J. Woodcroft, Kevin R. Bobbitt
Journal: Journal of Allergy and Clinical Immunology (2017)
Effect of sequential docetaxel followed by mTOR inhibitor temsirolimus on suppression of PI3K overactivation resistance mechanism.
Authors: Chao Hui Huang, Peter J. Van Veldhuizen, Ayten Gadashova, Stephen K. Williamson, Faris Farassati
Journal: Journal of Clinical Oncology (2012)

88 Background: Mammalian target of rapamycin (mTOR) is a downstream regulatory protein of the PI3K/Akt signal transduction pathway. This is a common pathway for a several cell surface receptors including IGFR (Insulin-like Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor). The activation of these receptors through PI3K/Akt pathway is essential in cell proliferation, angiogenesis, and anti-apoptosis process. The upregulation of PI3K could be a mechanism of resistance of mTOR inhibitors. Docetaxel (D) is commonly used in the treatment of lung cancer. We demonstrated previously that the sequence of D followed by mTOR inhibitor temsirolimus (T) in lung cancer cell lines (LCCL) had synergistic effect in suppressing cell proliferation compared with T→D. The exact mechanism of this effect is unknown. We studied the expression of mTOR and PI3K in these cell lines treated in different time points to investigate the activity of this pathway when using these sequences of drug treatment. Methods: Adenocarcinoma LCCL H2122 and H1437 were plated and exposed to temsirolimus 1000nM and docetaxel 100nM. The cell viability was measured by optical density (OD) at 24, 48, and 72h. We tested effect of drugs D and T alone as well as the sequence of D treated for 24h followed by addition of T and the reverse in both LCCL. We then prepared cell lysate at 24h, 48h, and 72h time points and studied the expression of phospho mTOR (pmTOR) and PI3K by western blot using antibody obtained from cell signaling. Results: The use of T alone increased the expression of PI3K in both H2122 and H1437 cell lines at 48h time point. The use of D had a variable response: absent in H1437 and present in H2122 at 48 H. The sequence of D→T suppressed the expression of pmTOR and PI3K at 48 and 72 h compared with the opposite sequence of T→D. Conclusions: The combination of D → T is synergistic in suppression of pmTOR and inhibited the overactivation of upstream PI3K in both LCCL compared with opposite sequence. Therefore, the sequential treatment of D followed by T is able to overcome the PI3K overactivation mechanism of resistance in lung cancer cell line when treated with T. This would have implications in the use of these agents in treatment of lung cancer.
A randomized phase II study of leucovorin, 5-fluorouracil with or without oxaliplatin (LV5FU2 vs. FOLFOX) for curatively-resected, node-positive esophageal squamous cell carcinoma
Authors: S.H. Lim, Y.-L. Choi, S.-H. Jung, M.-J.A. Ahn, K. Park, J.I. Zo, Y.M. Shim, J.-M. Sun
Journal: Annals of Oncology (2016)
Improved Concordance of Minimal Residual Disease Measurements By Quantitative PCR and 10-Color Flow Cytometry in Pediatric Acute Lymphoblastic Leukemia
Authors: Mary Sartor, Draga Barbaric, Tamara Law, DR Anuruddhika Dissanayake, Nicola C Venn, Mawar Karsa, Sue W J Wong, Murray D Norris, Tamas Revesz, Petra Ritchie, Peter J Shaw, Kenneth F Bradstock, Luciano Dalla Pozza, Toby N Trahair, Rosemary Sutton
Journal: Blood (2015)
Analysis of somatic copy number alterations in pediatric solid tumors using array comparative genomic hybridization.
Authors: Alanna Church, Leslie Grimmett, AeRang Kim, Julia Lynne Glade Bender, Steven G. DuBois, Laura E. MacConaill, Kimberly Stegmaier, Wendy B. London, Brian D. Crompton, Suzanne Shusterman, Lisa Diller, Carlos Rodriguez-Galindo, Neal Ian Lindeman, Katherine A. Janeway, Marian H. Harris
Journal: Journal of Clinical Oncology (2014)

1538 Background: Somatic structural changes in tumor genomes are known to be significant in the diagnosis, prognosis, and therapy of pediatric solid tumors. Translocations, focal deletions and amplifications, whole arm and whole chromosome gains and losses are routinely assayed by karyotype and FISH at the time of diagnosis. Array comparative genomic hybridization (aCGH) is another technique to interrogate somatic copy number alterations (SCNAs). aCGH has the advantage of being compatible with formalin-fixed, paraffin-embedded (FFPE) tissue, and offers higher resolution for SCNAs than other techniques. Here we investigate the clinical utility of copy number assessment in pediatric solid tumors. Methods: Patients were enrolled on a multi-institutional translational research study, designed to test the feasibility of using somatic genetic analysis to guide the therapy of advanced pediatric solid tumors. For each patient with adequate available material, tumor tissue was analyzed for both sequence variants and SCNAs. This analysis focuses on copy number changes at 38 pre-selected oncology-related genes. aCGH results were reviewed by an expert panel of oncologists and molecular pathologists. Results: Of the 100 patients enrolled, 32 cases have been analyzed by aCGH: 3 carcinomas, 16 sarcomas, 7 embryonal tumors, 4 undifferentiated malignancies, and 2 others. 26 cases (81%) had SCNAs reported, of which 6 cases had focal (<1Mb) changes, and 20 had only large-scale changes. Focal changes included MYC, MYCN, SMARB1 (INI1), CDKN2A, and ERBB2 (Her2). In addition it was occasionally possible to visualize chromosomal translocations, such as EWSR1 rearrangements, with this methodology. 9/32 (28%) of cases had findings with diagnostic, prognostic or therapeutic significance. Conclusions: Copy number assessment of pediatric solid tumors by aCGH on FFPE tissue is feasible and reveals clinically relevant findings in a significant number of cases.