tbuckley/cabot-search huggingface dataset:
Abstract B10: Clinical validation of targeted next-generation sequencing for glioblastoma patients
Authors: Anne-Laure Trépant, Marie Le Mercier, Calliope Maris, Nancy De Nève, Oriane Blanchard, Nicky D'Haene, Isabelle Salmon
Journal: Cancer Research (2015)

Abstract Objective: Glioblastomas (GBMs) are the most common malignant primary brain tumours in adults. These tumours are resistant to conventional treatment approaches including surgical resection, radiotherapy and chemotherapy. International efforts to catalogue mutations for multiple forms of cancer coupled with the successes of targeted agents in patients with molecularly defined tumors and improvements in genomic technology have generated enthusiasm for incorporating genomic profiling into clinical cancer practice. The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Therefore, the number of biomarkers that will need to be assessed is expected to increase rapidly. Recently, next generation sequencing (NGS) has begun to supplant other technologies for gene panel sequencing. However, few studies have validated the use of targeted NGS for GBM patients. In the present study we evaluate the clinical applicability of targeted NGS for patients with GBM. Methods: DNA from 50 GBM samples (formalin-fixed paraffin-embedded tissue) was retrospectively subjected to targeted NGS with the Ampliseq Cancer Hotspot Panel, using the Ion Torrent Personal Genome Machine, which allowed us to analyze 2850 known cancer-related mutations in 50 genes. In addition, MGMT methylation status, EGFR amplification and 1p19q deletion were evaluated by Methylation Specific PCR (MSP), chromogenic in situ hybridisation (ISH) and fluorescence ISH, respectively. Results: Preliminary results on 28 patients, all successfully sequenced, showed that the most frequent mutations were found in TP53 (25%) and EGFR (18%). Potentially actionable mutations were identified in 9 patients (32%), including 5 EGFR mutations, 2 PIK3CA mutations, 1 PTEN mutation, 1 PDGFRA mutation and 1 IDH1 mutation. The frequencies of these variants detected by NGS were consistent with frequencies reported in public databases. Moreover, PDGFRA and EGFR amplifications were detected by coverage analysis for 10 (36%) and 2 (7%) patients respectively. Conclusions: Overall, the AmpliSeq Cancer Hotspot Panel can be applied in daily practice for GBM samples. Moreover, it can provide clinically relevant information for GBM patients. Citation Format: Anne-Laure Trépant, Marie Le Mercier, Calliope Maris, Nancy De Nève, Oriane Blanchard, Nicky D'Haene, Isabelle Salmon. Clinical validation of targeted next-generation sequencing for glioblastoma patients. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B10.
Community-Oriented Primary Care
Authors: Fitzhugh Mullan
Journal: New England Journal of Medicine (1982)

An Agenda for the '80sThe landscape of health services has changed dramatically in the past 20 years. The 1960s saw the emergence of community medicine as a discipline. The 1970s produced the family-medicine and primary-care movements. Undergirding and stimulating these developments has been the enormous growth in aggregate educational capacity of the medical schools of the nation. The number of new physicians graduated annually is now more than double what it was in 1960. Given these new features, much of the current debate concerns the future. Are we producing too many physicians? What specialties will they choose? How will . . .
Isolated Nodal Failure after Stereotactic Body Radiotherapy for Lung Cancer: The Role for Salvage Mediastinal Radiotherapy
Authors: Matthew C. Ward, Steven C. Oh, Yvonne D. Pham, Neil M. Woody, Gaurav Marwaha, Gregory M.M. Videtic, Kevin L. Stephans
Journal: Journal of Thoracic Oncology (2016)
Risk Factor Analysis Of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndromes: A Multicenter Study
Authors: Hirozumi Sano, Ryoji Kobayashi, Junji Tanaka, Satoshi Hashino, Shuichi Ota, Yoshihiro Torimoto, Yasutaka Kakinoki, Satoshi Yamamoto, Mitsutoshi Kurosawa, Naoki Hatakeyama, Yoshihito Haseyama, Hajime Sakai, Kazuya Sato, Takashi Fukuhara
Journal: Blood (2013)
Frequent Expression of the B-Cell–Specific Activator Protein in Reed-Sternberg Cells of Classical Hodgkin’s Disease Provides Further Evidence for Its B-Cell Origin
Authors: Hans-Dieter Foss, Regina Reusch, Gudrun Demel, Georg Lenz, Ioannis Anagnostopoulos, Michael Hummel, Harald Stein
Journal: Blood (1999)
Systematic surgical staging: stage I ovarian cancer.
Authors: M S Piver
Journal: Journal of Clinical Oncology (1997)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1997.15.2.864 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9053518 Systematic surgical staging: stage I ovarian cancer. M S PiverxM S PiverSearch for articles by this author https://doi.org/10.1200/JCO.1997.15.2.864 PDF "Systematic surgical staging: stage I ovarian cancer.." Journal of Clinical Oncology, 15(2), pp. 864–865© 1997 by American Society of Clinical Oncology
Influence of Extracellular pH on the Accumulation and Cytotoxicity of N-(4-Methylphenylsulfonyl)-N′-(4-chlorophenyl)urea in Human Cell Lines
Authors: J Sosinski, C Chapin, J H Thakar, P J Houghton
Journal: Cancer Communications (1991)

The effect of extracellular pH (pH(e)) on the accumulation and cytotoxicity of the diarylsulfonylurea antitumor agent N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (MPCU) has been examined. In a human colon adenocarcinoma cell line, GC3/C1, the initial rate of uptake of [3H]MPCU (2.4 microM) was increased by 4.5-fold as pH(e) was reduced from 7.4 to 6.5. Steady state levels of MPCU were inversely proportional to pH(e) and were 5-fold greater at pH 6.0 compared to 7.4. Similar results were obtained using Rh30 cells derived from an alveolar rhabdomyosarcoma. MPCU rapidly re-equilibrated after achieving steady state when pH(e) was altered, indicating that MPCU was not tightly bound within cells. In both cell lines, the uncoupling agent, carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), significantly reduced (GC3/C1) or completely inhibited (Rh30) accumulation of MPCU at each pH(e) examined. Sodium azide had the same effect on the accumulation of MPCU as FCCP. The effects of FCCP and azide appeared to be due to collapse of the pH differential across the mitochondrial inner membrane rather than the gradient across the plasma membrane. As extracellular pH (pH(e)) decreased, intracellular pH(pH(i)) also decreased in GC3/C1 cells, such that the greatest pH differential (pH(i) - pH(e)) was 0.2 units at pH(e) 6.0. Neither FCCP nor azide significantly altered this pH gradient, indicating a minor role, if any, for the plasma membrane pH gradient in accumulation of MPCU in GC3/C1 cells. The effect of pH(e) (7.4 to 6.0) on cytotoxicity of MPCU was determined after exposure of cells for 4 hr to various concentrations of MPCU in the presence of 10% fetal bovine serum. Decreasing the pH(e) from 7.4 to 6.0 increased the potency of MPCU by 4.7- and 4.5-fold in Rh30 and GC3/C1 cells, respectively. In cells exposed to drug/pH(e) combinations that resulted in 50% reduction in colony forming potential, the steady state levels of [3H]MPCU were similar (range 8.8 +/- 0.9 to 10.56 +/- 0.6 nmol/10(6) cells). These results demonstrate that decrease of pH(e) significantly enhanced the uptake of MPCU accumulation into an FCCP/azide-sensitive compartment, and cytotoxicity of this agent. These data further support the hypothesis that sequestration of diarylsulfonylureas into the FCCP/azide-sensitive compartment (probably mitochondria) was associated with its cytotoxicity. The role of pH(e) in determining therapeutic selectivity of diarylsulfonylureas is discussed.
Surgery for Severe Ischemic Mitral Regurgitation
Authors: Ibrahim Kara, Cengiz Koksal, Gökhan Kahveci
Journal: New England Journal of Medicine (2016)

To the Editor: Goldstein et al. (Jan. 28 issue)1 report on 2-year outcomes of the Cardiothoracic Surgical Trials Network trial of surgical treatment of severe ischemic mitral regurgitation. The aim of restrictive mitral annuloplasty in patients with this condition is to eliminate mitral regurgitation and provide an adequate surface for coaptation. Proper patient selection is therefore the key to avoiding a risky repeat operation.2,3 Certain echocardiographic criteria (such as coaptation depth, tethering area, left ventricular end-diastolic and end-systolic diameters, posterior leaflet angle, and annular dilatation) and clinical criteria play an important role in determining which patients should undergo an undersized ring annuloplasty.4,5 If patients are not selected properly, recurrent mitral regurgitation and disease progression may occur after undersized annuloplasty for severe ischemic mitral regurgitation. The above-mentioned echocardiographic and clinical criteria will help to identify patients for whom undersized annuloplasty would be appropriate. If these criteria are not met, we think that procedures other than restrictive annuloplasty should be considered, and valve replacement with preservation of the integrity of the subvalvular apparatus may be performed.
Erratum: Corrigendum: Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
Authors: Jessica Okosun, Rachel L Wolfson, Jun Wang, Shamzah Araf, Lucy Wilkins, Brian M Castellano, Leire Escudero-Ibarz, Ahad Fahad Al Seraihi, Julia Richter, Stephan H Bernhart, Alejo Efeyan, Sameena Iqbal, Janet Matthews, Andrew Clear, José Afonso Guerra-Assunção, Csaba Bödör, Hilmar Quentmeier, Christopher Mansbridge, Peter Johnson, Andrew Davies, Jonathan C Strefford, Graham Packham, Sharon Barrans, Andrew Jack, Ming-Qing Du, Maria Calaminici, T Andrew Lister, Rebecca Auer, Silvia Montoto, John G Gribben, Reiner Siebert, Claude Chelala, Roberto Zoncu, David M Sabatini, Jude Fitzgibbon
Journal: Nature Genetics (2016)
Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Oncology Group Study
Authors: WM Crist, JJ Shuster, J Falletta, DJ Pullen, CW Berard, TJ Vietti, CS Alvarado, MA Roper, E Prasthofer, CE Grossi
Journal: Blood (1988)
Mood, major depression, and fluoxetine response in cigarette smokers
Authors: G W Dalack, A H Glassman, S Rivelli, L Covey, F Stetner
Journal: American Journal of Psychiatry (1995)

Two smoking cessation studies provided venues to 1) look for differences in affective symptoms between cigarette smokers with and without a history of major depression or other psychiatric diagnoses who were not currently depressed and 2) evaluate the efficacy of fluoxetine in ameliorating affective symptoms in smokers with a history of major depression but not currently depressed.Part I: Three hundred sixty-eight smokers who enrolled in a smoking cessation treatment study completed baseline self-rating scales. The relationship between the scale scores and a history of major depression and other psychiatric diagnoses was examined. Part II: Thirty-nine smokers with a history of major depression were enrolled in a randomized, double-blind study that examined the utility of fluoxetine as an aid to smoking cessation. Self-rated scales were compared at baseline and after 3 weeks of medication treatment before the attempt to quit.A history of major depression had significant main effects across all scale scores; subjects with such a history rated themselves as more symptomatic. The effects of other psychiatric diagnoses were neither as pervasive nor as robust. There were no differences in baseline scores between the fluoxetine- and placebo-treated groups and no change within the placebo group after 3 weeks. There was significant improvement from baseline in several subscale scores for the group treated with fluoxetine. However, comparison of the score changes for the placebo and fluoxetine groups did not show a statistically significant difference, which limited the ability to conclude that active treatment was better than placebo.Subjects with a history of major depression, but without current affective illness, reported themselves to be more symptomatic than those without such-a history. Furthermore, in a group of smokers with a history of major depression, affective symptoms, without concurrent syndromal illness, may be ameliorated by treatment with fluoxetine.
Abstract 54: TOMA OS-seq: A high efficiency targeted re-sequencing strategy for detecting gene amplifications, rearrangements, indels and point mutations in tumor DNA isolated from FFPE solid tumors and plasma
Authors: Yosr Bouhlal, Alexander McKenzie, Austin P. So
Journal: Clinical Cancer Research (2016)

Abstract Critical genetic errors, namely specific mutations, are required for the development and maintenance of cancer. Molecular diagnostics that leverage the breadth of next-generation sequencing (NGS) to identify this mutational landscape are therefore becoming an important clinical tool in the precision treatment of cancer. However, widespread adoption of NGS technologies in the clinic is hampered by the complexity of the NGS workflow, and the resulting limits in analytical capabilities arising from noise introduced by poor step-wise yields and bias from extensive application of PCR. To address these deficiencies, we introduce TOMA OS-Seq, a complete targeted resequencing workflow designed specifically for the requirements of the clinical laboratory. Based on oligo-selective sequencing (OS-seq), a panel of 96 genes - each with diagnostic or prognostic value - can be sequenced end-to-end from as little as 1 ng of input material, enabling the analysis of DNA purified from fine-needle aspirates and plasma. Utilizing a minimal number of high efficiency processing steps to create a targeted library, this simple workflow minimizes the requirement for PCR amplification, preserving the quantitative relationship among the loci interrogated in the original sample. TOMA OS-Seq is therefore capable of detecting copy number alterations, in addition to rearrangements/fusions, insertions/deletions, and single nucleotide variants. Citation Format: Yosr Bouhlal, Alexander McKenzie, Austin P. So. TOMA OS-seq: A high efficiency targeted re-sequencing strategy for detecting gene amplifications, rearrangements, indels and point mutations in tumor DNA isolated from FFPE solid tumors and plasma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 54.
De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival
Authors: Rachel M. Cymerman, Yongzhao Shao, Kun Wang, Yilong Zhang, Era C. Murzaku, Lauren A. Penn, Iman Osman, David Polsky
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Although 20% to 30% of melanomas are histopathologically 'nevus associated,' the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival. Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided. Results: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus-associated tumors. Conclusions: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in melanoma outcomes.
The Medical Benevolent Fund
Authors: W. H. Broadbent
Journal: BMJ (1881)

Cockayne9s syndrome is a multisystem disease that begins in infancy and is inherited as an autosomal recessive. We studied a 4-year-old girl with nystagmus, ataxia, motor weakness, peripheral neuropathy, deficient growth, and developmental delay. Nerve biopsy revealed segmental demyelination and granular lysosomal inclusions on ultrastructural examination.
GPs urge NHS to plan for sudden loss of primary care services
Authors: Abi Rimmer
Journal: BMJ (2016)

GPs have called for the NHS in England to plan for the possibility that large numbers of patients will be left without general practice services at short notice.

GPs attending the BMA’s conference of local medical committees (LMCs), the bodies that represent GPs at a local level, in London on Friday 20 May voted in favour of a motion calling for “the urgent incorporation of …
Spectral and Chemical Properties of Pyruvoylglycine
Authors: Maurice Errera, Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1947)

Spectral and Chemical Properties of Pyruvoylglycine Get access Maurice Errera, Maurice Errera research fellow Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse P. Greenstein Jesse P. Greenstein chief biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 8, Issue 1, August 1947, Pages 39–43, https://doi.org/10.1093/jnci/8.1.39 Published: 01 August 1947 Article history Received: 02 June 1947 Published: 01 August 1947
Abstract P4-14-26: Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases
Authors: RD Baird, H-T Arkenau, S Deva, N Cresti, J Garcia-Corbacho, L Hogarth, E Frenkel, K Kawaguchi, A Arimura, K Donaldson, J Posner, D Sarker, D Jodrell, R Plummer, J Spicer, A Italiano
Journal: Cancer Research (2016)

Abstract BACKGROUND S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during the dose-escalation phase, (maximum dose 1600 mg QD). PK and efficacy data supported a daily dose of 800 mg. An expansion cohort of patients has been treated to further explore safety and efficacy. METHODS Subjects with advanced solid tumors expressing EGFR and/or overexpressing HER2 were enrolled. S-222611 800 mg daily was administered until disease progression or unacceptable toxicity. RESULTS 76 patients were included in this phase 1 expansion cohort with a variety of tumor types. Dose reduction was required because of adverse events in 15 patients; the most frequent of which being diarrhea and elevated bilirubin. Two patients discontinued treatment due to drug- related adverse events. Of the 25 patients with HER2-positive metastatic breast cancer (MBC), 4 partial responses were observed, and prolonged stable disease (≥ 6 months) was observed in 3 additional patients. These 25 patients had received prior HER2-directed therapy as shown in Table 1. Table 1. Prior therapies received by patients with HER2-positive MBCPrior therapyn (%)Trastuzumab22 (88)T-DM13 (12)Lapatinib16 (64)Chemotherapy23 (92) Six of these patients had brain metastases, in whom 1 intracranial response and 2 prolonged stable disease (≥ 6 months) were observed (Table 2). Table 2. HER2-positive MBC patients with brain metastases - best overall response to S-222611Pts #HER2 IHCBrain metastasesBest overall response (RECIST 1.1)Patient 13+Target lesionPRPatient 23+Target lesionSD (≥12 M)Patient 33+Target lesionSD (6.0 M)Patient 43+Non-target lesionSD (4.7 M)Patient 53+Non-target lesionSD (3.3 M)Patient 63+Non-target lesionNE The patient showing intracranial response was previously treated with lapatinib and capecitabine after diagnosis of BM. CONCLUSIONS S-222611 was well tolerated at a dose of 800 mg once daily. Anti-tumour activity, including shrinkage of brain metastases, was evident in a heavily pre-treated population of patients with HER2-positive breast cancer. Citation Format: Baird RD, Arkenau H-T, Deva S, Cresti N, Garcia-Corbacho J, Hogarth L, Frenkel E, Kawaguchi K, Arimura A, Donaldson K, Posner J, Sarker D, Jodrell D, Plummer R, Spicer J, Italiano A. Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-26.