tbuckley/cabot-search huggingface dataset:
Role of Nuclear Inositide Signalling and microRNA Signature in Myelodysplastic Syndromes during Azacitidine and Lenalidomide Therapy
Authors: Matilde Follo, Sara Mongiorgi, Cristina Clissa, Annalisa Astolfi, Domenico Russo, Marco Gobbi, Costanza Bosi, Monica Crugnola, Marta Stanzani, Stefano Ratti, Sarah Parisi, Marilena Barraco, Lucia Manzoli, Andrea Pession, Lucio Cocco, Carlo Finelli
Journal: Blood (2016)
Non-classical BRAF melanoma: A retrospective review of disease characteristics and prognostic implications.
Authors: Ambika Parmar, Harriet Feilotter, Tara D. Baetz
Journal: Journal of Clinical Oncology (2017)

e21060 Background: Activating mutations in the BRAF gene occur in 40-60% of melanomas with the majority of mutations resulting in V600E/K. Previous cohort studies have identified rates of non-V600E/K BRAF mutations to occur in 5-12% of patients. Despite this, there remains limited evidence characterizing the disease characteristics and outcomes of patients who harbor the non-classical BRAF mutation. Methods: Retrospective review of all melanoma patients treated at a tertiary cancer center that had BRAF mutation testing through targeted sequencing. Three groups of patients were identified and compared with respect to patient and disease characteristics: a) BRAF negative; b) BRAF V600E/K positive; c) BRAF non-V600E/K positive. Results: BRAF testing was performed in 168 melanoma patients of which 101 (60%) were BRAF negative; 55 (33%) were BRAF V600E/K positive; 12 (7%) were BRAF non-V600E/K positive (2 G466E, 1 of each G469E, K601N, K601E, L597Q, L597S, V741I, N594G, D594N, V600R and 1 with both K601N &amp; V600E). Of these, 147 patients had baseline demographic and treatment data available for analysis. BRAF mutations were more common among males (45.6% of men vs. 22.7% of women, p = 0.03). No significant differences between other baseline patient demographics noted. Pathological characteristics revealed a non-significant trend toward poorer prognostic factors with BRAF non-V600E/K patients having increased Breslow depth (7.0 mm vs. 5.0 mm BRAF negative, 4.3 mm BRAF V600E/K) and higher rates of ulceration (71% vs. 44% BRAF negative, 30% BRAF V600E/K). BRAF non-V600E/K patients displayed a non-significant trend toward poorer overall survival (71 months vs. 215 months BRAF negative, 125 months BRAF V600E/K). Conclusions: Non-V600E/K BRAF positive patients appear to display less favorable disease characteristics and outcomes as compared to BRAF negative and BRAF V600E/K positive patients. Non-V600E/K melanoma show limited response to BRAF targeted therapy; however, evidence suggests the presence of non-classical mutations may confer susceptibility to MEK inhibition. Further characterization of non-V600E/K BRAF melanoma may allow for more refined prognostication and treatment decisions.
The potential of circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy decision making in locally advanced rectal cancer (LARC).
Authors: Jeanne Tie, Joshua Cohen, Yuxuan Wang, Lu Li, Isaac Kinde, Hany Elsaleh, Rachel Wong, Suzanne Kosmider, Desmond Yip, Margaret Lee, Ben Tran, Matthew E. Burge, David Goldstein, Madhu Sudan Singh, Luis A. Diaz, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2017)

3521 Background: The optimal approach to adjuvant chemotherapy for rectal cancer is keenly debated. Routine practice and clinical guidelines vary widely. After pre-operative chemoradiation (CRT), a pathologic complete response (pCR) or nodal involvement (pN+) are prognostic markers that can guide clinical decision-making, but markers that better define the patients (pts) that are likely or unlikely to benefit from chemotherapy are urgently needed. We investigated the potential role of ctDNA as a biomarker to guide therapy. Methods: We conducted a prospective, multi-centre study in pts with LARC (T3/T4 and/or N+) planned for CRT and curative resection. Serial plasma samples were collected pre-CRT, post-CRT, and 4-10 weeks after surgery. Somatic mutations in individual pts’ tumor were identified via sequencing of 15 genes commonly mutated in colorectal cancers. We then designed personalized assays to quantify ctDNA in plasma samples. Pts received adjuvant therapy at clinician discretion. Results: 200 pts were enrolled between Apr-2012 and Dec-2015. Median age was 62 years (range 28-86), 67% were male and 159 pts had pre-CRT and post-op ctDNA samples available for analysis. Of these, 122 (77%) pts had detectable ctDNA prior to therapy. After surgery, 19 pts had detectable ctDNA and 11 of these 19 (58%) have recurred during a median follow up of 22 months. Recurrence occurred in only 12 of 140 (8.6%) with negative ctDNA (HR 12, p &lt; 0.001). One hundred and two (64%) pts received adjuvant chemotherapy. Post-op ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy (chemo: HR 10, p &lt; 0.001; no chemo: HR 16, p &lt; 0.001). Thirty-four pts (21%) achieved a pCR, 43 (27%) had pN+ disease. pCR (vs non-pCR) was associated with a trend for lower recurrence risk (HR 0.31, p = 0.089) and pN+ (vs pN0) with a higher recurrence risk (HR 4.2, p &lt; 0.001). ctDNA detection remained predictive of recurrence among pts with a pCR (HR 14, p = 0.014) or with pN+ disease (HR 11, p &lt; 0.001). Conclusions: Post-op ctDNA analysis stratifies pts with LARC into very high and low risk groups. ctDNA analysis remains strongly predictive of recurrence among pts with both lower risk (pCR) and higher risk (pN+) disease.
Phase II study of tivantinib (ARQ 197) and cetuximab in patients with EGFR inhibitor-resistant, MET-High, KRAS wild-type (KRASwt) metastatic colorectal cancer (mCRC)
Authors: Lorenza Rimassa, Silvia Bozzarelli, Stefano Cordio, Filippo Pietrantonio, Laura Toppo, Sara Lonardi, Alberto Zaniboni, Roberto Bordonaro, Maria Di Bartolomeo, Wanda Liguigli, Vittorina Zagonel, Chiara Tronconi Maria, Luca Di Tommaso, Laura Giordano, Armando Santoro
Journal: Annals of Oncology (2017)
Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases.
Authors: Myung-Ju Ahn, Dong-Wan Kim, Byoung Chul Cho, Sang-We Kim, Jong-Seok Lee, Jin Seok Ahn, Tae Min Kim, Chia-Chi Lin, HyeRyun Kim, Tom John, Stephen Chuan-Hao Kao, Jonathan Wade Goldman, Wu-Chou Su, Ronald B. Natale, Philip Overend, Zhenfan Yang, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2017)

2006 Background: The dose escalation phase is complete forAZD3759, the first EGFR inhibitor primarily designed to cross the blood brain barrier (BBB) to treat patients with EGFRm NSCLC with CNS metastases. AZD3759 is being further evaluated in patients with brain (BM) and leptomeningeal metastases (LM) in TKI-naïve and TKI pre-treated cohorts (data presented separately) (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Dose levels of 200 and 300 mg BID AZD3759 were assessed based on safety and efficacy data in dose escalation cohorts. Results: As of24 September, 2016,38 patients with EGFRm NSCLC were recruited into the expansion cohorts of this study: 16 patients with TKI naïve BM and 4 patients with TKI naïve LM. 15 and 5 patients were treated with 200 and 300 mg BID of AZD3759, respectively. No DLTs were observed at either dose, while 200 mg BID AZD3759 was better tolerated than 300 mg BID during &gt; 2 month treatment. The longest duration on treatment was &gt; 9 months. Drug-related adverse events (AEs) seen are typically observed for EGFR TKIs. In BM cohort, 56% and 13% of patients had dose interruptions and reductions respectively due to drug-related AEs. The C trough free plasma and CSF exposure at both doses were above pEGFR IC 90 . By investigators’ assessment, the intracranial objective response rate (ORR) was 63% (12 out of 19 evaluable patients) and achieved confirmed/unconfirmed partial/complete response [PR/CR]), extracranial ORR was 50% (10 out of 20 evaluable patients), and the overall ORR was 60% (12 out of 20 evaluable patients). 4 patients have not reached the 6-week RECIST assessment at the data cut-off. 18 of 20 patients are still ongoing (median 4-month follow up). 2 patients have withdrawn, one due to disease progression (de novo T790M mutation in both plasma and CSF), and another due to a non-drug related SAE. Conclusions: AZD3759 was well tolerated at the selected doses, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor efficacy in both intracranial and extracranial tumors in TKI-naïve patients with CNS metastases. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
Comprehensive genomic profiling (CGP) with loss of heterozygosity (LOH) to identify therapeutically relevant subsets of ovarian cancer (OC).
Authors: Julia Andrea Elvin, Yuting He, James Sun, Kunle Odunsi, James Brian Szender, Kathleen N. Moore, Laurie M. Gay, Garrett Michael Frampton, Jo-Anne Vergilio, James Suh, Shakti Ramkissoon, Eric Allan Severson, Sugganth Daniel, Kevin K. Lin, June YiJuan Hou, Camille Catherine Gunderson, Laura L. Holman, Phil Stephens, Mitch Raponi, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2017)

5512 Background: Defective homologous recombination DNA repair (HRD) is associated with high grade serous (OC-S) histology, longer survival, and platinum (Pt) or PARP inhibitor (PARPi) sensitivity. HRD causes LOH, a pattern of allelic imbalance detectable by CGP. BRCAwt OC-S can have LOH and respond to PARPi, while non-serous (OC-NS) or difficult to classify (OC-NOS) OC are often less responsive to Pt-based therapy. Integrating multiple genomic features derived from CGP may define other therapeutically relevant subsets. Methods: DNA from FFPE tumor tissue obtained during clinical care for 4114 advanced OC was analyzed for all classes of genomic alterations (GA) by hybrid-capture, next-generation sequencing of up to 315 genes. Tumor subtype counts were OC-S, n = 2770; OC-NOS, n = 807; OC-NS, n = 537 (mucinous, clear cell, endometrioid, neuroendocrine, carcinosarcomas, and low grade serous). Algorithms evaluated microsatellite instability (MSI), tumor mutation burden (TMB; TMB-H ≥ 10 muts/Mb), and LOH (LOH-H ≥ 14, LOH-L &lt; 14). Results: 706/4114 (17.2%) OC had ≥1 deleterious BRCA GA, OC-S (18.7%) more so than OC-NS (4.4%). Median LOH score for OC-S was significantly higher than OC-NS (12.8 vs. 5.8, p &lt; 0.05). BRCAmut OC-S and OC-NS were similarly LOH-H (86% and 75%), unlike BRCAwt OC-S (38.4%) or OC-NS (18%). Regardless of LOH, similar co-occurrence of MYC (26.9%) and/or NF1 (19%) GA was seen in BRCAmut OC. BRCAwt LOH-L OC commonly had CCNE1 (19.7%), KRAS (19%), PIK3CA (16.2%), AKT2 (7.4%), ERBB2 (4.7%), or BRAF(3.3%) GA. Frequency of TMB-H was 2.5% and MSI-H 1%. Correlation of GA with treatment, clinical histories and outcomes for some patients will be presented. Conclusions: BRCAmut or OC-S are commonly LOH-H; ~1 in 5 BRCAwt OC-NS, including carcinosarcomas and mucinous, are also LOH-H. Genes co-mutated in late stage LOH-H OC may be linked to treatment resistance. CGP of this large OC cohort reveals molecular, rather than histologic, patient subsets that may benefit from PARPi (46.2% BRCAmut or LOH-H), targeted therapy ( &gt; 50% BRCAwt LOH-L, excluding TP53) or immunotherapy (3.5% TMB-H or MSI-H), providing more support for insurance coverage and integration into OC clinical trials.
Quantitative bone ultrasonography at phalanges in patients with high-risk monoclonal gammopathy of unknown significance (MGUS) and myeloma treated with zoledronic acid
Authors: F. Iuliano, I. Guzzo, F. Deterlizi, M. Di Maio, S. Infusino, A. Perricelli, A. Pomillo, S. Molica, M. Baserga
Journal: Journal of Clinical Oncology (2007)

8115 Background: Bisphosphonates are commonly used for metastatic bone disease in order to prevent skeletal-related events, to reduce bone pain and to improve quality of life. Zoledronic acid is commonly used in myeloma patients (pts), but additional studies are needed to determine the optimal timing, schedule and duration of treatment. Aim of the present study is to assess bone mineral density (BMD) in patients with high-risk MGUS and myeloma receiving zoledronic acid, using quantitative ultrasound analysis in transmission through phalanges. Methods: DBM Sonic Bone Profiler is the only ultrasound device that applies the method of signal analysis in transmission through phalanges. This technique has proven to be particularly effective in the diagnosis and treatment monitoring of post-menopausal osteoporosis. Measurements of BMD were performed by ultrasonography at distal metaphysis of the first phalanx of the II, III, IV and V hand finger, at baseline and at 1, 3, 6, 9, 12, 15 and 18 months. Results: 12 pts with high-risk MGUS (8 IgG k, 4 IgG lambda) and 4 pts with myeloma IIIA (3 IgG k, 1 IgA lambda), 6 males/ 10 females, median age 69 years, received zoledronic acid 4 mg intravenously every 4 weeks for at least 12 courses. All subjects took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). Myeloma patients also received chemotherapy. 4/6 males (66%) and 5/10 females (50%) improved amplitude-dependent speed of sound (AD-SoS) over the least significant change after 6 months. Mean difference from baseline value of AD-SoS shows a trend after 4 months of treatment, and became significant after 16 months (p&lt;0.005). Conclusions: Densitometric-structural evaluation of bone tissue at phalanges is safe and useful to evaluate bone quality changes during treatment with zoledronic acid, that determines a significant and sustained increase in ultrasonographic parameters of bone density and structure. No significant financial relationships to disclose.
Role of Pre-Transplant Cardiac and Hepatic T2* Magnetic Resonance for Risk Assessment in Patients with Thalassemia Major Undergoing an Allogeneic Stem Cell Transplantation
Authors: Vikram Mathews, Alfred Inbaraj, Anu Korula, Nisham PN, Fouzia NA, Anup Joseph Devasia, Kavitha M Lakshmi, Aby Abraham, Aparna Irodi, Biju George, Elizabeth Joseph, Alok Srivastava
Journal: Blood (2016)
Tumor Response Dynamics of Advanced Non–small Cell Lung Cancer Patients Treated with PD-1 Inhibitors: Imaging Markers for Treatment Outcome
Authors: Mizuki Nishino, Suzanne E. Dahlberg, Anika E. Adeni, Christine A. Lydon, Hiroto Hatabu, Pasi A. Jänne, F. Stephen Hodi, Mark M. Awad
Journal: Clinical Cancer Research (2017)

Purpose: We evaluated tumor burden dynamics in patients with advanced non-small cell lung cancer (NSCLC) treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS).Experimental Design: The study included 160 patients with advanced NSCLC treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS.Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median, +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (P = 0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS, 12.4 vs. 4.6 months, P < 0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR, 0.24; Cox P < 0.0001) after adjusting for smoking (HR, 0.86; P = 0.61) and baseline tumor burden (HR, 1.55; P = 0.062), even though some patients met criteria for RECIST progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression.Conclusions: Objective response or durable disease control was noted in 24% of patients with advanced NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors. Clin Cancer Res; 23(19); 5737-44. ©2017 AACR.
Strong epistatic and additive effects of linked candidate SNPs for Drosophila pigmentation have implications for analysis of genome-wide association studies results
Authors: Jean-Michel Gibert, Jorge Blanco, Marlies Dolezal, Viola Nolte, Frédérique Peronnet, Christian Schlötterer
Journal: Genome biology (2017)

The mapping resolution of genome-wide association studies (GWAS) is limited by historic recombination events and effects are often assigned to haplotype blocks rather than individual SNPs. It is not clear how many of the SNPs in the block, and which ones, are causative. Drosophila pigmentation is a powerful model to dissect the genetic basis of intra-specific and inter-specific phenotypic variation. Three tightly linked SNPs in the t-MSE enhancer have been identified in three D. melanogaster populations as major contributors to female abdominal pigmentation. This enhancer controls the expression of the pigmentation gene tan (t) in the abdominal epidermis. Two of the three SNPs were confirmed in an independent study using the D. melanogaster Genetic Reference Panel established from a North American population. We determined the functional impact of SNP1, SNP2, and SNP3 using transgenic lines to test all possible haplotypes in vivo. We show that all three candidate SNPs contribute to female Drosophila abdominal pigmentation. Interestingly, only two SNPs agree with the effect predicted by GWAS; the third one goes in the opposite direction because of linkage disequilibrium between multiple functional SNPs. Our experimental design uncovered strong additive effects for the three SNPs, but we also found significant epistatic effects explaining up to 11% of the total variation. Our results suggest that linked causal variants are important for the interpretation of GWAS and functional validation is needed to understand the genetic architecture of traits.
Morphoproteomic profile of mTOR, Ras/Raf kinase and NF-κB pathways in human gastric adenocarcinoma
Authors: Wei Feng, R Brown, C Truong, W Li, M Javle, T Khoury, S Alrawi, K Xie, J Yao, D Tan
Journal: Cancer Research (2008)

4448    Background:  The prognosis of gastric adenocarcinoma (GAC) remains poor in the United States. Treatment is limited to surgical excision due to poor response to radiotherapy and chemotherapy. Preclinical in vitro and in vivo studies using human gastric carcinoma cell lines have shown that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, can inhibit tumor growth and that the extracellular signal-regulated kinase (ERK) of the Ras/Raf kinase pathway is related to chemoresistance and apoptosis. We examined the state of activation of components of mTOR, Ras/Raf kinase, and nuclear factor (NF)-κB signal transduction pathways, as well as cell-cycle protein analyte correlates in GAC.   Design:  Formalin-fixed paraffin-embedded tissue microarray blocks containing samples from 215 cases of GAC of all grades and stage were examined. Immunohistochemistry was utilized to detect the following antigens in these tissues: s100p, upstream stimulator of ERK and NF-κB pathways; phosphorylated (p)-mTOR(Ser 2448), p-ERK-1/2(Thr 202/Tyr 204) and one of their common downstream effectors, p-p70S6K(Thr 389); p-NF-κBp65(Ser 536); and cell cycle-associated proteins Ki-67, S phase kinase-associated protein (Skp-2), and cyclin D1. Intensity (0-4+) of protein compartmentalization and expression were assessed by light microscopy.   Results:  Majority of cases showed positive (1-4+) cytoplasmic/plasmalemmal p-mTOR (88%), and moderate-strong (2-4+) nuclear p-p70S6K (93%) and nuclear S100P (81%) expression. A subset of cases exhibited moderate-strong nuclear p-ERK-1/2 (15%) and p-NF-κBp65 (36%) expression. Majority of cases showed concomitant moderate-strong (2-4+) nuclear Ki-67 (71%) and Skp-2 (68%). The expression level of p-mTOR correlated positively with the nuclear expression level of p-p70S6K, p-ERK, and p-NF-κBp65 (p Conclusion:  Morphoproteomic analysis reveals constitutive activation of mTOR and to some extent, Ras/Raf kinase and NF-κB pathways in GAC as evidenced by: increased cytoplasmic p-mTOR, nuclear translocation of p-p70S6K and p-ERK, phosphorylated at putative sites of activation, Ser 2448, Thr 389, and Thr 202/Tyr 204, respectively; as well as correlative expression of Ki-67, and Skp-2. These results suggest that morphoproteomic profiling and combinatorial treatment strategy targeting the mTOR, Ras/Raf kinase and NF-κB pathways may be developed for GAC.
Evaluation of Chest Pain in the Emergency Department
Authors: Frederic G. Jones
Journal: Annals of Internal Medicine (1995)

Letters15 August 1995Evaluation of Chest Pain in the Emergency DepartmentFrederic G. JonesFrederic G. JonesSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-4-199508150-00022 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read with interest the timely comments on the issues and possible solutions for optimizing assessment of patients presenting with suspected cardiac chest pain [1]. One of these approaches used decision-based computer models and probability analysis. Several references were listed, but surprisingly absent was the potential role for artificial neural networks in the decision-making process. A summary recently published in the September/October issue of American College of Cardiology Journal Review titled “Prognostication, Procrastination and Artificial Neural Networks.” Many references were given in that review, including those to the work by Baxt that describes the use of the ...References1. Kaul S, Abbott RD. Evaluation of chest pain in the emergency department (Editorial). Ann Intern Med. 1994; 121:976-8. Google Scholar2. Baxt WG. Use of an artificial neural network for the diagnosis of myocardial infarction. Ann Intern Med. 1991; 115:845-8. Google Scholar3. Baxt WG. Analysis of the clinical variables driving decision in an artificial neural network trained to identify the presence of myocardial infarction. Ann Emerg Med. 1992; 21:1439-44. Google Scholar Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAcquaintance to Artificial Neural Networks and use of artificial intelligence as a diagnostic tool for tuberculosis: A review 15 August 1995Volume 123, Issue 4Page: 314-318KeywordsArtificial intelligenceEmergency departmentHealth careIschemiaMyocardial infarctionNeural networksSimulation and modeling Issue Published: 15 August 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Bright spots, physical activity investments that work: Agita Mundo global network
Authors: Victor K R Matsudo, Estelle V Lambert
Journal: British Journal of Sports Medicine (2017)

### Programme Card

Agita Mundo is a global network and, more recently, an independent council of the International Society for Physical Activity and Health, the main objective of which is to promote physical activity as a health-enhancing behaviour for people of all ages and abilities, through social mobilisation.1 2 Social mobilisation has been defined as ‘a process that raises awareness and motivates people …
Projection-Resolved Optical Coherence Tomography Angiography of Macular Retinal Circulation in Glaucoma
Authors: Hana L Takusagawa, Liang Liu, Kelly N Ma, Yali Jia, Simon S Gao, Miao Zhang, Beth Edmunds, Mansi Parikh, Shandiz Tehrani, John C Morrison, David Huang
Journal: Ophthalmology (2017)