tbuckley/cabot-search huggingface dataset:
<i>MET</i> Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent <i>MET</i> Genomic Amplification and c-Met Overexpression
Authors: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, Suman Verma, James Christensen, Peter S. Hammerman, Lynette M. Sholl
Journal: Journal of Clinical Oncology (2016)

Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations.We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available.MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14-mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14-mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14-wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib.MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.
Glucocorticoid Cell Priming Enhances Transfection Outcomes in Adult Human Mesenchymal Stem Cells
Authors: Abby M Kelly, Sarah A Plautz, Janos Zempleni, Angela K Pannier
Journal: Molecular Therapy (2015)

Human mesenchymal stem cells (hMSCs) are one of the most widely researched stem cell types with broad applications from basic research to therapeutics, the majority of which require introduction of exogenous DNA. However, safety and scalability issues hinder viral delivery, while poor efficiency hinders nonviral gene delivery, particularly to hMSCs. Here, we present the use of a pharmacologic agent (glucocorticoid) to overcome barriers to hMSC DNA transfer to enhance transfection using three common nonviral vectors. Glucocorticoid priming significantly enhances transfection in hMSCs, demonstrated by a 3-fold increase in efficiency, 4-15-fold increase in transgene expression, and prolonged transgene expression when compared to transfection without glucocorticoids. These effects are dependent on glucocorticoid receptor binding and caused in part by maintenance of normal metabolic function and increased cellular (5-fold) and nuclear (6-10-fold) DNA uptake over hMSCs transfected without glucocorticoids. Results were consistent across five human donors and in cells up to passage five. Glucocorticoid cell priming is a simple and effective technique to significantly enhance nonviral transfection of hMSCs that should enhance their clinical use, accelerate new research, and decrease reliance on early passage cells.
A randomized prospective assessment of recombinant leukocyte A human interferon with or without aspirin in advanced renal adenocarcinoma.
Authors: E T Creagan, D I Twito, S L Johansson, D J Schaid, P S Johnson, M A Flaum, T R Buroker, L H Geeraerts, M H Veeder, D H Gesme
Journal: Journal of Clinical Oncology (1991)

We performed a prospective, controlled trial of recombinant leukocyte A interferon (IFN-alpha 2A) with or without aspirin (ASA) in 176 patients with assessable advanced renal cell cancer in light of a 34% response rate (10 of 29 patients) from the two-agent regimen in an earlier nonrandomized trial. This encouraging result was substantially higher than the 15% response rate typically achieved with IFN therapy alone. Eighty-seven patients received IFN-alpha 2A 20 x 10(6) U/m2 intramuscularly three times a week, and 89 received the same IFN therapy with ASA 600 mg orally four times each day. Each group was balanced as to relevant prognostic discriminants. Response rates were 8% for the group receiving ASA in addition to IFN, and 13% for the group receiving IFN alone (P = .30). The median times to progression were 1.9 months for the group receiving IFN with ASA and 2.7 months for the group receiving IFN alone (log-rank P = .36). The median survival durations were 8.8 months for the IFN and ASA group and 8.0 months for the IFN-only group (log-rank P = .60). These figures are also inferior to those typically reported from other studies. Our findings reemphasize the crucial role of randomized trials, admittedly cumbersome and time-consuming, to determine accurately the value of apparently promising therapies. Although some patients may derive benefit from IFN therapy, our findings raise disturbing questions regarding the potential IFN-alpha 2A according to the dose and schedule used in this trial to have any substantive impact on the ultimate outcome of disseminated renal cell cancer.
Prognostic impact of<i> BRAF</i> and <i>KRAS</i> mutations and their relationship to DNA mismatch repair (MMR) status in 2,686 stage III colon cancer patients (pts) treated in a phase III study of adjuvant FOLFOX with or without cetuximab: NCCTG N0147.
Authors: Frank A. Sinicrope, Michelle R. Mahoney, Thomas C. Smyrk, Stephen N. Thibodeau, Richard M. Goldberg, Garth D. Nelson, Daniel J. Sargent, Steven R. Alberts
Journal: Journal of Clinical Oncology (2012)

3514 Background: Activating mutations in the BRAF oncogene (mutBRAF) are associated with deficient MMR (dMMR) in sporadic colon cancers and are mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF and KRAS in relation to MMR and disease-free survival (DFS) in stage III pts treated with adjuvant FOLFOX +/-cetuximab; study was amended mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010). Methods: Extracted DNA from archival tumors was analyzed for BRAF exon 15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated with high grade, proximal site, T 3-4 , &gt;4 LNs, and dMMR (all p&lt;0.002); mutKRAS with low grade, proximal, &lt;3 LNs, and pMMR (all p&lt;0.02). Among dMMR tumors, mutKRAS was more frequent in distal vs proximal cancers (28% vs. 8%, p=0.0004). Both mutKRAS (HR=1.42, p=0.0001) and mutBRAF (HR=1.34, p=0.02) were associated with worse DFS and remained significant after adjustment for treatment, MMR, grade, site, T stage and LNs. mutBRAF (p=0.003) and mutKRAS (p=0.003) were each prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p=0.79; BRAF, p=0.60). While MMR was not significant univariately, proximal dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS, BRAF, grade, T stage and LNs (p interaction =0.02). pMMR/mutBRAF (p=0.027) and pMMR/mutKRAS (p&lt;0.001) had worse DFS vs pMMR/bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated with worse DFS independent of treatment, covariates, and each other, with the DFS impact restricted to pMMR tumors. Prognostic impact of MMR was dependent upon tumor site after adjusting for covariates. Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer.
Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis
Authors: Geerte Hoeke, Sander Kooijman, Mariëtte R. Boon, Patrick C.N. Rensen, Jimmy F.P. Berbée
Journal: Circulation Research (2016)

Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading cause of morbidity and mortality in Western society, and new therapeutic strategies are highly warranted. Brown adipose tissue (BAT) is metabolically active in human adults. Although positron emission tomography-computed tomography using a glucose tracer is the golden standard to visualize and quantify the volume and activity of BAT, it has become clear that activated BAT combusts fatty acids rather than glucose. Here, we review the role of brown and beige adipocytes in lipoprotein metabolism and atherosclerosis, with evidence derived from both animal and human studies. On the basis of mainly data from animal models, we propose a model in which activated brown adipocytes use their intracellular triglyceride stores to generate fatty acids for combustion. BAT rapidly replenishes these stores by internalizing primarily lipoprotein triglyceride-derived fatty acids, generated by lipoprotein lipase-mediated hydrolysis of triglycerides, rather than by holoparticle uptake. As a consequence, BAT activation leads to the generation of lipoprotein remnants that are subsequently cleared via the liver provided that an intact apoE-low-density lipoprotein receptor pathway is present. Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Initial studies suggest that BAT activation in humans may also reduce triglyceride and cholesterol levels, but potential antiatherogenic effects should be assessed in future studies.
Disabled children risk further abuse after unsubstantiated referral for neglect, research finds
Authors: Jacqui Wise
Journal: BMJ (2016)

Children with disabilities who have an initial unsubstantiated referral for neglect are at increased risk of being maltreated subsequently, a research letter published in JAMA has warned.1

Researchers analysed data from the National Child Abuse and Neglect Data System, which collects data …
Tumors of the Central Nervous System of Rats: With Report of Two Tumors of the Spinal Cord and Comments on Posterior Paralysis&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: J. R. M. Innes, G. Borner
Journal: JNCI Journal of the National Cancer Institute (1961)

The topic of tumors of the central nervous system of rats is reviewed. An ependymoma and a sarcoma of the spinal cord are reported. Comments are made on the clinical problem of posterior paralysis in rats and the difficulties in neurologic diagnosis in rodents.
THU0510 Igg ACPA Level Increase Drives Rheumatoid Factor Response Maturation in Patients before Onset of Clinically Apparent Rheumatoid Arthritis
Authors: W. Falkenburg, W.H. Bos, A. Sohrabian, J. Rönnelid, G. Wolbink, D. van Schaardenburg
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> In Rheumatoid Arthritis (RA) the pathophysiological role of both rheumatoid factor (RF) and anti citrullinated protein antibodies (ACPA) is still subject of debate. Since the antigen for RF is the constant domain (Fc) of IgG immunoglobulins in immune complexed form, we hypothesized that high or increasing titers of IgG ACPA targeting their antigen during the development of RA will provide an antigenic stimulus for RF producing B cells, leading to a rise in RF level and maturation of the RF response resulting in class-switching from IgM to IgG and IgA. <h3>Objectives</h3> To test this hypothesis we analyzed serial preclinical serum samples from a previously described cohort of patients during development of RA.[1] <h3>Methods</h3> Three sequential serum samples from 26 IgG ACPA positive RA patients who had donated blood before disease onset were selected and levels of IgG anti-cyclic citrullinated peptide 2 (anti-CCP2), IgM RF, IgG RF and IgA RF, measured using the Phadia ImmunoCap system[2], were plotted individually (Figure 1). Antibody level patterns were then grouped and frequencies of patterns definitely supporting, possibly supporting or refuting our hypothesis were determined. <h3>Results</h3> As shown in figure 1, 16 patients (62%) showed patterns directly supporting our hypothesis, including 11 patients with an IgG ACPA increase followed by or together with an IgM RF increase associated with an IgG/IgA RF increase, and 5 patients with high IgG ACPA levels at all three time points and high or rising IgM and IgG/IgA RF levels. Patterns compatible with, but not directly supporting the hypothesis were found in 8 patients (31%) including 3 patients without a significant IgG ACPA level increase and low RF levels at all time points, 2 patients with rising IgG ACPA only at the last time point together with minimal RF rise, and 3 patients with inconclusive patterns. 2 patients (8% of total) showed a pattern refuting our hypothesis, namely rising ACPA levels without rising RF or without evidence of class-switching. <h3>Conclusions</h3> Studying individual ACPA and RF profiles during the development of RA suggests that an IgG ACPA level increase drives rheumatoid factor response maturation in patients developing rheumatoid arthritis. <h3>References</h3> Nielen et al. Arthritis and Rheumatism 2004, Feb;50(2):380-6. Kokkonen et al. Arthritis Research &amp; Therapy 2011, Feb 3;13(1):R13. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4582
S100P tumor-marker response to chemotherapy in patients with advanced pancreatic cancer.
Authors: Shuichi Mitsunaga, Kumiko Umemoto, Kazuo Watanabe, Hiroyuki Okuyama, Yusuke Hashimoto, Hideaki Takahashi, Izumi Ohno, Satoshi Shimizu, Atsushi Ochiai, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2015)

265 Background: The serum tumor-marker in monitoring response to chemotherapy is not valid in advanced pancreatic cancer (PC). S100 calcium-binding protein P (S100P) has been reported as a predictive diagnostic index for PC and may serve as an early marker to activity of chemotherapy. The aim of this study was to analyze the correlation between the efficacies of chemotherapy and the kinetics of tumor-markers including serum S100P, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in prospective cohort of advanced PC. Methods: Patients who were treatment naïve for advanced PC with liver mets were eligible. Serum levels of S100P, CEA, and CA19-9 were measured at baseline and at one month later. The patients without monitoring of tumor-markers were excluded. A response of tumor-marker was defined as a decrease of at least 25%. Clinical data including radiological response according to the Response Evaluation Criteria In Solid Tumors ver. 1.1 were prospectively collected. S100P, CEA, and CA19-9 responses were tested in association with progression free survival (PFS) and overall survival (OS). Results: Fifty patients were analyzed in this study (male: 64%, median age: 67 years, Eastern Cooperative Oncology Group performance status [PS] 0: 60%). All of 50 patients received chemotherapy (gemcitabine [GEM]: 13 pts, GEM doublets: 34 pts, 5FU-based regimen: 3 pts). PFS and OS were 2.8 and 6.1 months. Responses of S100P, CEA, and CA19-9 were founded in 50%, 16%, and 32% of all, respectively. Multivariate analysis for PFS in Cox regression hazard model was performed using age, gender, PS, CEA, CA19-9, and S100P, and revealed that the independent predictors to longer PFS were responses of S100P (HR to progression: 0.47, P=0.02) and CEA (HR: 0.29, P=0.01). S100P or CEA responders showed better OS in univariate analysis using log-rank test, compared to non-responders of S100P (responder vs. non-responder: 8.4 vs. 3.7 months, P=0.04) or CEA (12.0 vs. 5.9 months, P=0.02), but not in multivariate analysis. Conclusions: Biochemical response of S100P might be useful for monitoring response to chemotherapy in advanced PC, which warranted further study in relationship between serum S100P response and treatment efficacies.
Phase I trial of BMS-247550 and gemcitabine in patients with advanced solid tumor malignancies
Authors: S. Anderson, D. Dizon, P. Sabbatini, J. Dupont, S. Pezzulli, A. Massey, C. Aghajanian
Journal: Journal of Clinical Oncology (2004)

2098 Background: BMS 2247550 (BMS) is a semi-synthetic analog of the natural non-taxane product Epothilone B, one of a new class of tubulin polymerizing agents. Preliminary trials demonstrate BMS has a broad range of anti-tumor activity. Based on our previous study evaluating Gemcitabine and Docetaxel we have pursued the investigation of Gemcitabine with this promising micro-tubulin stabilizer. Method: phase I trial to establish MTD and evaluate pharmacokinetics of BMS over 3 hours day 8 with GEM infused over 90 minutes day 1 and 8 of 21 day cycle. Patients (pts) were evaluated for response via RECIST criteria. To date 18 pts (median age 63 years [range 46–75]; Male 7: Female 11; median PS 1) have been treated with various solid tumors at 3 dose levels. A total of 44 cycles have been given with median = 2. Results: 6 pts were initially treated at dose level 1(BMS/GEM 20/900 mg/m2). Three pts were treated at dose level 2(BMS/GEM 30/900 mg/m2): 2 pts experienced gr (grade) 4 neutropenia, but did not have fever or require hospitalization. Of the 2 pts with DLT hematologic (heme) toxicity, 1 also experienced gr3 ALT elevations after cycle 1. Thus, level 1 was expanded to 9 pts and determined to be MTD. Of these 9 pts at level 1 heme toxicity was notable for gr4 neutropenia: 2, gr3 neutropenia: 4, gr3 thrombocytopenia: 3 and non heme toxicity: gr4 constipation:1, gr3 bilirubin:1, gr4 constipation:1. One patient had a severe allergic reaction to BMS associated with reversible EKG changes, chest pain and negative cardiac work up. Four pts were treated at level 3(BMS/GEM 30/750 mg/m2): 1 pt experienced gr4 heme toxicity (neutropenia and thrombocytopenia) and 2 pts experienced gr3 heme toxicity (neutropenia). 1 patient was admitted for fever without neutropenia. Of 12 evaluable pts, 5 (1 leiomyosarcoma, 2 ovarian, 2 uterine) demonstrated stable disease. No partial responses have been observed. In addition, 2 pts with ovarian cancer followed with non-evaluable lesions and CA125 elevation had > 50% decrease in their CA125. Conclusion: This promising trial continues to accrue. Updated information and pharmacokinetic data will be presented. (NCI sponsored trial) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly
FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Authors: R. Pirker, A. Szczesna, J. von Pawel, M. Krzakowski, R. Ramlau, K. Park, U. Gatzemeier, E. Bajeta, M. Emig, J. R. Pereira
Journal: Journal of Clinical Oncology (2008)

3 Background: Epidermal growth factor receptor (EGFR) dysregulation is common in NSCLC and is associated with poorer prognosis. This phase III study assessed the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin/vinorelbine (CV) compared with CV alone in advanced NSCLC. Methods: Patients with EGFR- detectable advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m2 initial dose, then 250 mg/m2/wk) plus C (80 mg/m2 d1) and V (25 mg/m2 d1, d8) q3w (arm A) or CV alone (arm B). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival, tumor response, disease control, and safety. Randomization was stratified by ECOG performance status (0/1 vs 2) and tumor stage (wet IIIb vs IV). Results: 1,125 patients were randomized: 557 to arm A, 568 to arm B, 70% male, median age 59 (18–83) years, 94% stage IV, 47% adenocarcinoma (AC), 34% squamous cell carcinoma (SCC), 83% ECOG 0/1. Survival analysis was performed after 868 events had occurred. OS was significantly improved in arm A (stratified log-rank test). Preliminary results of prespecified subgroup analyses suggest a greater benefit in Caucasians independent of histology and a general better prognosis in Asians. Analyses of secondary endpoints are ongoing. Conclusions: Cetuximab plus CV demonstrated superior survival over CV alone in patients with advanced EGFR-detectable NSCLC. There was a remarkable difference between the outcome of Asian and Caucasian patients. This is the first study to demonstrate a survival benefit of an EGFR- targeted agent in combination with platinum-based chemotherapy in advanced first-line NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC. MedianOS (mo) Arm A Median OS (mo) Arm B HR[95% CI] p-value All (n=1125) 11.3 10.1 0.871 [0.762–0.996] 0.0441 Caucasians (n=945) 10.5 9.1 0.800 [0.692–0.924] 0.0025 with AC (n=412) 12.0 10.2 0.809 [0.644–1.016] 0.0673 with SCC (n=347) 10.2 8.9 0.794 [0.626–1.007] 0.0567 Asians (n=121) 17.6 20.4 1.179 [0.730–1.905] Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Serono Merck
Lipid laden macrophages in patients with chronic cough
Authors: Begoña Palomo, Jose Belda, Miguel Arias, C.J. Rrguz. Pandiella, Paz Paniagua, Magdalena Rebollo, Pere Casan
Journal: European Respiratory Journal (2011)

Background:  Gastroesophageal reflux disease (GER) has been described as common cause of chronic cough by either esophageal acid-induced bronchoconstriction or recurrent microaspirations of gastric content. Lipid laden macrophages (LLM) in sputum can appear in these patients as a marker of aspiration. This finding could be interesting mainly when symptoms are absent (up to 75% percent or cases, “silent” GER). However, it is not clear what the presence of LLM in the airways could imply in terms of lung function, radiological lesions or symptoms. We aim to compare a group of patients with chronic cough and LLM in sputum with another group without LLM.   Methods:  Twenty five patients with chronic cough that could not be attibuted to any known etiology were included in the study group. Subjects were questioned for pulmonary and GER symptoms, Rhinitis, drugs and underwent physical examination, chest X-rays, bronchial challenge test with methacholine and sputum induction. Prepared cytospins were stained with oil red-O to detect lipid laden macrophages.   Results:  68% were lipid laden positive but only 40% had reflux symptoms. Patients with LLM had similar dyspnea, phlegm9s but not rhinitis and 25% were methacholine positive and diagnosed of having asthma. Patients with LLM had radiological findings (mild lesions) in 60% of them and they had less FEV1 240 ml (11% of ref val) and FVC 364 ml (7% ref. val) when adjusted by asthma and anthrometric characteristics.   Conclusions:  The presence of LLM in sputum could represent worse pulmonary disease in patients with chronic cough even in absence of GER symptoms.