tbuckley/cabot-search huggingface dataset:
Intravitreal Sirolimus for Noninfectious Uveitis: A Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA)
Authors: Quan Dong Nguyen, Pauline T. Merrill, W. Lloyd Clark, Alay S. Banker, Christine Fardeau, Pablo Franco, Phuc LeHoang, Shigeaki Ohno, Sivakumar R. Rathinam, Stephan Thurau, Abu Abraham, Laura Wilson, Yang Yang, Naveed Shams
Journal: Ophthalmology (2016)

To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis).Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus.Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol.Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 μg, administered on Days 1, 60, and 120.The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e., tapering to a prednisone-equivalent dosage of ≤5 mg/day), and changes in best-corrected visual acuity (BCVA). Adverse events during the double-masked treatment period are presented.A total of 347 subjects were randomized. Higher proportions of subjects in the intravitreal sirolimus 440 μg (22.8%; P = 0.025) and 880 μg (16.4%; P = 0.182) groups met the primary end point than in the 44 μg group (10.3%). Likewise, higher proportions of subjects in the 440 μg (52.6%; P = 0.008) and 880 μg (43.1%; P = 0.228) groups achieved a VH score of 0 or 0.5+ than in the 44 μg group (35.0%). Mean BCVA was maintained throughout the study in each dose group, and the majority of subjects receiving corticosteroids at baseline successfully tapered off corticosteroids (44 μg [63.6%], 440 μg [76.9%], and 880 μg [66.7%]). Adverse events in the treatment and active control groups were similar in incidence, and all doses were well tolerated.Intravitreal sirolimus 440 μg demonstrated a significant improvement in ocular inflammation with preservation of BCVA in subjects with active NIU of the posterior segment.
Non-alcoholic fatty liver disease as driving force in coronary heart disease?
Authors: Giovanni Targher
Journal: Gut (2016)

Non-alcoholic fatty liver disease (NAFLD) has emerged as an imperative public health problem worldwide. NAFLD is now the most common chronic liver disease in high-income countries, and is estimated to affect at least 25%–30% of the general population.1 

NAFLD typically exists in a ‘ milieu ’ of altered metabolism, including abdominal obesity, insulin resistance, dysglycaemia and atherogenic dyslipidaemia.1 Cumulatively, these aetiological factors increase the risk for cardiovascular disease (CVD), and so it is, perhaps, not surprising that CVD is the leading cause of mortality in patients with NAFLD.

The challenge over the past decade has been to tease apart the complex inter-relationships between NAFLD and these aetiological factors, to establish whether NAFLD per se increases the risk of developing CVD. The validation of NAFLD as an independent risk factor would have direct relevance for primary preventative strategies against CVD.

A prior narrative review published in 2010 by Ghouri et al 2 concluded that a diagnosis of NAFLD was not sufficient to consider patients as being at high risk for CVD, and that the evidence base for CVD risk screening based on the presence of NAFLD was weak.

However, over the years increasing evidence supports the existence of a strong association between NAFLD and increased CVD risk. Several cross-sectional studies have consistently demonstrated that NAFLD was associated with both clinically manifest CVD and various markers of subclinical atherosclerosis (including also increased coronary artery calcium (CAC) score).3 All these associations were independent of conventional CVD risk factors across a wide range of patient populations. Moreover, NAFLD was also associated with an increased prevalence of …
Drug efflux pump expression in 50,000 molecularly-profiled cancer patients.
Authors: Rebecca Feldman, Brian L. Abbott, Sandeep K. Reddy, Michael Castro
Journal: Journal of Clinical Oncology (2015)

11108 Background: The multidrug resistance (MDR) phenotype reduces the efficacy of various chemotherapies. MDR is linked to the overexpression of ATP-binding cassette (ABC) transporters in cancer cells, including P-glycoprotein (PGP/ABCB1), multidrug resistance protein (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). We assessed protein expression patterns of the drug efflux pumps across all tumor types for insight on how to exploit MDR status to circumvent treatment dilemmas. Methods: 51,939 patients molecularly profiled with a commercial multiplatform approach (Caris Life Sciences) were evaluated. Protein expression by IHC was assessed. The Caris Registry was queried for patients in this analysis with available clinical outcomes. Results: Across all tumors profiled (n = 51,939), MRP1 positivity (pos.) was highest at 81% (19935/24682), BCRP at 66% (8849/13409) and PGP the lowest at 23% (11969/51313). GI cancers exhibited the most abundant expression of all three drug pumps (80%, 90%, 53%), with highest average combined expression observed in liver cancers (81%). In contrast, brain, thymic and head and neck cancers exhibited the lowest average combined expression of all 3 drug pumps (39%, 40% and 42%, respectively). 6,002 patients were evaluable for co-expression with 29% (1728/6002) exhibiting pos. for all 3 drug pumps (ABC+) (highest frequencies in colon, pancreas, ovary, breast and lung), 42% (2494/6002) pos. for 2/3 drug pumps and 21% (1263/6002) pos. for 1/3 drug pumps. Only 9% (517/6002) exhibited negative status for all 3 drug pumps (ABC-) (highest frequencies in breast, lung, ovary, skin and endometrial). To determine the prognostic role of the drug pumps on patient survival, we assessed the differences in median survival between a cohort of ABC+ (n = 31) and ABC – (n = 27) patients with breast (n = 6, 2), ovary (n = 12, 6) and lung cancers (n = 13,19). Median survival since specimen used for profiling was collected for ABC + was 596 days compared to 855 days for ABC – patients. Conclusions: Tumors show broad and overlapped expression patterns for drug efflux pumps. Further study is needed to determine how transporter expression may impact clinical outcomes (e.g. ABC - status is more favorable than ABC + status).
PARP inhibition in BRCA2-mutated prostate cancer
Authors: C. Nientiedt, Y. Tolstov, A.-L. Volckmar, V. Endris, D. Bonekamp, U. Haberkorn, D. Jäger, H. Sültmann, A. Stenzinger, M. Hohenfellner, C. Grüllich, S. Duensing
Journal: Annals of Oncology (2016)
The Arg123-Tyr166 central domain of human ApoAI is critical for HDL mediated inhibition of macrophage homing and early atherosclerosis in ApoE knockout mice independent of cholesterol efflux
Authors: Paul Holvoet, K Peeters, S Lund-Katz, Ann Mertens, M Lox, E Deridder, Hilde Bernar, G Theilmeier, MC Phillips
Journal: Circulation (2001)
Genetic Polymorphisms In Candidate Genes Predict Increased Toxicity With Methotrexate Therapy In Children With Acute Lymphoblastic Leukemia In Lebanon
Authors: Nathalie K Zgheib, Maya Akra-Ismail, Carol Aridi, Rami Mahfouz, Raya Saab, Miguel R. Abboud, Hassan Solh, Samar A. Muwakkit
Journal: Blood (2013)
RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy
Authors: Debora Fumagalli, David Venet, Michail Ignatiadis, Hatem A. Azim, Marion Maetens, Françoise Rothé, Roberto Salgado, Ian Bradbury, Lajos Pusztai, Nadia Harbeck, Henry Gomez, Tsai-Wang Chang, Maria Antonia Coccia-Portugal, Serena Di Cosimo, Evandro de Azambuja, Lorena de la Peña, Paolo Nuciforo, Jan C. Brase, Jens Huober, José Baselga, Martine Piccart, Sherene Loi, Christos Sotiriou
Journal: JAMA Oncology (2016)

In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents.To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents.The neoadjuvant NeoALTTO trial randomized 455 women with HER2-positive early-stage breast cancer to trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The present substudy, which was planned in the NeoALTTO main protocol, evaluated the association of pretreatment gene expression levels defined using RNA sequencing with pCR and event-free survival (EFS).Gene expression-based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome.Sequencing data were available for 254 (56%) of the NeoALTTO participants (mean [SD] age of substudy participants, 48.8 [11.2] years). The expression of ERBB2/HER2 was the most significant predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment arm, ER immunohistochemical analysis scores, Genomic Grade Index, immune, proliferation, and AKT/mTOR GSs. Adjusting for clinicopathological variables and treatment arms, ERBB2/HER2, HER2-enriched subtype, ESR1, and Genomic Grade Index remained significant. Immune GSs were associated with higher pCR only in the combination arm (odds ratio, 2.1; 95% CI, 1.2-4.0; interaction test P = .01), while the stroma GSs were significantly associated with higher pCR in the single arms and with lower pCR in the combination arm (odds ratio, 0.46; 95% CI, 0.25-0.84; P = .009). None of the evaluated variables was associated with EFS after correction for multiple testing, but this analysis was underpowered.High levels of ERBB2/HER2 and low levels of ESR1 were associated with pCR in all treatment arms. In the combination arm, high expression of immune and stroma GSs were significantly associated with higher and lower pCR rates, respectively, and should be further explored as candidate predictive markers.clinicaltrials.gov Identifier: NCT00553358.
Non-Redundant Roles for an Epo/EpoR/STAT5 Regulated Intracellular Serpin, Serpina-3G, during Epo- and Anemia- Induced Erythropoiesis
Authors: Arvind Dev, Jing Fang, Don McCrann, Christine Emerson, Anamika Pradeep, Sarah Browne, Philip Ashton-Rickardt, Don M. Wojchowski
Journal: Blood (2008)
Correlation of the EGFR gene mutation, gene amplification and protein expression in non-small cell lung cancer with clinical outcomes of erlotinib monotherapy: An exploratory analysis of biomarkers by the Korean Cancer Study Group
Authors: M. Ahn, J. Ahn, S. Kim, H. Kim, J. Lee, J. Cho, H. Song, S. Park, S. Shin, K. Park
Journal: Journal of Clinical Oncology (2007)

7608 Background: Mutations in epidermal growth factor receptor (EGFR) are considered to be strong predictive marker for response to the EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. The aim of this study conducted by the Korean Cancer Study Group (KCSG) was to determine the clinical implications of EGFR gene mutation, increased gene copy number or protein over- expression in Korean patients with advanced NSCLC who had been treated with erlotinib. Patients and Methods: A total of 120 patients received erlotinib at a dose of 150 mg daily as part of an open label phase II monotherapy trial between January 2005 and May 2006 in Korea. Ninety-two tissue samples obtained from these patients were analyzed for EGFR mutations (exon 18–21), 88 samples for EGFR gene amplification by real time PCR, and 77 samples for EGFR protein expression by immunohistochemical (IHC) staining. Results: Twenty-four out of 92 patients (26.1%) had EGFR mutations in exon 18, 19, or 21, most commonly in exon 19 (75%, 18/24). A higher frequencies were noted in female patients (40.0% vs 17.5%, p=0.017). Higher rate of response to erlotinib was noted in patients with EGFR mutations compared to wild type (N=14/24 (58.3%) vs 11/68 (16.2%), p&lt;0.001). With the median follow-up duration of 14.5 months, time to progression (TTP) and overall survival (OS) were also significantly longer in patients with mutations than those without mutations (p=0.003, p=0.042). Increased EGFR gene copy number was found in 44.9% (36/88). Patients with increased gene copy number achieved higher rate of response to erlotinib (N=14/36 (38.9%) vs 9/52 (17.3%), p=0.023). Also patients with high gene copy number showed longer TTP and OS (p&lt;0.001, p=0.022). Forty six out of 75 patients showed (+) IHC staining for EGFR protein although there was no relationship between the EGFR expression and the response to erlotinib, TTP or OS (p=0.82, p=0.35, p=0.83). Conclusion: EGFR mutation and gene amplification were shown to be important predictive markers not only for response but also for survival of the Korean patients with advanced NSCLC who had been treated with erlotinib. No significant financial relationships to disclose.
Induction of HIF-1alpha expression in monocytic cells during differentiation under nowhypoxic conditions and effect on production of pro-angiogenic factors
Authors: J. Westra, I. A. M. van Roosmalen, E. Brouwer, M. D. Posthumus, C. G. M. Kallenberg, P. C. Limburg
Journal: Annals of the Rheumatic Diseases (2007)
Fixed-Dose, Weight-Adjusted, Unfractionated Heparin (UFH) Given Subcutaneously (sc) without Laboratory Monitoring for Acute Treatment of Venous Thromboembolism (VTE): Randomized Comparison with Low-Molecular-Weight-Heparin (LMWH).
Authors: Clive Kearon, Jeffrey J. Ginsberg, Jim Julian, James Douketis, Susan Solymoss, Paul Ockelford, Sharon Jackson, Graham Turpie, Donna McCarty, Betsy MacKinnon, Jack Hirsh, Michael Gent
Journal: Blood (2004)
Clinton promises to expand healthcare access and cut out-of-pocket costs
Authors: Michael McCarthy
Journal: BMJ (2016)

The Democratic presidential candidate, Hillary Clinton, has promised to defend and expand the Affordable Care Act, reduce patients’ out-of-pocket costs, and implement reforms aimed at halting the fragmentation of the US healthcare system.

In an invited commentary in the New England Journal of Medicine, published 28 September, Clinton wrote, “As President, I will fight for every American to have access to affordable, quality healthcare—regardless of their zip code, income, or medical history. Healthcare should be a right, not a privilege.”1

The journal’s editors said that they had invited both nominees of the two major parties to explain …
Clinician perceptions of care difficulty and quality of life for lung cancer patients: Results from the ECOG SOAPP study (E2Z02).
Authors: H. A. Hamann, J. Lee, J. H. Schiller, L. Horn, C. S. Cleeland, J. Manola, L. I. Wagner, V. T. Chang, M. Fisch
Journal: Journal of Clinical Oncology (2010)

9102 Background: Emerging evidence suggests that lung cancer patients experience disparities in medical care compared to other cancer patients. This may be due to providers' perceptions that lung cancer patients are more difficult to care for and have a poorer quality of life (QOL). Methods: Participants included clinicians treating breast (n = 1543), colorectal (n = 717), prostate (n = 320), and lung (n = 522) cancer patients enrolled in the Eastern Cooperative Oncology Group (ECOG) study of Symptom Outcomes and Practice Patterns (SOAPP; Protocol E2Z02). Data included clinicians' written responses to questions about patient QOL and difficulty of care. Analyses focused on repeated measures (baseline and 28-35 day follow-up) analysis of covariance (ANCOVA) with planned comparisons for reports of lung cancer v. other cancer (breast, prostate, and colorectal) patients. Results: After controlling for relevant patient factors (sex, race/ethnicity, current status/stage of disease, metastatic sites, performance status, weight loss, current treatment, number of moderate/severe symptoms) and institution type, clinicians reported greater difficulty in care for lung cancer patients compared to other cancer patients (p < .01). After adding patients' baseline reports of QOL as a covariate (in addition to the above factors), clinicians also estimated a lower QOL for lung cancer patients (p < .001). Conclusions: Even after controlling for a number of relevant patient and disease factors, clinicians reported higher difficulty of care and lower QOL for lung cancer patients compared to patients with other common solid tumors. These data generate the hypothesis that providers have more pessimistic attitudes about lung cancer care, which could lead to disparities in treatment. Further research is needed to confirm these findings and explore potential explanations for these clinician perceptions related to lung cancer patients. No significant financial relationships to disclose.
Complete Response (CR) with Total Therapy 2 (TT2) for Multiple Myeloma (MM): Low Frequency in Case of Prior MGUS without Adverse Consequences for Survival - Yet Critical for Disease Control in Presumed “De Novo” MM.
Authors: Athanasios Fassas, Erik Rasmussen, John Shaughnessy, Guido Tricot, Maurizio Zangari, Frits van Rhee, Elias Anaissie, Klaus Hollmig, Michele Fox, Joshua Epstein, John Crowley, Bart Barlogie
Journal: Blood (2005)
Phosphorylation of Receptor Tyrosine Kinase ROR1 At Tyrosine 641, 646 and Serine 652 residues Might Be of Importance for the Survival of CLL Leukemic Cells
Authors: Mohammad Hojjat-Farsangi, Amir Hossein Daneshmanesh, Martin Norin, Åsa Sandin, Abdul Salam Khan, Ali Moshfegh, Eva Rossmann, Anders Osterborg, Hakan Mellstedt
Journal: Blood (2012)
P0275 : PDGFRA-mediated laminin B1 deposition induces invasion in human hepatocellular carcinoma
Authors: O. Govaere, M. Petz, J. Wouters, Y.-P. Vandewynckel, A. Ceulemans, B. Topal, C. Verslype, H. Van Vlierberghe, F. Nevens, W. Mikulits, T. Roskams
Journal: Journal of Hepatology (2015)
Clinical guideline on the prophylactic use of G-CSF on neutropenia by chemotherapy.
Authors: Roberto Rivera-Luna, Alejandro G Gonzalez-Garay, Liliana Velasco-Hidalgo, Jose Luis Mayorga-Butron
Journal: Journal of Clinical Oncology (2013)

3050 Background: Febrile neutropenia (FN) is common in patients with chemotherapy. It requires conventional treatment, however, many studies have reported that G-CSF reduces the incidence of FN; the results were not clear and the physicians use it at their discretion. In this guideline we evaluated the efficacy and safety of the prophylactic use of G-CSF. Methods: We analyzed controlled trials (G-CSF, pegylated form or placebo) given to adult or pediatric patients with chemotherapy for leukemia (LEU), lymphoma and solid tumors (L&amp;ST) or stem cell transplant (SCT), without infections and large radiation ports. Two independent reviewers applied CONSORT to determine the methodological quality; for ranking the evidence we used GRADE and the recommendations were developed by Delphi method. We developed subgroups according to age and type of intervention to analyze the outcomes (risk, duration, severity of FN and adverse events). We performed random-effects or fixed-effects meta-analysis methods according to their heterogeneity. Results: Of 1,776 studies,112 were included. For the risk of FN between C-GSF or pegylated form vs placebo found that G-CSF reduces the risk in adults with LEU (RR 0.89, 95% CI 0.81-0.98; p=0.024), L&amp;ST (RR 0.758, 95% CI 0.68-0.84; p=0.000) and SCT (RR 0.85, 95% CI 0.74–0.97, p=0.017). The risk of developing severe neutropenia reduces in the adults with L&amp;ST with the factor (RR 0.79, 95% CI 0.71-0.88; p=0.000) and pediatric patients with LEU (RR 0.789, 95% CI 0.71-0.88; p=0.000). While the duration of neutropenia in children with L&amp;ST the time reduces with the factor (SMD -0.559; 95% CI -0.841 to -0.28; p=0.000). The G-CSF vs pegylated form, the evidence was inconclusive. Conclusions: When the risk and duration of neutropenia is present we suggest the use of G-CSF in adult and pediatric patients. For adults, we suggest the use of pegylated form, but for pediatric patients we do not have a specific suggestion because the evidence is nonexistent, so it is necessary to carry out clinical trials to obtain evidence.
Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage
Authors: Lintao Wang, Qian Chen, Haixia Qi, Chunming Wang, Cheng Wang, Junfeng Zhang, Lei Dong
Journal: Cancer Research (2016)

Abstract Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicin-induced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631–42. ©2016 AACR.
Case 45-1963
Authors: John B. Stanbury, Benjamin Castleman
Journal: New England Journal of Medicine (1963)

Presentation of Case First admission. A fifty-seven-year-old widow was admitted to the hospital because of weakness and anemia.Two months previously the patient entered another hospital after an episode of pain in the left side of the chest, which was diagnosed as "herpes"; the pain subsided with bed rest alone. Thereafter she was aware of persistent weakness and fatigue, and a week before admission her physician told her that she was severely anemic. Two transfusions of blood were given, and after an upper gastrointestinal series she was informed that "something was wrong with the esophagus."Two years before admission an . . .