tbuckley/cabot-search huggingface dataset:
A multi-center phase II open-label study (CheckMate 204) to evaluate safety and efficacy of nivolumab (NIVO) in combination with ipilimumab (IPI) followed by NIVO monotherapy in patients (pts) with melanoma (MEL) metastatic to the brain.
Authors: Kim Allyson Margolin, Hussein Abdul-Hassan Tawbi, Marc S. Ernstoff, F. Stephen Hodi, David F. McDermott, Robin Edwards, Alexandre Avila, Michael B. Atkins
Journal: Journal of Clinical Oncology (2015)

TPS9080 Background: Brain metastasis develops in approximately 50% of pts with metastatic MEL. In these pts, progressive brain disease is the major cause of tumor-related death (median overall survival [OS] after diagnosis, 4 months). NIVO (a fully human IgG4 PD-1 immune checkpoint inhibitor antibody) and IPI (a fully human IgG1 CTLA-4 immune checkpoint inhibitor antibody) are each approved as monotherapy for advanced MEL. In a phase II study, IPI showed activity in some pts with advanced MEL and brain metastases. Building upon the success of that study, this open-label, multi-site, US, phase II study is the first to evaluate NIVO combined with IPI followed by NIVO monotherapy for pts with MEL metastatic to the brain. It is anticipated that approximately 50% of enrolled pts will have had prior stereotactic radiotherapy (SRT). Methods: Pts ≥ 18 years of age with MEL measurable in extracranial sites and with asymptomatic brain metastases are eligible. Pts with a history of leptomeningeal involvement, a history of whole brain irradiation, autoimmune disease or corticosteroid use will be excluded. Pts will receive NIVO 1 mg/kg combined with IPI 3 mg/kg every three weeks (Q3W; 4 doses), followed by NIVO monotherapy 3 mg/kg Q2W until progression or unacceptable toxicity. SRT for progression of a single central nervous system (CNS) lesion will be permitted. The primary objective is to assess the CNS clinical benefit rate (CBR; complete response + partial response + stable disease [SD] ≥ 6 months) per protocol-defined response criteria; this endpoint was selected based on its relevance in this population and ability to capture both objective response and durable SD. Secondary objectives are to assess extracranial CBR per RECIST v1.1; global CBR (CNS plus extracranial) per RECIST v1.1 with modifications; CNS, extracranial and global CBR per immune-related response criteria; OS and safety. Exploratory correlates are also planned. An estimated 110 pts will be enrolled. Clinical trial registration number: NCT02320058. Clinical trial information: NCT02320058.
Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab
Authors: Nihar R. Desai, Robert P. Giugliano, Scott M. Wasserman, John P. Gibbs, Thomas Liu, Rob Scott, Marc S. Sabatine
Journal: JAMA Cardiology (2017)

Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of evolocumab varies based on an individual's baseline PCSK9 level remains unknown.To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with evolocumab differs based on PCSK9 levels.This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12.Placebo-controlled percentage change in LDL-C level with evolocumab, 140 mg every 2 weeks and 420 mg once monthly, across quartiles of baseline PCSK9 levels.Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P < .001) and had significantly lower baseline LDL-C level (123 mg/dL, 124 mg/dL, 128 mg/dL, and 137 mg/dL in the fourth through first quartiles; P < .001). After stratifying by statin use, there was no correlation between PCSK9 levels and LDL-C levels (ρ = 0.03 [95% CI, -0.04 to 0.10] for nonstatin users, P = .39, and ρ = 0.03 [95% CI, -0.01 to 0.08] for statin users, P = .12). Across all quartiles of baseline PCSK9 levels, both evolocumab 140 mg every 2 weeks and 420 mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both evolocumab 140 mg every 2 weeks and 420 mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71% (P < .001), regardless of PCSK9 levels (P for interaction = .76 and .21, respectively).Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.
Gene Dosage Effects in B-Chronic Lymphocytic Leukemia with Del 13q14.
Authors: Ludger Sellmann, Rene Scholtysik, Holger Nueckel, Tanja Boes, Alexander Carpinteiro, Ulrich Duehrsen, Ludger Klein-Hitpass, Jan Duerig, Ralf Kueppers
Journal: Blood (2009)
Cancer cachexia staging: A systematic review of factors to classify involuntary weight loss
Authors: D. Blum, A. G. Omlin, J. Walker, F. Strasser
Journal: Journal of Clinical Oncology (2008)

20556 Background: The concept of anorexia/cachexia is evolving as its mechanisms are discovered, but the current - simple - diagnostic criteria (weight loss [WL], anorexia) nowadays guide poorly clinical care decisions or clinical trial design. We systematically reviewed factors and systems used to classify cancer cachexia. Methods: Three combined search strings (cachexia, cancer, classification) were applied in MEDLINE, Cochrane, EMBASE, PsycINFO, and CinAhl, from 1976–2007. Three investigators (interrater-reliability before consensus 93%) screened citations, abstracts and papers for inclusion criteria: original work, english/german, and a) systems (≥2 factors) or b) a single factor to classify cancer patients with WL or c) to predict response to anticachexia treatment. Results: Of 9817 citations, 1275 abstracts and 585 papers, 126 papers (7 systems, 112 factors, 7 subgroup analysis [84 anticachexia trials]) were included; representing 7913 patients (50% gastrointestinal, 20% lung cancer). Four systems combined anthropometrics (AM), nutritional intake (NI), symptoms (SY) and inflammation (INF), two systems AM/NI and either SY or INF, one added REE and hormones. All 6 systems challenge the old definition of a sole anorexia/cachexia syndrome. Only 1 study reports a multivariate analysis: 3 factor model (WL, NI, INF). One system classifies patients by dietary patterns. Of the single factors, AM and INF, also muscle strenght and ghrelin classify patients with cachexia in most studies, whereas NI, symptoms, metabolic alterations, REE, and leptin, are variably reported. Few studies describe hormons (testosterone, thyroxin), gastrointestinal dysmotility, and proteolysis-inducing factor. Tumor biology and anti-cancer treatment was not explored. Attempts to define subgroups of responders in anticachexia trials by single factors failed. Conclusions: This novel systematic review supports a multiple factor staging of cancer patients with involuntary weight loss. Future research for validation is required. Main factors used to classify cancer patients with involuntary weight loss Factor Patients (#) Studies (#), (long./c- sect) Classifcation of patients with weight loss by factor Muscle mass/fat mass 1070 9 (2/7) 6 pos, 1 neg, 2 unclear Inflammation (CRP, other) 2316 28 (2/26) 21 pos, 3 neg, 4 unclear Nutritional intake 2429 14 (1/13) 5 pos, 3 neg, 6 unclear Anorexia, early satiety, abdominal symptoms, depression; PG- SGA, FAACT, QOL. 2195 16 (1/15) variable* Muscle strenght 238 2 (0/2) 2 pos Metabolism (glucose/insulin resistance, fat, amino acids, albumine) 533 23 (1/22) variable* Resting Energy Expenditure 1289 9 (2/7) 3 pos, 5 neg, 1 unclear Leptin 642 11 (2/9) 5 pos, 6 neg Ghrelin 497 5 (4/1) 4 pos, 1 neg Pos: positive, neg: negative. Long: longitudinal, c-sect: cross-section. * : see text in results No significant financial relationships to disclose.
Three Arterial Grafts Improve Late Survival
Authors: Mario Gaudino, John D. Puskas, Antonino Di Franco, Lucas B. Ohmes, Mario Iannaccone, Umberto Barbero, David Glineur, Juan B. Grau, Umberto Benedetto, Fabrizio D’Ascenzo, Fiorenzo Gaita, Leonard N. Girardi, David P. Taggart
Journal: Circulation (2017)

Background: Little evidence shows whether a third arterial graft provides superior outcomes compared with the use of 2 arterial grafts in patients undergoing coronary artery bypass grafting. A meta-analysis of all the propensity score-matched observational studies comparing the long-term outcomes of coronary artery bypass grafting with the use of 2-arterial versus 3-arterial grafts was performed. Methods: A literature search was conducted using MEDLINE, EMBASE, and Web of Science to identify relevant articles. Long-term mortality in the propensity score-matched populations was the primary end point. Secondary end points were in-hospital/30-day mortality for the propensity score-matched populations and long-term mortality for the unmatched populations. In the matched population, time-to-event outcome for long-term mortality was extracted as hazard ratios, along with their variance. Statistical pooling of survival (time-to-event) was performed according to a random effect model, computing risk estimates with 95% confidence intervals. Results: Eight propensity score-matched studies reporting on 10 287 matched patients (2-arterial graft: 5346; 3-arterial graft: 4941) were selected for final comparison. The mean follow-up time ranged from 37.2 to 196.8 months. The use of 3 arterial grafts was not statistically associated with early mortality (hazard ratio, 0.93; 95% confidence interval, 0.71–1.22; P =0.62). The use of 3 arterial grafts was associated with statistically significantly lower hazard for late death (hazard ratio, 0.8; 95% confidence interval, 0.75–0.87; P &lt;0.001), irrespective of sex and diabetic mellitus status. This result was qualitatively similar in the unmatched population (hazard ratio, 0.57; 95% confidence interval, 0.33–0.98; P =0.04). Conclusions: The use of a third arterial conduit in patients with coronary artery bypass grafting is not associated with higher operative risk and is associated with superior long-term survival, irrespective of sex and diabetic mellitus status.
New Prognostic Factors in the Assessment of Bone Complications in Gaucher Disease. Report from the Argentinian Group for Diagnostic and Treatment for Gaucher Disease
Authors: Guillermo I. Drelichman, Nicolas Fernandez Escobar, Nora F Basack, Maria S Larroude, Gabriel Aguilar, Hugo Robledo, Leonardo J Feldman, Graciela Elena, Nora Watman, Moira Bolesina, Juan Jose Chain, Paola Reichel, Alba A Ruiz, Maria F Cuello, Alcira B Fynn, Marcela A Aznar, Marta Dragosky, Norberto B Guelbert, Adriana Arizo, Graciela A Pujal, Katja G Muller
Journal: Blood (2014)
Treatment of Primary Bone Lymphoma with Intensive Chemotherapy
Authors: Anna Morozova, Eugene Zvonkov, Vasilii Mamonov, Alla M. Kovrigina, Sergei Kravchenko, Yuri Lorie, Vladimir I. Vorobyev, Ekaterina Penskaya, Eduard Gemdjian, Valeriy G Savchenko
Journal: Blood (2012)
Involvement of a Rac1-Dependent Macropinocytosis Pathway in Plasmid DNA Delivery by Electrotransfection
Authors: Mao Mao, Liangli Wang, Chun-Chi Chang, Katheryn E. Rothenberg, Jianyong Huang, Yingxiao Wang, Brenton D. Hoffman, Paloma B. Liton, Fan Yuan
Journal: Molecular Therapy (2017)

Electrotransfection is a widely used method for delivering genes into cells with electric pulses. Although different hypotheses have been proposed, the mechanism of electrotransfection remains controversial. Previous studies have indicated that uptake and intracellular trafficking of plasmid DNA (pDNA) are mediated by endocytic pathways, but it is still unclear which pathways are directly involved in the delivery. To this end, the present study investigated the dependence of electrotransfection on macropinocytosis. Data from the study demonstrated that electric pulses induced cell membrane ruffling and actin cytoskeleton remodeling. Using fluorescently labeled pDNA and a macropinocytosis marker (i.e., dextran), the study showed that electrotransfected pDNA co-localized with dextran in intracellular vesicles. Furthermore, electrotransfection efficiency could be decreased significantly by reducing temperature or treatment of cells with a pharmacological inhibitor of Rac1 and could be altered by changing Rac1 activity. Taken together, the findings suggested that electrotransfection of pDNA involved Rac1-dependent macropinocytosis.
Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study
Authors: Rebecca C. Richmond, Nicholas J. Timpson, Janine F. Felix, Tom Palmer, Romy Gaillard, George McMahon, George Davey Smith, Vincent W. Jaddoe, Debbie A. Lawlor
Journal: PLoS Medicine (2017)

Background It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood. Methods and Findings We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21–0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21–0.30) at age 7 and 0.03 SD (95% CI -0.26–0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19–0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11–0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates. Conclusions Our findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.
Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sézary Syndrome
Authors: Charlotte Hurabielle, Nicolas Thonnart, Caroline Ram-Wolff, Hélène Sicard, Armand Bensussan, Martine Bagot, Anne Marie-Cardine
Journal: Clinical Cancer Research (2017)

Abstract Purpose: KIR3DL2 is a recently discovered marker of the malignant clonal cell population in Sézary syndrome. We intended to evaluate the expression of KIR3DL2 on blood T cells as a diagnostic, prognostic, and follow-up marker of Sézary syndrome. Experimental Design: Sixty-four patients diagnosed with Sézary syndrome were included in this monocentric study. We collected the percentage of KIR3DL2+ cells among CD3+ T cells, obtained by flow cytometry, and other classical diagnostic criteria for Sézary syndrome at diagnosis and during the follow-up. Results: Compared with the classical diagnostic factors, KIR3DL2 was the most sensitive diagnostic factor for Sézary syndrome. Univariate and multivariate analyses established that an eosinophil cell count &amp;gt;700/mm3 and a percentage of KIR3DL2+ cells within the CD3+ T cells &amp;gt;85% at diagnosis were associated with a significantly reduced disease-specific survival. Moreover, KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, the detection of the residual disease following treatment, and the occurrence of relapse, even though patients clinically experienced complete remission and/or undetectable circulating Sézary cells by cytomorphologic analysis. Conclusions: We show that KIR3DL2 expression is the most sensitive diagnostic criterion of Sézary syndrome when compared with all other available biological criteria. It also represents the best independent prognostic factor for Sézary syndrome–specific death and the most relevant feature for the follow-up of Sézary syndrome, showing the invasion of the functional lymphocytes pool by Sézary cells. KIR3DL2 therefore represents a valuable tool for routine use as a clinical parameter at diagnosis, for prognosis and during patient follow-up. Clin Cancer Res; 23(14); 3619–27. ©2017 AACR.
Blocking Complement-Mediated Hemolysis Using RNA Aptamers That Bind Complement Component C8.
Authors: Jun-ichi Nishimura, Shahid M. Nimjee, Haixiang Jiang, Thad A. Howard, George A. Pitoc, Christopher P. Rusconi, Mitsuhiro Omine, Nelson J. Chao, Michael M. Frank, Bruce A. Sullenger, Russell E. Ware
Journal: Blood (2005)
Familial Risk and Heritability of Colorectal Cancer in the Nordic Twin Study of Cancer
Authors: Rebecca E. Graff, Sören Möller, Michael N. Passarelli, John S. Witte, Axel Skytthe, Kaare Christensen, Qihua Tan, Hans-Olov Adami, Kamila Czene, Jennifer R. Harris, Eero Pukkala, Jaakko Kaprio, Edward L. Giovannucci, Lorelei A. Mucci, Jacob B. Hjelmborg
Journal: Clinical Gastroenterology and Hepatology (2017)
Pain control and delay in time to skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA): Long-term follow-up.
Authors: Ethan M. Basch, Johann Sebastian De Bono, Howard I. Scher, Arturo Molina, Cora N. Sternberg, Karim Fizazi, Scott A. North, Kim N. Chi, Robert J. Jones, Oscar B. Goodman, Paul N. Mainwaring, Amanda M. Farr, Margaret Rothman, Yanni Hao, Cameron S. Liu, Thian San Kheoh, Christopher M. Haqq, Eleni Efstathiou, Christopher Logothetis
Journal: Journal of Clinical Oncology (2012)

183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increased overall survival in mCRPC post-docetaxel (D) in both interim and updated analyses at 552 and 775 events, respectively. Interim data also showed a significant benefit of AA on patient (pt) reported pain. We present long-term outcomes of the effect of AA on pain and SREs. Methods: In this international randomized double blind study of AA (1 g QD) + prednisone (P) (5 mg BID) vs placebo + P in mCRPC post-D, pain was assessed at baseline and each treatment cycle until treatment discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) were evaluated using a priori definitions. P-INT palliation was defined as ≥ 30% improvement in pt reported “worst pain in last 24 h” (on 0-10 numerical rating scale) durable for ≥ 28 d without increased analgesic use (by WHO criteria) in eligible pts (those with significant baseline pain). Conversely, P-INT progression was defined as ≥ 30% deterioration, or increased analgesic use, over ≥ 28 d. Results: 797 pts were randomized to AA + P, 398 to placebo + P. Median follow-up was 20.2 mos. Median time to SRE was 25.0 mos (AA + P) vs 20.3 mos (placebo + P), p = 0.0001. Pain data were available for most patients; the cumulative amount of missing data ranged from 5% at Cycle 1 to 7% at Cycle 20. AA + P improved P-INT outcomes (Table); P-INF benefits were similar and also highly significant. Conclusions: Benefits of AA + P observed in the interim analysis, including superior and more durable pain relief and delay of pain progression and SREs, were maintained with longer follow-up. Additional analyses of the potential relationships between pain/SREs and other outcomes, as well as of prednisone’s effect on pain palliation in the control arm, are ongoing. [Table: see text]
Late Relapses Following Reduced Intensity Conditioning Allogeneic Haematopoietic Stem Cell Transplantation for Myeloid Malignancies Can Be Effectively Salvaged with Intensive Chemotherapy Followed by Cellular Therapy.
Authors: Austin Gladston Kulasekararaj, Ziyi Lim, Pramila Krishnamurthy, M. Mansour Ceesay, Michelle Kenyon, Janet Hayden, Judith C W Marsh, Aloysius YL Ho, Antonio Pagliuca, Ghulam J Mufti
Journal: Blood (2009)
A Weekly Dose of Pegylated Interpheron alpha-2b (Pegintron®) as Maintenance Treatment after Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) in Multiple Myeloma (MM): Preliminary Experience.
Authors: A. Alegre, B. Aguado, J. San Miguel, J. Garcia-Laraña, F. Lara, J.J. Lahuerta, B. Navas, J. Loscertales, A. Durán, A. García, B. Iñigo, E. Moreno, J.M. Fernández-Rañada
Journal: Blood (2005)
Safety of Intrathecal Rituximab as Prophylaxis or Treatment in CD20+ Acute Lymphoblastic and Aggressive Lymphoma: Report from a Mexican Pilot Study.
Authors: Luis Villela, Rocio Caballero-Caballero, Josefa Piedras-Ross, Hetor Garcia-Herrera, Dolores Mejia, Jose R. Borbolla Escoboza
Journal: Blood (2006)