tbuckley/cabot-search huggingface dataset:
Bringing Science to Clinical Practice
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2014)

Life is complicated. In my practice, I care for patients with pancreatic adenocarcinoma, and it’s not easy. Available treatments, although improving, are still sparse. Often these patients don’t live very long. So it’s not surprising that they are keenly interested in having their tumors tested for things that might increase their therapeutic options, such as genetic mutations or amplifications or protein expression. And we doctors want to provide those options. So we faithfully send biopsies out for testing and hope that the findings will steer us toward a clinical trial when the time is right. Often, however, no trial is available, and we’re faced with the dilemma of having an actionable finding with no body of evidence to support use of the drug in the context of the disease at hand. Right now, I have a patient—a young woman with pancreatic cancer—who, surprisingly, has a somatic BRCA mutation and HER2 amplification. At first, I found it reassuring that we might have some different options to pursue. But when her disease began to progress after standard therapy, we couldn’t find an open trial with a poly(ADP)-ribose polymerase (PARP) inhibitor or with an antibody or small molecule targeting HER2. Her disease was progressing rapidly, and we made a decision to start trastuzumab and pertuzumab, off-label. I acknowledge having no evidence on which to base this decision. Long ago, a negative trial evaluating trastuzumab was performed in HER-positive pancreatic cancer. Of course, the effort preceded our current techniques for measuring HER2 positivity and we didn’t appreciate the concomitant advantage of blocking HER2 dimerization. Although my patient was prepared to pay for the off-label treatment out-ofpocket, a miracle happened and her insurance authorized the treatment. It’s too soon to know whether this strategy will help her, and I lie awake each night wondering if we did the right thing. As long as I can remember, off-label use of drugs has been common in oncology. We don’t have a method for tracking the outcomes of off-label use, but our formerly lenient payer system accommodated the practice. However, with the cost of cancer care soaring—largely because of expensive new drugs—the landscape is changing and we must find a way to use these drugs conservatively. NCCN is tackling this head on. In this issue, you will find an NCCN Working Group Report, “Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies.” This represents the beginning of an effort within NCCN to create a framework for establishing the value of targeted therapy in unique subsets. We already know that, in common diseases, even a small fraction of patients defined by a common mutation can serve as a sizable cohort for clinical trials. But how do we handle unique patients or really small subsets? How do we create an evidence base when large randomized clinical trials are not
Evaluation of trastuzumab without chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients: Randomized controlled trial (RESPECT).
Authors: Masataka Sawaki, Tsuyoshi Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai
Journal: Journal of Clinical Oncology (2018)

510 Background: The relative value of trastuzumab (H) monotherapy as an adjuvant treatment compared to the standard combination treatment with chemotherapy (CT) is not clear for elderly breast cancer (BC) patients (pts). Methods: We randomly assigned pts over 70 years (yrs) old with HER2-positive invasive BC who received curative surgery into either H (H group) or H plus CT (H+CT group) selected from pre-specified regimens (PTX/DTX/TC/AC/EC/FEC/CMF/TCb [CBDCA]). The primary endpoint was disease-free survival (DFS), and the total required numbers of events and pts were set to 120 and 260, respectively, for assuring a statistical power of 80% for a 95% confidence interval (CI) with a hazard ratio (HR) of H to H+CT not to exceed 1.69. Restricted mean survival time (RMST) was calculated as a supplementary endpoint for interpreting the relative benefit of H because the blinded interim analysis showed the number of events was much fewer than expected, and the statistical power of the non-inferiority test based on HR is not assured. Results: A total of 275 pts were randomized from 2009 to 2014. The median age was 73.5 (70-80) yrs and the median follow up time was 3.52 yrs. Stage I (pT > 0.5cm) 43.6%, IIA 41.7%, IIB 13.5%, IIIA 1.1%. The planned analysis showed that DFS at 3 yrs was 94.8% in H+CT (n = 131, 12 events) vs 89.2% in H (n = 135, 18 events) (HR = 1.42; 95% CI, 0.68 to 2.95, P = 0.35). The difference in RMST between arms at 3 yrs was 0.45 months (mo). Relapse-free survival at 3 yrs was 95.6% (9 events with 4 deaths) in H+CT vs 91.7% (13 events with 5 deaths) in H. Common adverse events (AE) in H+CT vs H were anorexia (44.3% vs 7.4%, P < 0.0001), alopecia (71.8% vs 2.2%, P < 0.0001) and grade 3/4 non-hematological AE were 29.8% vs 11.9% (P = 0.0003). The total score of FACT-G improved more in H at 12 mo (H: 42.9% vs H+CT: 25.3%, P = 0.021). Conclusion: Small number of events precluded the evaluation of H monotherapy based on HR of DFS, and comparison of RMSTs revealed the lost survival due to omitting CT was less than 1 mo at 3 yrs. In light of less toxicity and a better QOL profile, H monotherapy can be an option as an adjuvant therapy for elderly HER2-positive BC pts. Clinical trial information: NCT01104935.
Nanofibrous clinical-grade collagen scaffolds seeded with human cardiomyocytes induces cardiac remodeling in dilated cardiomyopathy
Authors: Pierre Joanne, Maria Kitsara, Solène-Emmanuelle Boitard, Hany Naemetalla, Valérie Vanneaux, Mathieu Pernot, Jérôme Larghero, Patricia Forest, Yong Chen, Philippe Menasché, Onnik Agbulut
Journal: Biomaterials (2015)
Extracorporeal Cardiopulmonary Resuscitation (E-CPR) During Pediatric In-Hospital Cardiopulmonary Arrest Is Associated With Improved Survival to Discharge
Authors: Javier J. Lasa, Rachel S. Rogers, Russell Localio, Justine Shults, Tia Raymond, Michael Gaies, Ravi Thiagarajan, Peter C. Laussen, Todd Kilbaugh, Robert A. Berg, Vinay Nadkarni, Alexis Topjian
Journal: Circulation (2015)

Although extracorporeal cardiopulmonary resuscitation (E-CPR) can result in survival after failed conventional CPR (C-CPR), no large, systematic comparison of pediatric E-CPR and continued C-CPR has been reported.Consecutive patients <18 years old with CPR events ≥10 minutes in duration reported to the Get With the Guidelines-Resuscitation registry between January 2000 and December 2011 were identified. Hospitals were grouped by teaching status and location. Primary outcome was survival to discharge. Regression modeling was performed, conditioning on hospital groups. A secondary analysis was performed with the use of propensity score matching. Of 3756 evaluable patients, 591 (16%) received E-CPR and 3165 (84%) received C-CPR only. Survival to hospital discharge and survival with favorable neurological outcome (Pediatric Cerebral Performance Category score of 1-3 or unchanged from admission) were greater for E-CPR (40% [237 of 591] and 27% [133 of 496]) versus C-CPR patients (27% [862 of 3165] and 18% [512 of 2840]). Odds ratios (ORs) for survival to hospital discharge and survival with favorable neurological outcome were greater for E-CPR versus C-CPR. After adjustment for covariates, patients receiving E-CPR had higher odds of survival to discharge (OR, 2.80; 95% confidence interval, 2.13-3.69; P<0.001) and survival with favorable neurological outcome (OR, 2.64; 95% confidence interval, 1.91-3.64; P<0.001) than patients who received C-CPR. This association persisted when analyzed by propensity score-matched cohorts (OR, 1.70; 95% confidence interval, 1.33-2.18; P<0.001; and OR, 1.78; 95% confidence interval, 1.31-2.41; P<0.001, respectively].For children with in-hospital CPR of ≥10 minutes duration, E-CPR was associated with improved survival to hospital discharge and survival with favorable neurological outcome compared with C-CPR.
A randomized study of epirubicin monotherapy every four or every two weeks in advanced breast cancer. A Hellenic Cooperative Oncology Group study
Authors: G. Fountzilas, A. Athanassiades, T. Giannakakis, E. Briasoulis, D. Bafaloukos, A. Kalogera-Fountzila, A. Onienaoum, H. Kalofonos, D. Pectasides, E. Andreopoulou, C. Bamia, P. Kosmidis, N. Pavlidis, D. Skarlos
Journal: Annals of Oncology (1997)
Schizoaffective mania reconsidered
Authors: D F Levinson, M E Levitt
Journal: American Journal of Psychiatry (1987)

Schizoaffective mania refers to a heterogeneous group of disorders characterized by mixtures of schizophrenic and manic (or bipolar) symptoms. Of the proposed diagnostic criteria, the Research Diagnostic Criteria (RDC) most clearly distinguish relevant subgroups. Family, clinical, and treatment studies suggest that the RDC's mainly affective subtype of schizoaffective mania is a variant of psychotic bipolar disorder. Limited available data suggest that the mainly schizophrenic subtype has a poorer prognosis and includes cases more closely related to schizophrenia. Schizoaffective mania also overlaps with proposed categories such as reactive and cycloid psychosis. It is premature to assume that all schizoaffective manic disorder represents a bipolar variant. Further studies that differentiate patients according to subtype, drug response, and course are needed.
Reovirus activated NK cells show enhanced cetuximab mediated antibody-dependent cellular cytotoxicity against colorectal cancer cells
Authors: Xing Zhao, Narendiran Rajasekaran, Cariad Chester, Atsushi Yonezawa, Suparna Dutt, Matt Coffey, Holbrook E Kohrt
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The naturally occurring oncolytic virus, reovirus, exhibits cytotoxic effects on cancer cells. Reovirus is safe, and currently is in multiple clinical trials testing for the treatment of different cancers. NK cells are innate immune effectors that mediate antibody dependent
Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels
Authors: S. Ghazal-Aswad, M.J. Tilby, M. Lind, N. Baily, D.P. Sinha, A.H. Calvert, D.R. Newell
Journal: Annals of Oncology (1999)
Gene regulatory divergence among species estimated by altered developmental patterns in interspecific hybrids.
Authors: H R Parker, D P Philipp, G S Whitt
Journal: Molecular Biology and Evolution (1985)

Disturbances in the schedules of gene expression in developing interspecific fish hybrids have been used to draw inferences about the extent of gene regulatory divergence between species and about the degree to which this gene regulatory divergence is correlated with structural gene divergence, as estimated by genetic distance. Sperm from each of 10 different species representing six genera within the family Centrarchidae was used to fertilize eggs of the Florida largemouth bass (Micropterus salmoides floridanus). The genetic distances (D; Nei 1978) between the parental species used to form the hybrids ranged from 0.133 to 0.974. The developmental success and temporal patterns of gene expression of each of the hybrids were compared with those of the Florida largemouth bass. As the genetic distance between the paternal species and the Florida largemouth bass increased, there was a general decline in developmental success in the hybrid embryos as demonstrated by the observed reductions in the percentage of hatching and by progressively earlier and more extensive morphological abnormalities. Concomitantly, progressively more marked alterations in developmental schedules of expression of 15 enzyme loci occurred in the hybrids as the genetic distance between parental species increased. However, observed deviations from this trend for a few species may represent an uncoupling of the rates and modes of evolution of structural genes from those for genes regulating developmental processes.
Tendances récentes des gonococcies - l'émergence d'un nouveau problème de santé publique ?
Authors: Gwenda Hughes, Kevin Fenton
Journal: Eurosurveillance (2000)

L’infection a Neisseria gonorrhoeae reste l’une des maladies sexuellement transmissibles (MST) bacteriennes la plus repandue dans bon nombre de pays industrialises. Le controle de cette infection constitue une priorite en sante publique, du fait de son poids, en particulier chez les populations urbaines precaires, et de ses consequences sur la fertilite (1). Les infections incidentes temoignent de comportements sexuels a haut risque relativement recents, et ont ete utilisees pour etudier les comportements susceptibles de faciliter la transmission du VIH (2). Dans ce numero d’Eurosurveillance, Veronique Goulet et ses collegues rapportent une augmentation brutale de la gonococcie en France en 1998, identifiee par le reseau national de surveillance des laboratoires, RENAGO (Reseau National du Gonocoque). Une augmentation similaire a ete observee en Angleterre en 1996 (3), laquelle s’est poursuivie en 1997 (4). Dans ces deux pays, ces observations sont particulierement alarmantes car elles surviennent apres des tendances a la baisse qui se sont maintenues entre le milieu et la fin des annees quatre-vingt. Comment faut-il interpreter ces augmentations ? Sont-elles le signe d’un retour des comportements sexuels a risque ?
Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial
Authors: Thomas Fremming Dejgaard, Christian Seerup Frandsen, Tanja Stenbæk Hansen, Thomas Almdal, Søren Urhammer, Ulrik Pedersen-Bjergaard, Tonny Jensen, Andreas Kryger Jensen, Jens Juul Holst, Lise Tarnow, Filip Krag Knop, Sten Madsbad, Henrik Ullits Andersen
Journal: The Lancet Diabetes & Endocrinology (2015)
Endogenous altered peptide ligands can affect peripheral T cell responses.
Authors: K Vidal, B L Hsu, C B Williams, P M Allen
Journal: The Journal of Experimental Medicine (1996)

T cells potentially encounter a large number of endogenous self-peptide/MHC ligands in the thymus and the periphery. These endogenous ligands are critical to both positive and negative selection in the thymus; however, their effect on peripheral T cells has not been directly ascertained. Using the murine allelic Hbd (64-76)/I-Ek self-antigen model, we have previously identified altered peptide ligands (APLs) which are able to stimulate some but not all TCR-mediated effector functions. To determine directly the effect of endogenously synthesized APL/MHC complexes on peripheral T cells, we used a TCR transgenic mouse which had reversed our normal antigen system, with Ser69 peptide now being the agonist and Hbd(64-76) being the APL. In this report, we show that the constitutive level of endogenous Hbd(64-76)/I-Ek complexes presented by APCs in vivo is too low to affect the response of Ser69 reactive T cells. However, by increasing the number of Hbd(64-76)/I-Ek complexes expressed by the APCs, TCR antagonism is observed for both primary T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells changes the response pattern to endogenously presented Hbd(64-76)/I-Ek ligand. These findings demonstrate that T cells are selected to ignore the constitutive levels of endogenous complexes they encounter in the periphery. T cell responses can be affected by endogenous APLs in the periphery under limited but attainable circumstances which change the efficacy of the TCR/ligand interaction. Thus, endogenous APLs play a role in both the selection of T cells in the thymus and the responses of peripheral T cells.
Abstract 275: ER-886046, an antagonist of PGE2 receptor type-4, induces an effective antitumor immune response in mice by attenuating intratumoral MDSCs and TAMs
Authors: Diana I. Albu, Zichun Wang, Jiayi Wu, Kuan-chun Huang, Wei Li, Diana Liu, Galina Kuznetsov, Qian Chen, Xingfeng Bao, Mary Woodall-Jappe
Journal: Cancer Research (2015)

Abstract One of the hallmarks of an immunosuppressive tumor microenvironment is the presence of myeloid-derived suppressor cells (MDSCs) and type 2 tumor-associated macrophages (TAMs). These myeloid cells derive from immature monocytes and their differentiation is highly regulated by the engagement of prostaglandin E2 (PGE2) receptor type 4 (EP4) with PGE2 in the tumor microenvironment. To understand the importance of EP4 for tumor support, we implanted mouse tumors in EP4 inducible knockout mice and found that these tumors grew significantly more slowly than in wild type mice, indicating an important role of host cell EP4 signaling for tumor progression. Here we report the development and evaluation of ER-886046, a novel and specific EP4 antagonist, for cancer treatment. Daily oral administration of ER-886046 inhibited the growth of multiple mouse syngeneic tumor models with an inhibitory activity up to 100%. The anti-tumor activity of ER-886046 was T cell-dependent since it was not observed in T cell deficient mice. Furthermore, we found in vitro and in vivo mechanistic evidence that ER-886046 interferes with tumor-induced monocyte differentiation into immunosuppressive type 2 macrophages and MDSCs, instead supporting monocyte differentiation into APCs and facilitating intratumoral T cell accumulation. Importantly, ER-886046 has a desirable pharmacokinetic and metabolism profile in mice, rats and dogs which qualifies it as a good candidate for clinical studies in humans. Thus, the preclinical data support further investigation of targeting EP4 signaling by ER-886046 as a novel immune therapy for cancer treatment in clinical setting. Citation Format: Diana I. Albu, Zichun Wang, Jiayi Wu, Kuan-chun Huang, Wei Li, Diana Liu, Galina Kuznetsov, Qian Chen, Xingfeng Bao, Mary Woodall-Jappe. ER-886046, an antagonist of PGE2 receptor type-4, induces an effective antitumor immune response in mice by attenuating intratumoral MDSCs and TAMs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2015-275
Building Sustainable Capacity for Cardiovascular Care at a Public Hospital in Western Kenya
Authors: Cynthia A. Binanay, Constantine O. Akwanalo, Wilson Aruasa, Felix A. Barasa, G. Ralph Corey, Susie Crowe, Fabian Esamai, Robert Einterz, Michael C. Foster, Adrian Gardner, John Kibosia, Sylvester Kimaiyo, Myra Koech, Belinda Korir, John E. Lawrence, Stephanie Lukas, Imran Manji, Peris Maritim, Francis Ogaro, Peter Park, Sonak D. Pastakia, Wilson Sugut, Rajesh Vedanthan, Reuben Yanoh, Eric J. Velazquez, Gerald S. Bloomfield
Journal: Journal of the American College of Cardiology (2015)
Neuro-Oncology: Past Milestones and the Journey Ahead
Authors: W. K. Alfred Yung
Journal: Neuro-Oncology (2013)

As the journal enters this new era, I find myself reflecting on the milestones it has already reached.The journal has experienced impressive growth and success during its relatively short history, much of which is due to the ambitious vision with which it was founded and the support of numerous individuals and professional societies that are committed to the science and practice of neuro-oncology.
Human African trypanosomiasis in travellers to Kenya
Authors: F Gobbi, Z Bisoffi
Journal: Eurosurveillance (2012)

Preview this article: Human African trypanosomiasis in travellers to Kenya, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/17/10/art20109-en-1.gif
Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection.
Authors: C Van Kooten, J G Boonstra, M E Paape, F Fossiez, J Banchereau, S Lebecque, J A Bruijn, J W De Fijter, L A Van Es, M R Daha
Journal: Journal of the American Society of Nephrology (1998)

Local production of cytokines plays a critical role in the regulation of pathophysiologic processes leading to rejection of transplanted organs. In the present study, the possible role of interleukin-17 (IL-17), a recently identified cytokine with unique properties, was investigated. IL-17 is specifically produced by activated T cells, whereas biological activities are restricted to the activation of nonhematopoietic cells. In vitro, IL-17 induced primary human proximal tubular epithelial cells, a type of cell regulating local interstitial inflammatory responses, to secrete higher levels of IL-6, IL-8, and monocyte chemoattractant protein-1, but not of the chemokine RANTES. The effect was specific for IL-17, because it was completely abrogated by a neutralizing anti-IL-17 antibody and was demonstrated to be dose- and time-dependent. In addition, IL-17 increased the production of complement component C3 by human proximal tubular epithelial cells, but not of other complement components. Immunofluorescence showed expression of IL-17 in kidney biopsies from patients suffering from graft rejection (8 of 8 positive), whereas pretransplant biopsies and normal kidneys were negative (0 of 6). Analysis of whole kidney isolates confirmed the presence of IL-17 mRNA by reverse transcription-PCR. IL-17 expression could also be found in in vitro cultured and activated graft-infiltrating T cells. These results represent the first demonstration of IL-17 protein expression in pathologic conditions and suggest that IL-17 might be important in the regulation of local inflammatory responses.
Hypomagnesemia and the Risk of New-Onset Diabetes Mellitus after Kidney Transplantation
Authors: Johnny W. Huang, Olusegun Famure, Yanhong Li, S. Joseph Kim
Journal: Journal of the American Society of Nephrology (2015)

Several studies suggest a link between post-transplant hypomagnesemia and new-onset diabetes after transplantation (NODAT), but this relationship remains controversial. We conducted a retrospective cohort study of 948 nondiabetic kidney transplant recipients from January 1, 2000, to December 31, 2011, to examine the association between serum magnesium level and NODAT. Multivariable Cox proportional hazards models were fitted to evaluate the risk of NODAT as a function of baseline (at 1 month), time-varying (every 3 months), and rolling-average (i.e., mean for 3 months moving at 3-month intervals) serum magnesium levels while adjusting for potential confounders. A total of 182 NODAT events were observed over 2951.2 person-years of follow-up. Multivariable models showed an inverse relationship between baseline serum magnesium level and NODAT (hazard ratio [HR], 1.24 per 0.1 mmol/L decrease; 95% confidence interval [95% CI], 1.05 to 1.46; P=0.01). The association with the risk of NODAT persisted in conventional time-varying (HR, 1.32; 95% CI, 1.14 to 1.52; P<0.001) and rolling-average models (HR, 1.34; 95% CI, 1.13 to 1.57; P=0.001). Hypomagnesemia (serum magnesium <0.74 mmol/L) also significantly associated with increased risk of NODAT in baseline (HR, 1.58; 95% CI, 1.07 to 2.34; P=0.02), time-varying (HR, 1.78; 95% CI, 1.29 to 2.45; P<0.001), and rolling-average models (HR, 1.83; 95% CI, 1.30 to 2.57; P=0.001). Our results suggest that lower post-transplant serum magnesium level is an independent risk factor for NODAT in kidney transplant recipients. Interventions targeting serum magnesium to reduce the risk of NODAT should be evaluated.