tbuckley/cabot-search huggingface dataset:
Prognostic factors of <i>KIT</i>-negative GIST-like patients (KNGL): A Spanish Group for Sarcoma Research (GEIS) study.
Authors: J. Martin Broto, X. Garcia del Muro, J. Rubio, A. Gutierrez, J. Martinez-Trufero, I. Sevilla, N. Lainez, R. Andres, R. Ramos, J. A. Lopez-Guerrero
Journal: Journal of Clinical Oncology (2010)

10070 Background: Few studies have been published around KNGL patients mainly due to the rarity of such cases. We analyzed prognostic factors for relapse free survival (RFS) and overall survival (OS) in a series of 28 cases of KNGL tumors. This subset resulted from clinical, mutational and pathological review (paraffin block) of 624 presumptive GIST. Methods: We studied the relative risk for recurrence and death for the various prognostic factors using the Log-rank test. The factors assessed were: age, tumor location, size, mitoses per 50 HPF, cellularity and mutation profile. Results: The male and female rate was 16/17 and the median age was 62 years (25-74). All 28 localized cases underwent complete resection and, with a median follow-up of 92 months, 10 relapses were recorded. The morphology was epitheliod (53%), spindle (18%), mixed (14,5%) and categorized as pleomorphic 14.5%. The median size was 5 cm (0.5-20) and the locations were stomach (16), small-bowel (10), rectum (3), colon (1) and omentum (2). Mutations were found in 12 out of 23 localized cases (52%) for which a sufficient DNA material was available. The position of mutations was: exon 11 (5); exon 13 (2) and exon 17 (1) within KIT gene and exon 12(1) and exon 18 (3) of PDGFR gene. Median RFS and OS at 7 years were 63% and 73% respectively. Considering RFS at 7 years, the univariate analyses showed that only mitotic rate (0-10 mit/50hpf: 74% vs > 10 mit/50hpf: 44%; p:0.13) and location (gastric: 77% vs other 45%; p:0.05) showed a clear trend to signification. Regarding OS, only age raised statistical signification (0-60 y: 92% vs >60 y: 50%; p= 0.016). Conclusions: In spite of the relatively low statistical power of this series, we find some differences between KNGL and kit+ GIST patients such as the absolute lack of prognostic relevance of size. We are analyzing mRNA of some genes of this series in order to achieve a better characterization of these patients, specially the wild-type cases. No significant financial relationships to disclose.
Changes in bone mineral density during 5 years of adjuvant exemestane therapy in postmenopausal women with early breast cancer.
Authors: Akira Hirano, Hiroaki Inoue, Kaoru Ogura, Akinori Hattori, Hiroko Yukawa, Shiho Sakaguchi, Aya Matsuoka, Mari Kamimura, Jun Kinoshita, Yoshihiko Naritaka, Tadao Shimizu
Journal: Journal of Clinical Oncology (2016)

e12003 Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. The effect of 5 years of treatment with anastrozole on bone mineral density (BMD) was previously reported (Eastell R. J Clin Oncol 26:1051-1058, 2008). However, the effect of long-term (more than 2 years) therapy with exemestane (EXE) on BMD is still unknown. We assessed changes in BMD from baseline to 5 years of treatment in patients receiving EXE as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine-responsive breast cancer receiving EXE as adjuvant therapy at our hospital since 2005 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48, and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed with osteoporosis with a T-score of 2.5 or lower. Observation was censored when treatment of EXE was stopped because of relapse or other diseases. Results: Eighty-one patients were enrolled in the study between 2005 and 2010. Patients’ median age was 67 years, and the median follow-up period was 60 months. Forty-two patients were administered Bis (upfront use of Bis: 28 patients; delayed use of Bis: 14 patients). Within 6 months of hormone therapy, BMD increased by 2.4% from baseline in the lumbar spine and decreased by 0.5% in the femoral neck. After 5 years of treatment, however, BMD had increased by 7.8% in the lumbar spine and by 3.4% in the femoral neck. In patients treated with upfront Bis (n = 28), a 5.7% increase in BMD from baseline was noted in the lumbar spine, whereas in those without Bis (n = 39), BMD decreased by 1.8% from baseline within 12 months (P < 0.0001). Fractures were observed in 10 patients (12.3%), and 8 (9.9%) had fragility-related fractures. Conclusions: Oral Bis improves BMD in the lumbar spine among patients with osteoporosis. Treatment with EXE for 5 years with proper use of Bis maintains BMD in the lumbar spine and femoral neck. Clinical trial information: UMIN000020499.
Thymic Stromal Chemokine TSLP Acts through Th2 Cytokine Production to Induce Cutaneous T-cell Lymphoma
Authors: Naomi Takahashi, Makoto Sugaya, Hiraku Suga, Tomonori Oka, Makiko Kawaguchi, Tomomitsu Miyagaki, Hideki Fujita, Shinichi Sato
Journal: Cancer Research (2016)

Thymic stromal lymphopoietin (TSLP) activates dendritic cells to induce Th2-mediated inflammation. Periostin, an extracellular matrix protein produced by fibroblasts, induces chronic inflammation by stimulating TSLP production. Recently, a reinforcing cycle linking Th2-type immune responses with periostin-induced keratinocyte activation has been proposed in atopic dermatitis pathogenesis. In this study, we investigated the role of TSLP and periostin in the development of cutaneous T-cell lymphoma (CTCL), where Th2 cytokines and chemokines are also dominant. TSLP and periostin mRNA expression levels were elevated in CTCL lesional skin, both of which correlated with IL4 expression levels. In vitro and ex vivo, IL4 or IL13 stimulated periostin expression by dermal fibroblasts, and fibroblasts from CTCL lesional skin expressed higher levels of periostin than those from control skin. Serum periostin levels of CTCL patients were also significantly higher than those of healthy individuals. Hut78 and MJ, CTCL cell lines, and peripheral blood mononuclear cells from leukemic CTCL patients expressed the TSLP receptor. TSLP induced production of IL4 and IL13 by Hut78 and MJ cells through the activation of STAT5. Moreover, TSLP induced proliferation of CTCL cells both in vitro and in vivo These data suggest that periostin-mediated TSLP production by keratinocytes directly stimulates CTCL tumor cell growth in addition to inducing a Th2-dominant tumor environment in CTCL. Cancer Res; 76(21); 6241-52. ©2016 AACR.
Final analysis of WSG-ADAPT HER2+/HR- trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant dual blockade with trastuzumab + pertuzumab ± weekly paclitaxel in HER2+/HR- early breast cancer (EBC).
Authors: Ulrike Nitz, Oleg Gluz, Matthias Christgen, Eva-Maria Grischke, Doris Augustin, Sherko Kümmel, Michael Wilhelm Braun, Jochem Potenberg, Andreas Kohls, Katja Krauss, Andrea Stefek, Claudia Schumacher, Helmut Forstbauer, Toralf Reimer, Hans Holger Fischer, Cornelia Liedtke, Rachel Wuerstlein, Hans Heinrich Kreipe, Nadia Harbeck
Journal: Journal of Clinical Oncology (2016)

518 Background: In HER2+ EBC pCR rates after neoadjuvant chemo (CT)+/- anti-HER2 therapy differ according to hormone receptor (HR) status. The neoadjuvant ADAPT HER2+/HR- phase II trial aims to identify early responders (at 3 weeks) and evaluates the impact of additional paclitaxel (Pac) on pCR in patients receiving dual anti-HER2 blockade with trastuzumab + pertuzumab (T+P). Methods: 134 HER2+/HR-, cT1-4c, cN0/+ patients were randomized (2.5:1) to 12 weeks of neoadjuvant T+P ± weekly Pac (2/14-12/15). After surgery, standard therapy (CT+T) was recommended. Trial (planned n=220) tests non-inferiority of pCR (ypT0/is, ypN0) in T+P responders vs. T+P+Pac. Biomarkers are measured in baseline and 3-week biopsies. At the pre-planned interim analysis (IA), DSMB recommended 2ndIA (n=120) for validation of trial assumptions and re-evaluation of responder definition (Ki-67 drop > 30% or low cellularity). Results: Of the IA cohort 82 patients were evaluable for T+P and 38 for T+P+Pac. Baseline characteristics (T+P/T+P+Pac): median age: 54/51.5; cT2: 51/53%, cT3/4: 8.5/ 2.6%, cN+ 48 /39%. pCR rate was 36.3% with T+P and 89.2% with T+P+Pac (n=3 missing values). Second biopsy was not available in 28% (T+P) vs. 46% (T+P+Pac). 3 weeks early response defined as low cellularity (<500 tumor cells) and/or Ki-67 drop > 30% was observed in 50% (T+P) vs. 51.4% (T+P+Pac). With T+P pCR was achieved in 38.5% of responders vs. in 11.8% of non- reponders (n.s.). So far, only 10 SAEs have been reported (total of n=5 in both arms). The DSMB recommended premature study closure due to a clear superiority of the Pac-containing arm and a <1% probability for demonstrating non-inferiority with the preplanned sample size. Complete efficacy /safety data for all 134 patients will be presented at the meeting. Conclusions: For the first time, WSG ADAPT focused on HR- HER2+ eBC in a phase II trial. pCR rate is substantial (89.2%) with T+P+Pac and clearly higher than with P+T (all: 36.3%; responders: 38.5%). Early response at 3 weeks seems to be positively correlated with pCR. Further biomarker analysis will help to further characterize this population. Clinical trial information: 2011-001462-17.
The childhood obesity strategy
Authors: Cécile Knai, Mark Petticrew, Nicholas Mays
Journal: BMJ (2016)

Disappointment all round

The UK government’s policy document Childhood Obesity: A Plan for Action presents itself as “the start of a conversation rather than the final word.”1 This will be a relief to many given the criticism it has received for its lack of ambition, including from food retailers and manufacturers.2 3 4 5

The strategy, published on 18 August, includes the previously announced industry levy on soft drinks, which will require companies to pay a charge for drinks with added sugar and total sugar content ≥5 g/100 mL, and a higher charge for the drinks that contain ≥8 g/100 mL. Voluntary reformulation of selected products to remove 20% of sugar and a voluntary healthy rating scheme for primary schools, in which schools will be encouraged to show what progress they are making towards tackling obesity, are also included, along with support for the voluntary food guidelines in early years settings.

The strategy also encourages compliance with the existing school food standards, which aim to ensure that …
Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants
Authors: Peter F Wright, Ruth I Connor, Wendy F Wieland-Alter, Anne G Hoen, Austin W Boesch, Margaret E Ackerman, M Steven Oberste, Chris Gast, Elizabeth B Brickley, Edwin J Asturias, Ricardo Rüttimann, Ananda S Bandyopadhyay
Journal: The Lancet Infectious Diseases (2016)

Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools.In the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest-the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV-IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants.210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0·0001) and 53 of 87 infants receiving bOPV-IPV (p<0·0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0·0001) and mucosal type 2 neutralisation at challenge (p<0·0001).Mucosal type-2-specific antibodies can be measured in stool and develop in response to receipt of OPV type 2 either in the primary vaccine series or at challenge. These mucosal antibodies influence the amount of virus that is shed in an established infection.Bill & Melinda Gates Foundation.
Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial
Authors: Xian Su, Zhao-Ting Meng, Xin-Hai Wu, Fan Cui, Hong-Liang Li, Dong-Xin Wang, Xi Zhu, Sai-Nan Zhu, Mervyn Maze, Daqing Ma
Journal: The Lancet (2016)
Causes of Neonatal Mortality
Authors: J. L. Capps, E. Delzell, C. C. Bourguet, S. Grufferman
Journal: JAMA (1984)

<h3>To the Editor.—</h3> A recent study by Goldenberg and co-workers<sup>1</sup>found that among infants born in Alabama with a birth weight of at least 2,500 g, 43% of neonatal mortality is caused by lethal congenital malformations. In a subsequent letter, Bader<sup>2</sup>noted a similar percentage of 54% in Oregon. Goldenberg et al suggested that this relatively high proportion of neonatal deaths from presumably untreatable malformations indicates a need for greater emphasis on the prevention of birth defects. They also concluded that the lower proportion (12% ) of neonatal deaths from congenital malformations among infants with low birth weights (&lt;2,500 g) underscores the need for improvement in the medical care of this group. Neither Goldenberg nor Bader explored possible variation by race and maternal age in the rates and proportions of neonatal deaths caused by congenital malformations. To investigate such differences, we used the computerizedrecords of births and infant
Case 24-1962
Authors: Hugo W. Moser
Journal: New England Journal of Medicine (1962)

Presentation of CaseA sixty-one-year-old woman was admitted to the hospital because of headache.A right radical mastectomy was performed six months previously; pathological examination revealed adenocarcinoma with metastases in three axillary lymph nodes. Although the postoperative course was uneventful, the patient stated that she never seemed fully recovered. One month after the operation shortness of breath on exertion developed; the symptoms were unpredictable, inconstant and subjective. She also began to experience episodes of breathlessness at night that were more suggestive of panic than of paroxysmal dyspnea. Concurrently, she complained of frequent, severe, throbbing occipital headaches, with radiation behind the . . .
Diapers and Day Care
Authors: Janet Primomo
Journal: JAMA (1991)

<h3>To the Editor.</h3> —Since 1987, the Seattle-King County Nurses Association's Diaper Decision Group has followed issues related to diapering methods and has attempted to raise awareness about diapering choices. We are a nonprofit association with no financial ties to either the cloth or disposable diaper industries. From our work, a number of issues can be raised about the article by Van et al.<sup>1</sup>Although no financial support or affiliations were disclosed, Dr Pickering appeared in a 1990 Procter &amp; Gamble videotape about reducing illness in child-care settings. Readers should be cautioned that the results of the study are applicable only to disposable diapers with absorbent gelling material and cannot be generalized to all types of disposable diapers. The use of the term<i>paper</i>diapers was misleading. Paper diapers are composed of 65% wood-pulp fibers, yet the remaining nonbiodegradable materials include polyethylene plastic, tape, and superabsorbing crystals. It is possible
CCR7 As a New Biomarker in Graft-Versus-Host Disease: T Cells Expressing the Homing Receptor CCR7 Mediate the Pathogenesis of Gvhd
Authors: Itxaso Portero, Valle Gomez, Carlos Arandojo, Anna Kreutzman, Mercedes Royg, Ana Ramirez, Ana Marcos, Rafael De La Camara, Cecilia Muñoz
Journal: Blood (2014)
Two-Year Renal Hemodynamic Effects of Deferasirox in Patients with Transfusion-Dependent β-Thalassemia
Authors: Antonio Piga, Silvia Fracchia, Maria Eliana Lai, M Domenica Cappellini, Dany Habr, Antje Wegener, Emmanuel Bouillaud, Gian Luca Forni
Journal: Blood (2012)
Use and Effectiveness of Neoadjuvant Chemotherapy for Treatment of Ovarian Cancer
Authors: Larissa A. Meyer, Angel M. Cronin, Charlotte C. Sun, Kristin Bixel, Michael A. Bookman, Mihaela C. Cristea, Jennifer J. Griggs, Charles F. Levenback, Robert A. Burger, Gina Mantia-Smaldone, Ursula A. Matulonis, Joyce C. Niland, David M. O’Malley, Alexi A. Wright
Journal: Journal of Clinical Oncology (2016)

Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute–designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease ( P trend &lt; .001), and from 41% to 62% in stage IV disease ( P trend &lt; .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P &lt; .001) and from 27% to 61% ( P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have ≥ 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P ≤ .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or ≤ 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients.
Gene Expression Profiling In Leukemic Stem Cell-Enriched AML CD34+ Cell Fraction Identifies Target Genes That Predict Prognosis In Normal Karyotype AML
Authors: Carolien M Woolthuis, Hendrik JM de Jonge, Annet Z Vos, Andre B Mulder, Eva van den Berg, P.M. Kluin, Karen van der Weide, Evelina S. De Bont, Geert A Huls, Edo Vellenga, Jan J. Schuringa
Journal: Blood (2010)
Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation
Authors: Minah Kim, Breanna Allen, Emilia A. Korhonen, Maximilian Nitschké, Hee Won Yang, Peter Baluk, Pipsa Saharinen, Kari Alitalo, Christopher Daly, Gavin Thurston, Donald M. McDonald
Journal: Journal of Clinical Investigation (2016)

Angiopoietin-2 (ANG2) regulates blood vessel remodeling in many pathological conditions through differential effects on Tie2 signaling. While ANG2 competes with ANG1 to inhibit Tie2, it can paradoxically also promote Tie2 phosphorylation (p-Tie2). A related paradox is that both inactivation and overactivation of Tie2 can result in vascular remodeling. Here, we reconciled these opposing actions of ANG2 by manipulating conditions that govern its actions in the vasculature. ANG2 drove vascular remodeling during Mycoplasma pulmonis infection by acting as a Tie2 antagonist, which led to p-Tie2 suppression, forkhead box O1 (FOXO1) activation, increased ANG2 expression, and vessel leakiness. These changes were exaggerated by anti-Tie2 antibody, inhibition of PI3K signaling, or ANG2 overexpression and were reduced by anti-ANG2 antibody or exogenous ANG1. In contrast, under pathogen-free conditions, ANG2 drove vascular remodeling by acting as an agonist, promoting high p-Tie2, low FOXO1 activation, and no leakage. Tie1 activation was strong under pathogen-free conditions, but infection or TNF-α led to Tie1 inactivation by ectodomain cleavage and promoted the Tie2 antagonist action of ANG2. Together, these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels, but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop wherein FOXO1-driven ANG2 expression promotes vascular remodeling and leakage.