tbuckley/cabot-search huggingface dataset:
Safety of trastuzumab emtansine (T-DM1) in HER2-positive advanced breast cancer (BC) patients (pts): Primary results from KAMILLA study cohort 1.
Authors: Carlos H. Barrios, Rachel Wuerstlein, Antonio Anton, Suzette Delaloge, Filippo Montemurro, Jacques Bonneterre, Nathalie Quenel-Tueux, Sabine C. Linn, Peter Button, Nicolas Lindegger, Paul Anthony Ellis
Journal: Journal of Clinical Oncology (2017)

1033 Background: KAMILLA is a single-arm, open-label, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC from 278 sites in 40 countries. We report the primary analysis of the first study cohort (N = 2003). Methods: Pts with HER2-positive, locally advanced or metastatic BC (locally confirmed) with progression after prior treatment with chemotherapy and a HER2-directed agent for metastatic BC or within 6 mo of completing adjuvant therapy were enrolled. Pts received T-DM1 3.6 mg/kg every 3 wks until unacceptable toxicity, withdrawal, or disease progression. The primary outcome was safety. Results: A total of 2002 pts were treated (median age 55 yrs, range, 26–88). Most pts had a baseline ECOG score of 0 (n = 1110, 55.4%) or 1 (n = 775, 38.7%), and 1232 (61.5%) had ER and/or PR positive tumors. Median time since initial BC diagnosis was 5 yrs (range, 0–53). Most pts had received ≥2 prior lines of therapy (0–1 prior lines: 29.7%; ≥2: 66.0%); 1855 (92.8%) received prior targeted therapy in the locally advanced/metastatic setting. Median T-DM1 exposure was 5.6 mo (range, 0–46). Adverse events (AEs) were reported in 93.0% (n = 1862). Serious AEs occurred in 21.3% (n = 427), most commonly vomiting (17, 0.8%), pneumonia (16, 0.8%), anemia (13, 0.6%), and pyrexia (13, 0.6%). Grade ≥3 AEs occurred in 40.8% (n = 816), most commonly anemia (60, 3.0%), thrombocytopenia (55, 2.7%), and fatigue (50, 2.5%). Additional AEs of grade ≥3 (multiple individual items grouped) were thrombocytopenia/platelet count decrease (74, 3.7%), hepatic disorders (139, 6.9%), and hemorrhage (46, 2.3%). Grade 5 AEs occurred in 2.2% (n = 45). Treatment discontinuation was most often due to disease progression (1495, 78.1%). Median progression-free survival was 8.3 (95% CI: 8.0–9.7), 6.5 (5.6–8.0), 5.9 (5.6–8.1), 5.6 (5.0–5.9), and 5.6 (5.4–6.6) mo in pts with 0–1, 2, 3, 4, and 5+ prior lines of therapy. Median overall survival was 27.2 mo (95% CI: 25.5–28.7). Conclusions: KAMILLA isthe largest (to date) cohort of T-DM1 treated pts and these data are consistent with safety and efficacy seen in prior randomized studies, thereby supporting T-DM1 as therapy for previously treated HER2-positive advanced BC pts. Clinical trial information: NCT01702571.
Genomic analyses in cotton identify signatures of selection and loci associated with fiber quality and yield traits
Authors: Lei Fang, Qiong Wang, Yan Hu, Yinhua Jia, Jiedan Chen, Bingliang Liu, Zhiyuan Zhang, Xueying Guan, Shuqi Chen, Baoliang Zhou, Gaofu Mei, Junling Sun, Zhaoe Pan, Shoupu He, Songhua Xiao, Weijun Shi, Wenfang Gong, Jianguang Liu, Jun Ma, Caiping Cai, Xiefei Zhu, Wangzhen Guo, Xiongming Du, Tianzhen Zhang
Journal: Nature Genetics (2017)
Comparative Analysis of Tumor Cell Dissemination to the Sentinel Lymph Nodes and to the Bone Marrow in Patients With Nonmetastasized Colon Cancer
Authors: Benjamin Weixler, Carsten T. Viehl, Rene Warschkow, Ulrich Guller, Michaela Ramser, Guido Sauter, Markus Zuber
Journal: JAMA Surgery (2017)

<h3>Importance</h3> Small nodal tumor infiltrates (SNTI; isolated tumor cells and micrometastases) in sentinel lymph nodes and bone marrow micrometastases (BMM) were independently described as prognostic factors in patients with colon cancer. <h3>Objective</h3> To examine the association between the occurrence of SNTI and BMM as well as their prognostic relevance. <h3>Design, Setting, and Participants</h3> This prospective study was conducted at 3 university-affiliated institutions in Switzerland between May 2000 and December 2006. Statistical analyses were performed in October 2016. A total of 122 patients with stage I to III colon cancer were included. Follow-up time exceeded 6 years, with no patients lost to follow-up. <h3>Interventions</h3> Bone marrow aspiration from the iliac crests and in vivo sentinel lymph node mapping were performed during open standard oncological resection. Bone marrow aspirates were stained with the pancytokeratin marker A45-B/B3. All sentinel lymph nodes underwent multilevel sectioning and were stained with hematoxylin-eosin and the pancytokeratin marker AE1/AE3. <h3>Main Outcomes and Measures</h3> Association of SNTI in sentinel lymph nodes and BMM in patients with stage I to III colon cancer and the prognostic effect on disease-free survival (DFS) and overall survival (OS). <h3>Results</h3> Of the 122 patients, 63 (51.6%) were female, with a mean (SD) age of 71.2 (11.7) years. Small nodal tumor infiltrates and BMM were found in a total of 21 patients (17.2%) and 46 patients (37.7%), respectively. The occurrence of BMM was not associated with the presence of SNTI by standard correlation (κ, −0.07; 95% CI, −0.29 to 0.14;<i>P</i> = .49) nor by univariate logistic regression analysis (odds ratio, 0.64; 95% CI, 0.22-1.67;<i>P</i> = .37) or multivariate logistic regression analysis (odds ratio, 1.09; 95% CI, 0.34-3.28;<i>P</i> = .88). The presence of SNTI was an independent negative prognostic factor for DFS (hazard ratio [HR], 2.93; 95% CI, 1.24-6.93;<i>P</i> = .02) and OS (HR, 4.04; 95% CI, 1.56-10.45;<i>P</i> = .005), as was BMM (HR, 2.07; 95% CI, 1.06-4.06;<i>P</i> = .04; and HR, 2.68; 95% CI, 1.26-5.70;<i>P</i> = .01; respectively). The combined detection of BMM and SNTI demonstrated the poorest DFS (HR, 6.73; 95% CI, 2.29-19.76;<i>P</i> = .006) and OS (HR, 5.96; 95% CI, 1.66-21.49;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> This study demonstrates no association between the occurrence of SNTI and BMM in patients with stage I to III colon cancer. However, both SNTI and BMM are independent negative prognostic factors regarding DFS and OS, and the occurrence of both is associated with significantly worse prognosis compared with either one of them. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00826579
Phase 1/2, multicenter, non-randomized, open-label, multiple-dose first-in-human study of U3-1402 (anti-HER3 antibody drug conjugate) in subjects with HER3-positive metastatic breast cancer.
Authors: Takahiro Kogawa, Kan Yonemori, Yoichi Naito, Emi Noguchi, Chikako Shimizu, Kenji Tamura, Ako Hosono, Nobuaki Matsubara, Masahiro Sugihara, Hayao Ogawa, Shuji Majima, Channing Yu, Suguru Ueno, Toshimi Takano
Journal: Journal of Clinical Oncology (2017)

TPS1116 Background: There is a need for effective late-line treatments in metastatic breast cancer. HER3 overexpression in breast cancer is associated with poor prognosis, but there is as yet no approved targeted treatment against HER3. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a fully humanized anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1. Methods: This is a Phase 1/2, multicenter, non-randomized, open-label, multiple-dose, first-in-human study in subjects with HER3-positive metastatic breast cancer. The study consists of 3 parts: Dose Escalation, Dose Finding, and Phase 2. In Dose Escalation, safety and tolerability of U3-1402 are evaluated and the maximum tolerated dose is determined using the modified continuous reassessment method with escalation with overdose control. In Dose Finding, the recommended phase 2 dose (RP2D) of U3-1402 is determined using continued assessment of safety and efficacy as well as pharmacokinetic data of U3-1402. Efficacy and safety of the RP2D are further evaluated in Phase 2 part. Patients with locally advanced or metastatic breast cancer who have disease refractory to standard treatment, who cannot tolerate standard treatment, or for whom no standard treatment is available, will be enrolled. Key inclusion criteria include HER3-positive tumor, ECOG performance status 0–1, and measurable disease based on RECIST version 1.1. HER3 expression in tumor tissue will be evaluated with immunohistochemistry at a central laboratory. Prior chemotherapy regimens are restricted to 6 or fewer in Dose Finding and Phase 2, but not in Dose Escalation. Patients will receive U3-1402 intravenously every 3 weeks until unacceptable toxicity or disease progression. Enrollment of an estimated 80 patients is ongoing. Clinical trial information: 02980341.
Biosimilars—Curb Your Enthusiasm
Authors: Y. Tony Yang, Brian Chen, Charles L. Bennett
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
TLR-3/9 Agonists Synergize with Anti-ErbB2 mAb—Letter
Authors: Anna H. Turaj, Lekh N. Dahal, Stephen A. Beers, Mark S. Cragg, Sean H. Lim
Journal: Cancer Research (2017)

Charlebois and colleagues recently reported that the antitumor activity of anti-ErbB2 mAb is enhanced by local polyI:C and CpG administration in murine breast tumor models (1) and concluded that this activity was dependent on IFNs, CD8+ T, and natural killer (NK) cells. The requirement for NK cells was based on in vivo depletion using anti-asialo-GM1 (ASGM1) Ab.ASGM1 is a glycolipid highly expressed on the surface of mouse NK cells, but also expressed on T cells, NKT cells, eosinophils, basophils, and macrophages (2). Treatment with anti-ASGM1 Ab reduces NK-cell cytolytic ability in vitro, and in vivo, results in NK depletion by an unexplained mechanism (3). Anti-ASGM1 is available as polyimmunoglobulin (pIg) or IgG preparations. Most published studies, including Charlebois and colleagues' work, use the pIg. Our studies show that anti-ASGM1 pIg binds to macrophages at a higher level than anti-ASGM1 IgG (Fig. 1A and B) and that the IgG preparation is more efficient at depleting NK cells (Fig. 1C and D). When mice were treated with 50, 25, or 10 μL anti-ASGM1 on day 1, 10 μL of anti-ASGM1 IgG was as efficacious as 50 μL of pIg in depleting peripheral and splenic NK cells. Despite anti-ASGM1 binding to myeloid cells, we did not observe any significant changes in the number of these cells (Fig. 1E). Next, we examined the effects of anti-ASGM1 on macrophage function. Anti-ASGM1 pIG, but not IgG (at 10 μg/mL or a supersaturating level of 100 μg/mL), impaired macrophage-mediated phagocytosis of anti-CD20 (4)–opsonized human CD20–transgenic B cells in vitro (Fig. 2A and B). This effect was absent with deglycosylated anti-ASGM1 pIG, indicating that FcγR-dependent effector function was impaired. In vivo, anti-ASGM1 pIg reduced anti-CD20–mediated B-cell depletion to 60% in some mice (Fig. 2C). In contrast, the IgG preparation induced a less profound effect, especially at 10 μL, reducing depletion by only 10% at 48 hours.In summary, we demonstrate that the anti-ASGM1 Ab used by Charlebois and colleagues can disrupt macrophage function. Although we do not dispute that NK cells might have a role in the described antitumor activity, our data suggest that the authors may have inadvertently excluded the contribution of macrophages, which can be affected by pIg anti-ASGM1 and which are known to be critical mediators of mAb function (5). Therefore, we highlight an important caveat of using the pIg preparation of anti-ASGM1 to deplete NK cells and recommend the use of a pure IgG preparation.No potential conflicts of interest were disclosed.This work was supported by a Cancer Research U.K. Clinician Scientist Fellowship (C30010/A15269 to S.H. Lim) and a Bloodwise grant (12050 to M.S. Cragg).
The Students As LifeStyle Activists (SALSA) program
Authors: Smita Shah, Bridget C Foley, Inara Molinari, Kean-Seng Lim, Vanessa A Shrewsbury
Journal: British Journal of Sports Medicine (2017)

Adolescence is a critical time for developing healthy lifestyle behaviours. It is a period where young people assume a greater responsibility for their physical activity and eating habits, which often persist into adulthood.1 Schools are an ideal setting for promoting health, as most adolescents attend school and can be easily reached. There is also strong evidence demonstrating that school-based programmes can increase physical activity and improve dietary habits of students.2 3 

The Students As LifeStyle Activists (SALSA) programme uses a peer educational model, driven by students, to promote physical activity and healthy eating in a supportive school environment.4 Our premise is that students not only learn through teaching their peers, but they also serve as powerful motivators and role models for others.5 Adolescents can also be effective ‘change agents’ within their family and the wider school community.

The SALSA programme is underpinned by social cognitive theory and the empowerment education approach and aligns with the WHO’s health promoting schools framework.4 6 

Our unique peer education model involving university and high school students as learners and educators is demonstrated in this brief animation: http://tinyurl.com/SALSAprogram-model. In summary, volunteer university students from health/education faculties, who …
Lithium Use in Pregnancy and the Risk of Cardiac Malformations
Authors: Elisabetta Patorno, Krista F. Huybrechts, Brian T. Bateman, Jacqueline M. Cohen, Rishi J. Desai, Helen Mogun, Lee S. Cohen, Sonia Hernandez-Diaz
Journal: New England Journal of Medicine (2017)

There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein's anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited.
Here Comes Trouble
Authors: Stanton A. Glantz, John D. Rutherford
Journal: Circulation (2017)

Dr Glantz is Professor of Medicine in the Division of Cardiology, the Truth Initiative Distinguished Professor of Tobacco Control, and Director of the Center for Tobacco Control Research and Education at the University of California, San Francisco School of Medicine. He obtained a BSc in aerospace engineering from the University of Cincinnati in 1969 and an MSc and PhD in applied mechanics from Stanford University. He is the author of 4 books, including
Loss of Smooth Muscle α-Actin Leads to NF-κB–Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement
Authors: Jiyuan Chen, Andrew Peters, Christina L. Papke, Carlos Villamizar, Lea-Jeanne Ringuette, Jiumei Cao, Shanzhi Wang, Shuangtao Ma, Limin Gong, Katerina L. Byanova, Jian Xiong, Michael X. Zhu, Rosalinda Madonna, Patrick Kee, Yong-Jian Geng, Allan R. Brasier, Elaine C. Davis, Siddharth Prakash, Callie S. Kwartler, Dianna M. Milewicz
Journal: Circulation Research (2017)

Rationale: Mutations in ACTA2 , encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: Acta2 −/− mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2 −/− aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2 −/− aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. Conclusions: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.
Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial
Authors: Anne Katrine Pagsberg, Pia Jeppesen, Dea Gowers Klauber, Karsten Gjessing Jensen, Ditte Rudå, Marie Stentebjerg-Olesen, Peter Jantzen, Simone Rasmussen, Eva Ann-Sofie Saldeen, Maj-Britt Glenn Lauritsen, Niels Bilenberg, Anne Dorte Stenstrøm, Louise Nyvang, Sarah Madsen, Thomas M Werge, Theis Lange, Christian Gluud, Maria Skoog, Per Winkel, Jens Richardt M Jepsen, Birgitte Fagerlund, Christoph U Correll, Anders Fink-Jensen
Journal: The Lancet Psychiatry (2017)
Early stage “T2N0” breast cancer: Does it consist two different “T2” stages?
Authors: Cagatay Arslan, Ugur Sahin, Cemal Kizilarslanoglu, Mustafa Solak, Ibrahim Halil Gullu, Yavuz Ozisik, Kadri Altundag
Journal: Journal of Clinical Oncology (2013)

e11595 Background: Lymph node negative stage IIA early breast cancer (BC) patients (pts) according to TNM classification consists T2N0 tumors reprsenting a wide range of size (&gt;2-5 cm). We aimed to compare clinicopathological features and prognosis of T2N0 stage pts with tumor size larger vs smaller than 4 cm. Methods: Data of 2200 BC pts followed between years 1998 and 2012 at our institute were analysed, retrospectively. pT2N0 stage BC pts (T:2 to 4,9 cm) were divided into 2 subgroups as 2 to 3,9 cm (T2a) and 4 to 4,9 cm (T2b). Clinicopathological features and survival analyses were evaluated. Results: There were 268 (80%) T2a and 65 (20%) T2b pts among T2N0 (n=333) population. All but 2 pts in T2a (99%) and all pts in T2b subgroups were female. Mean age of diagnosis was 50.8±11 and 46.2±10.1 years in T2a and T2b subgroups, respectively (p= 0.003). Number of premenopausal pts were higher in T2b (n=39, 60%) compared to T2a (n=100, 37%) subgroup (p= 0.003). There were no differences in histopathological subtypes, tumor grade, ER, PR, HER-2 status, adjuvant radiotherapy and chemotherapy regimens, -cycle numbers, endocrine, and trastuzumab treatments between T2a and T2b subgroups. Higher number of pts in T2a subgroup was treated with breast conserving surgery [110 (%41.2) vs 11 (%16.9)] and higher number of pts in T2b subgroup were treated with mastectomy [T2a= 158 (%58.8) vs T2b= 54 (%83.1)]. Disease recurrence was seen in 25 pts in T2a and 13 pts in T2b subgroups. Median progression free survival (PFS) could not be reached in T2a subgroup. Median PFS was 96.5 (min – max: 66 – 127) months in T2b subgroup (p= 0.02). There were no differences in PFS and number of events between goups when all pts analysed according to menopausal status and surgical treatment type. Overall survival data could not be analyzed due to small number of events (5 pts in T2a and 1 patient in T2b subgroups were died). Conclusions: T2N0 subgroup of stage IIA BC consists a wide range of tumor size between &gt;2 to 4.9 cm. Pts with T2b (≥4 cm) tumors had shown worse prognosis compared to patients with T2a (&lt;4cm) tumors and might be treated with more agressive adjuvant chemotherapy. This finding might be helpful for treatment decisions but must be evaluated in studies with larger number of pts.
Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism
Authors: Masataka YOKOYAMA, Yoshio KOBAYASHI, Tohru MINAMINO
Journal: Circulation Research (2013)

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.