tbuckley/cabot-search huggingface dataset:
Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer
Authors: Alexandre Prieur, Monica Cappellini, Guillaume Habif, Marie-Paule Lefranc, Thibault Mazard, Eric Morency, Jean-Marc Pascussi, Maud Flacelière, Nathalie Cahuzac, Bérengère Vire, Benjamin Dubuc, Amandine Durochat, Pierre Liaud, Jérémy Ollier, Caroline Pfeiffer, Sophie Poupeau, Véronique Saywell, Chris Planque, Eric Assenat, Frédéric Bibeau, Jean-François Bourgaux, Pascal Pujol, Alain Sézeur, Marc Ychou, Dominique Joubert
Journal: Clinical Cancer Research (2017)

Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS-mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267-80. ©2017 AACR.
Discrepancy of pathologic complete response and outcome between breast tumor and axillary node in HER2 positive breast cancer after neoadjuvant chemotherapy.
Authors: Shin-Cheh Chen, Hsien-Kun Chang, Yung-Chang Lin, Shih Che Shen, Wen-Lin Kuo, Chi-Chang Yu, Hsu-Huan Chou, Yi-Ting Huang, Shir-Hwa Ueng
Journal: Journal of Clinical Oncology (2017)

e12503 Background: The pathologic complete response (pCR) rate in primary tumor and axillary node after different chemotherapy regimens of neoadjuvant chemotherapy (NAC) in HER2 positive breast cancer (BC) is unknown, the impact of pCR on disease free survival (DFS) and overall survival (OS) is still controversial. Methods: A cohort of 350 HER2 positive BC (296 cytologically proved axillary node metastasis) received NAC with different regimens, antracyclin with taxotere (AT), docetaxel with transtuzumab (DT) and docetaxel with transtuzumab and pertuzumab( DTP) between 2005 and 2016 in a large medical center were analyzed retrospectively. The impact of pCR rates of breast and axillary node on DFS and OS were analyzed. Results: Of 350 women with HER2 positive BC received NAC, median age was 50 years(18~93), median tumor size was 4.3 cm, the pCR rates of breast and axillary node were 16.2% and 28.7% ( P= 0.018) in patients received AT( n= 130) , 47.6% and 66.9% ( P= 0.00028 ) in patients received DT( n= 191) ,65.5% and 77.8% ( P= 0.372 ) in patients received DTP( n= 29), respectively. The 5-year DFS were 79.3% and 66.0% ( p= 0.0023), 5-year OS were 89.5% and 76.6% ( P= 0.0201) in patients with breast pCR and non-pCR, respectively. The 5-year DFS were 75.7% and 58.4% ( P= 0.00037), 5-year OS were 85.7% and 72.6% ( P= 0.0024) in axillary pCR and non-pCR patients, respectively. The 5-year DFS were 79.3% and 75.7% ( P= 0.430), and 5-year OS were 89.5% and 85.7% ( P= 0.695) in breast and axillary pCR, respectively . The 5-year DFS in breast pCR whom received targeted therapy (DT and DTP groups) was significantly better than whom not received targeted therapy (AT groups), 85.3% and 65.0% ( P= 0.039), respectively Conclusions: Higher pCR rate in axillary node than breast was found in this cohort. Either pCR in axillary node or breast was associated with improved DFS and OS, but no difference of DFS and OS between breast and axillary pCR . The 5-year DFS in breast pCR received targeted therapy were significantly better than breast pCR patients received chemotherapy alone.
DS-8201a, a HER2-targeting antibody-drug conjugate, to elicit immune responses and benefits in combination with an anti-PD-1 antibody.
Authors: Tomomi Nakayama Iwata, Chiaki Ishii, Yusuke Ogitani, Teiji Wada, Toshinori Agatsuma
Journal: Journal of Clinical Oncology (2017)

1031 Background: DS-8201a, a HER2-targeting antibody–drug conjugate (ADC), with a topoisomerase I inhibitor, exatecan drivative (DX-8951 derivative, DXd) has been shown to have antitumor effects in preclinical xenograft models and clinical trials, but the involvement of the immune system in the antitumor efficacy of DS-8201a has not been elucidated yet. Methods: The antitumor efficacy of DS-8201a individually and in combination with an anti-PD-1 antibody was determined in a syngeneic mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Mice whose tumors had been cured by DS-8201a treatment were rechallenged with CT26.WT-hHER2 cells; their splenocytes were co-cultured with CT26.WT-hHER2 or CT26.WT-mock cells, and IFN-g secretion by these cells was determined. To investigate effects of DXd and DS-8201a on dendritic cells (DCs), the expression of DC markers on bone marrow derived DCs (BMDCs) and intratumoral DCs was analyzed by flow cytometry. Furthermore, MHC class I and PD-L1 expression on tumor cells was analyzed. Results: At a weekly dosage of 10 mg/kg, DS-8201a showed significant antitumor effects in the mouse model. Mice whose tumors had been cured by DS-8201a treatment rejected the rechallenge with CT26.WT-hHER2 cells, and splenocytes from these mice were activated by both CT26.WT-hHER2 and CT26.WT-mock cells. In the mouse model, DS-8201a treatment raised a population of intratumoral DCs (CD45 + CD11c + MHC class II + ) and increased DC expression of CD86, a DC activation marker; DXd also up-regulated CD86 expression on BMDCs in vitro. Furthermore, DS-8201a up-regulated PD-L1 and MHC class I expression on tumor cells. Notably, antitumor effects of the combination of DS-8201a with an anti-PD-1 antibody were better than those of monotherapy. Conclusions: DS-8201a elicits immune responses via mechanisms other than cytotoxic effects on tumor cells. This finding suggests additional benefits of combining DS-8201a with an immune checkpoint inhibitor (ICI). The combination of DS-8201a and an anti-PD-1 antibody was effective in tumor suppression, indicating that DS-8201a may be successfully combined with an ICI in human clinical applications.
Primary surgery versus no surgery in synchronous metastastic breast cancer: Patient-reported outcomes of the ABCSG 28 Posytive trial.
Authors: Vesna Bjelic-Radisic, Florian Fitzal, Guenther G. Steger, Christian Marth, Marija Balic, Michael Knauer, Christian F. Singer, Michael Hubalek, Peter Schrenk, Anton Haid, Viktor Wette, Ursula Swoboda, Reinhold Fuegger, Richard Greil, Lidija Soelkner, Michael Gnant
Journal: Journal of Clinical Oncology (2017)

1074 Background: The ABCSG 28 Posytive trial compared primary surgery versus primary systemic therapy without surgery in synchronous metastatic breast cancer. The primary aim of the study was to investigate whether immediate resection of the primary tumor followed by standard systemic therapy improves median survival compared with no surgical resection (NCT01015625). This report describes quality-of-life (QoL) results. Methods: Patients were randomized between 2011 and 2015. Patients completed the EORTC QLQ-C30 and EORTC QLQ-BR 23 before treatment and every 6 months during follow-up. Results: 90 patients (45 with surgery, 45 with primary systemic therapy without surgery) from 15 centers were included in the QoL analysis. At 6 months patients after surgery reported more insomnia, breast symptoms and arm symptoms than patients without surgery, but these differences were no longer present at later follow-up visits. In the univariate and multivariate analysis the global health status and physical functioning scales of EORTC QLQ C30 were statistically significant predictors for OS and TTP (p &lt; 0.05). Over a 24-month follow-up, patients &gt; 60 years showed more QoL impairments than those &lt; 60 years, independent of treatment. Patients &lt; 60 years had better physical functioning and less fatigue, appetite loss, constipation and breast symptoms than older patients. There were no differences in QoL between patients with bone metastases vs those with visceral ± bone metastases. Conclusions: In patients with primary metastatic breast cancer primary surgery does not appear to improve QoL. Global health status and physical functioning scales of EORTC QLQ-C30 appears to be a predictive factor for OS and TTP. Clinical trial information: NCT01015625.
Analysis of everolimus starting dose as prognostic marker in HR+ mBC patients treated with everolimus (EVE) + exemestane (EXE): Results of the 3rd interim analysis of the non-interventional trial BRAWO.
Authors: Peter A. Fasching, Eva-Maria Grischke, Florian Schuetz, Thomas Decker, Christoph Uleer, Christoph Salat, Frank Foerster, Marcus Schmidt, Christoph Mundhenke, Hans Tesch, Christian Jackisch, Pauline Wimberger, Bahriye Aktas, Mark-Oliver Zahn, Oliver Tome, Wilhelm Bloch, Sven Hanson, Thomas Fischer, Joerg Schubert, Diana Lueftner
Journal: Journal of Clinical Oncology (2017)

1061 Background: BRAWO is a German non-interventional study, which enrolled more than 2400 patients (pts) with advanced/metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with EVE and EXE. Main objectives are a) the impact of physical activity on efficacy and quality of life, b) prophylaxis and management of stomatitis in clinical routine, and c) the sequence of therapy when EVE is used in daily clinical practice. Methods: In this update on the results of the 3rd interim analysis (data cut-off 18-Oct-2016) we analyzed under real world conditions the first 1.078 patients followed up until disease progression for their progression-free survival (PFS) events. A two-stage process based on a Cox regression model was used to check the relevance of the start dose on PFS. In the first step potentially relevant covariates defined by medical experts were evaluated for relevance. In the second step start dose and all covariates showing a p-value of at most 0.1 in first step including all two-interaction of start dose with these parameters were included into the model. Results: Our multivariate analysis support the evidence that predictive factors, such as body mass index (BMI, p-value: &lt; 0.001), therapeutic line (1st vs. 2nd+3rd vs. ≥4th; p-value: 0.013), presence of visceral metastases (p-value: &lt; 0.001) and ECOG (Eastern Cooperative Oncology Group, p-value: &lt; 0.001) status at the beginning of the therapy correlated significantly with the PFS. 283 patients started with 5mg and 795 Patients started with 10 mg. Starting dose had no significant impact on the PFS (neither as main effect nor within interactions, p-value: 0.44-0.88). Conclusions: Even though the approved and recommended starting dose for treatment with EVE is 10 mg, physicians sometimes start EVE-treatment with a lower starting dose, trying subsequently to increase the dose to the recommended dose of 10mg to allow the patient’s organism to adapt to the therapeutic. As the study was not powered to detect possible differences in PFS by starting dose, the result of showing no detrimental effect of a lower start dose may be the result of limited power. Clinical trial information: EUPAS9462.
Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα
Authors: Bo Sun, Nishant Dwivedi, Tyler J. Bechtel, Janet L. Paulsen, Aaron Muth, Mandar Bawadekar, Gang Li, Paul R. Thompson, Miriam A. Shelef, Celia A. Schiffer, Eranthie Weerapana, I-Cheng Ho
Journal: Science Immunology (2017)

Heightened citrullination promotes the expression of inflammatory cytokines in rheumatoid arthritis.
Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation
Authors: William F. Fearon, Kozo Okada, Jon A. Kobashigawa, Yuhei Kobayashi, Helen Luikart, Sean Sana, Tiffany Daun, Steven A. Chmura, Seema Sinha, Garett Cohen, Yasuhiro Honda, Michael Pham, David B. Lewis, Daniel Bernstein, Alan C. Yeung, Hannah A. Valantine, Kiran Khush
Journal: Journal of the American College of Cardiology (2017)
Efficacy of pertuzumab in combination with trastuzumab and a taxane in first-line treatment for metastatic breast cancer (MBC): A multicenter, retrospective, observational study.
Authors: Teresa Gamucci, Lucia Mentuccia, Isabella Sperduti, Alain Gelibter, Loretta D'Onofrio, Alessandra Cassano, Laura Iezzi, Andrea Botticelli, Laura Pizzuti, Luca Moscetti, Giacomo Barchiesi, Fedele Scinto, Luisa Carbognin, Maria Concetta Cursano, Jennifer Foglietta, Ernesto Rossi, Sandro Barni, Vincenzo Graziano, Emanuela Magnolfi, Patrizia Vici
Journal: Journal of Clinical Oncology (2017)

e12504 Background: Pertuzumab (P) , Trastuzumab (T) and Docetaxel (D) is standard first-line treatment in patients (pts) with HER2 + metastatic breast cancer (MBC). This multicenter retrospetive observational study was performed to evaluate the activity of P and T in combination with D or Paclitaxel (Tx) in real world HER2 + MBC pts. Methods: We identified HER2 + MBC pts treated with P, T and D or Ptx optionally followed by P, T and endocrine therapy (ET) maintenance in hormone positive (HR+) BC, in 17 Italian cancer centres between 09/2012 and 08/2016. Overall Survival (OS) and Progression Free Survival (PFS) were calculated by the Kaplan-Meier product-limit method. Log-rank test was used to assess differences between subgroups. Results: 191 pts were included in our analysis. Pts characteristics: median age 54 years (range 29-80); PS 0 in 127 (67%) pts and PS 1 in 54 (28%); 107 (56%) had visceral metastases (mts), 23 (12%) only bone mts and 28 (15%) brain mts, 130 (68%) were ER/PgR +. 76 pts (40%) were metastatic at diagnosis; 148 (78) were treated with D while 43 (22%) with Tx. The ORR was 78% (CI 95% 72-84), RC 18% and RP 60%, only 10 (5%) had PD. To date, of the 54 pts treated with ET maintenance, 26% had a further improvement of response (7 pts had RC). At median follow-up of 17 months (mo) (range 6- 52), median PFS was 20 mo (95% CI 14-26) and median OS at 2 years was 80%. No differences in PFS were found for age (p = 0.92), PS (p = 0.18), receptor status (p = 0.57), visceral mts (p = 0.54) and chemotherapy (cht) type (p = 0.47), whereas number of mts site (1 vs &gt; 1) affected PFS (28 vs 16 mo, p = 0.002). Moreover median PFS in naïve pts and in pts pretreated with only cht was 28 mo (95% CI, 20-36) and 27 mo (95% CI, 16-38) respectively, whereas in pts pretreated with T it was 12 mo (95% CI 16-38 p 0.002). In HR+ pts ET maintenance together with P and T had an impact on PFS (28 vs 15 mo, p = 0.01). Conclusions: Our analysis confirms, in real world HER2 MBC pts, the efficacy of P, T and a taxane combination in first line treatment; in this population PFS was shorter in pts pretreated with T. ET maintenance in association with P and T in HR+ pts improved PFS. Data collection is ongoing and update results will be presented.
Adherence and persistence to adjuvant hormonal therapy in early stage breast cancer patients: A population-based retrospective cohort study in Israel.
Authors: Tal Sella, Gabriel Chodick
Journal: Journal of Clinical Oncology (2017)

e12051 Background: Adjuvant hormonal therapy has been consistently proven to improve multiple outcomes in early breast cancer. Nonetheless, data on rates of adherence and persistence with therapy outside West Europe and North America are scarce. We assessed the adherence and persistence with adjuvant hormonal in a retrospective population based cohort of breast cancer survivors in Maccabi Health Services (MHS), Israel. Methods: We identified women who were diagnosed with breast cancer and initiated adjuvant hormonal therapy between January 2000 and November 2008. Subjects were followed retrospectively from first dispensed tamoxifen or aromatase inhibitor (AI) and up to the earliest of the following events: disease recurrence (indicated by surgery, radiotherapy, chemotherapy or other related therapies), leaving MHS, death, or completion of 5 years of treatment. Discontinuation of therapy was defined as a 180-day or longer treatment gap. Adherence with therapy was assessed using proportion of days covered (PDC) during follow-up period. Survival analysis was used to determine the effect of adherence on all-cause mortality. Results: A total of 4178 women with breast cancer were followed for a median 7.8 years. Over 90% of patients received tamoxifen as the initial hormonal agent. Mean PDC was 84% with lower rates associated with younger age, smoking status, comorbidities and year of diagnosis. Residential area did not affect adherence. Differences were not found. Discontinuation of therapy occurred in 23% of study patients. Among persistent patients, 70% were optimally adherent with therapy (PDC&gt;=80%). Association between adherence with therapy and survival is investigated. Conclusions: Adherence to adjuvant hormonal therapy among Israeli breast cancer patients with national health insurance is high in comparison to international reports. Nevertheless, suboptimal adherence was identified among younger (&lt;45y) patients. Because of the efficacy of hormonal therapy in preventing recurrence and death in women with early-stage breast cancer, interventions are necessary to identify and prevent suboptimal adherence among high risk subgroups.
Patients With Diabetes Without Significant Angiographic Coronary Artery Disease Have the Same Risk of Myocardial Infarction as Patients Without Diabetes in a Real-World Population Receiving Appropriate Prophylactic Treatment
Authors: Kevin K.W. Olesen, Morten Madsen, Gro Egholm, Troels Thim, Lisette O. Jensen, Bent Raungaard, Hans E. Bøtker, Henrik T. Sørensen, Michael Maeng
Journal: Diabetes Care (2017)

OBJECTIVE The risk of myocardial infarction (MI) in patients with diabetes is greater than for patients without diabetes. Consequently, prophylactic treatment is recommended for patients with diabetes and risk factors for ischemic heart disease. We aimed to estimate the risk of adverse cardiac events in patients with and without diabetes with and without coronary artery disease (CAD) after coronary angiography (CAG). RESEARCH DESIGN AND METHODS A population-based cohort of patients registered in the Western Denmark Heart Registry who underwent CAG between 1 January 2003 and 31 December 2012 was stratified according to the presence or absence of obstructive CAD and diabetes. End points were death, cardiac death, and MI. Unadjusted and adjusted rate ratios (RRs) were calculated by using patients without diabetes and without CAD as the reference group. RESULTS We included 93,866 patients of whom 12,544 (13.4%) had diabetes at the time of CAG. Median follow-up was 4.1 years. Patients with and without diabetes without obstructive CAD had the same adjusted risk of death (RR 1.03 [95% CI 0.92–1.15]), cardiac death (RR 1.21 [95% CI 0.90–1.64]), and MI (RR 0.88 [95% CI 0.65–1.17]). Patients with diabetes without CAD were more often treated with statins (75.3% vs. 46.0%) and aspirin (65.7% vs. 52.7%) than patients without diabetes and CAD. CONCLUSIONS In a real-world population, patients with diabetes with high rates of statin and aspirin treatment had the same risk of cardiovascular events as patients without diabetes in the absence of angiographically significant CAD.
Atg9b Deficiency Suppresses Autophagy and Potentiates Endoplasmic Reticulum Stress-Associated Hepatocyte Apoptosis in Hepatocarcinogenesis
Authors: Ning Wang, Hor-Yue Tan, Sha Li, Yibin Feng
Journal: Theranostics (2017)

The aim of this study was to investigate the mechanism underlying autophagy deficiency during hepatic carcinogenesis. For this purpose, we used choline-deficient, amino acid-defined (CDAA) hepatocarcinogenesis model in mice. miRNA microarrays combined with computational target predictions and GO analysis were used to identify molecular processes involved in carcinogenesis. PCR profiler array was employed to detect the dysregulated autophagy-related genes during carcinogenesis. We observed induction of hepatic tumours with increased inflammation, DNA damage, and cell death. These cellular processes were particularly detected upon oncogenic transformation of hepatocytes in which ER stress was excessively induced. Microarray combined with GO analysis showed that transformation of hepatocytes resulted in dysregulated events associated with cytoplasmic vesicle formation, which, in turn, was related to ER stress-induced autophagy. Defects of autophagy were observed in livers harbouring tumours and suffered a loss of expression of autophagy-related protein 9b (Atg9b). Hepatocytes lacking Atg9b were vulnerable to cell death induced by ER stress stimulus mainly caused by accumulation of ubiquitinated proteins. Loss of Atg9b also blocked recruitment of p62-associated ubiquitinated protein for autophagosome-lysosome degradation as Atg9b-driven phagophores may facilitate docking of both LC3 and p62 to initiate autophagy-associated degradation. miR-3091-3p from tumour-derived exosomes, which were internalised by hepatocytes, could suppress Atg9b expression. Observations from this study advance our knowledge about the regulation of autophagy during hepatocarcinogenesis.
Website of the week: Accessing ethical information
Authors: Douglas Carnall
Journal: BMJ (2000)

This week the BMJ discusses progress in medical ethics. Most of the changes seem to reflect thinking on ethics at a societal level: new guidance for setting priorities, new developments in biotechnology, and new awareness of error, driven to the forefront by an American report, Too Err is Human.

This was one of the few references that was not obviously available on the internet, but it was the work of moments, using the search engine Google (www.google.com/), to track it down (www.nap.edu/books/0309068371/html/). It is available on the web, but browsing it this way is not a happy experience: the information design (page by page in graphic files rather than HTML) seems designed to drive sales of the book rather than facilitate free access.

This is not a criticism that one could level at the Canadian Medical Association Journal's excellent collection of materials on ethics at www.cma.ca/cmaj/series/bioethic.htm. These teach basic principles such as truth telling, voluntariness, and confidentiality, as well as recent advances.

The relatively high number of URLs in Singer's article in this week's BMJ made me wonder how easy it would be to access the references on the web. All of the BMJ and JAMA papers are available, but Science, New England Journal of Medicine, Journal of Clinical Ethics, and Philosophy in Public Affairs all want you to pay for a subscription before you can download full text—though the last of these has an online publisher (www.jstor.org/about/) that lets collaborating institutions access the information freely.

Most British doctors won't be in that club—which poses the next question. What are the ethics of placing artificial barriers to the acquisition of knowledge in the path of scholars? After all, journals are supposed to be facilitators of scientific communication, not obstacles to it.