1,233 research outputs found
Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer
No full textWilliam J Gradishar Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Abstract: Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. Keywords: community oncologists, hormone receptor-positive advanced breast cancer, endocrine resistanc
SOPHIA : A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer
No full textAbstract
Background: Despite significant advances in targeted therapy, HER2+ metastatic breast cancer (MBC) remains incurable. Ideal treatment includes pertuzumab and trastuzumab in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine on progression. Optimal treatment regimens in the third and greater line of therapy are not defined, but continued anti-HER2 therapy is recommended. Margetuximab is a Fc-modified monoclonal antibody to HER2 that recognizes the same epitope on HER2 as does trastuzumab, with similar affinity. Margetuximab demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to trastuzumab. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to trastuzumab. In a Phase 1 dose escalation and expansion trial, margetuximab showed single agent clinical activity against HER2+ tumors in patients previously treated with trastuzumab and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that margetuximab plus chemotherapy (CTX) is more effective than trastuzumab plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is determined to have 80% power to detect a hazard ratio for OS of 0.75. Secondary endpoints are investigator assessed PFS and centrally assessed overall response rate. Eligibility includes prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine; no more than 3 prior lines of therapy in the metastatic setting; prior demonstration of HER2+ status at a local reference laboratory; and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician's choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either margetuximab or trastuzumab until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13.
Citation Format: Rugo HS, Pegram MD, Gradishar WJ, Cortes J, Curigliano G, Hong S, Wigginton JM, Lechleider RJ, Cardoso F. SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-07.</jats:p
Ashburn Anstalt v WJ Arnold & Co. Ltd [1989] Ch 1, Court of Appeal
No full textEssential Cases: Land Law provides a bridge between course textbooks and key case judgments. This case document summarizes the facts and decision in Ashburn Anstalt v WJ Arnold & Co. Ltd [1989] Ch 1, Court of Appeal. The document also includes supporting commentary from author Aruna Nair.</p
Treść i dynamika objawienia imienia Bożego w Księdze Wyjścia Część I: Analiza narracji Wj 3,16–24,18
No full textThe article addresses the significance of the formulas of the Divine Name: יְהוָה, אֶהְיֶה אֲשֶׁר אֶהְיֶה, and אֶהְיֶה (Exod 3:14–15). Referring to the narrative character of the Book of Exodus and assuming that the ambiguous formulas of the Divine Name in the initial part of the story are elements of a deliberate literary strategy, the author proposes interpreting these formulas using a narrative method. An analysis of two narrative sections of the Book of Exodus (3:16–18:27; 19:1–24:18) reveals that God, whose presence is initially depicted as concealed, is later portrayed, through the presentation of the Name formulas, as manifesting His presence through active intervention. The narrated events, in which YHWH acts on behalf of the Israelites against their enemies (Exod 3:16–18:27) and subsequently leads them to covenantal commitment (Exod 19:1–24:18), present God-YHWH as being. This notion clearly aligns with the declaration embedded in the Name formulas.Artykuł podejmuje zagadnienie znaczenia formuł imienia Bożego: יְהוָה, אֶהְיֶה אֲשֶׁר אֶהְיֶה oraz אֶהְיֶה (Wj 3,14-15). Odwołując się do narracyjnego charakteru Księgi Wyjścia oraz przyjmując założenie, że niejednoznaczne formuły imienia Bożego w początkowej części opowieści stanowią element przemyślanej strategii literackiej, autor proponuje tłumaczenie tych formuł za pomocą metody narratywnej. Przeprowadzona analiza dwóch fragmentów narracji Księgi Wyjścia (3,16–18,27; 19,1–24,18) pozwala zauważyć, iż Bóg, którego obecność na początkowym etapie opowieści zaprezentowana zostaje jako niejawna, wraz z przedstawieniem formuł imienia, ukazany zostaje jako manifestujący swoją obecność w aktywnym działaniu. Opowiedziane wydarzenia, w których JHWH jest podmiotem działającym na rzecz Izraelitów przeciw ich wrogom (Wj 3,16–18,27), a następnie doprowadzającym ich do zawarcia przymierza (Wj 19,1–24,18), ukazują Boga-JHWH jako będącego, co w czytelny sposób koresponduje z deklaracją zawartą w formułach imienia
Treść i dynamika objawienia imienia Bożego w księdze Wyjścia Część II: Analiza narracji Wj 25,1-40,38
No full textThe article constitutes a continuation of the study addressing the significance of the formulas of the Divine Name: יְהוָה, אֶהְיֶה אֲשֶׁר אֶהְיֶה, and אֶהְיֶה (Exod 3:14–15). The analysis focuses on the subsequent textual material of the Book of Exodus (Exod 25:1–40:38), where YHWH is primarily portrayed as manifesting His presence in the Tabernacle, which He commands to be built as His dwelling place. Applying the method of narrative analysis to the entirety of the narrative material, the author concludes that the primary communicative aim of the book is to present God as being. This concept is signaled in the formulas of the Divine Name and confirmed throughout the narrative representation of the events. The depiction of YHWH’s presence intensifies progressively as the narrative unfolds, with God transitioning from an unknown name and imperceptible presence to being known by the name YHWH and permanently present among the Israelites.Artykuł stanowi kontynuację studium podejmującego temat znaczenia formuł imienia Bożego: יְהוָה, אֶהְיֶה אֲשֶׁר אֶהְיֶה oraz אֶהְיֶה (Wj 3,14-15). Analizie poddana zostaje dalsza partia materiału tekstualnego Księgi Wyjścia (Wj 25,1–40,38), gdzie JHWH zaprezentowany jest przede wszystkim jako manifestujący swoją obecność w przybytku, który nakazuje zbudować na mieszkanie dla siebie. Stosując metodę analizy narratywnej do całości materiału narracyjnego, autor dochodzi do wniosku, że głównym celem komunikacyjnym księgi jest ukazanie Boga jako będącego, co jest sygnalizowane w formułach imienia Bożego i potwierdzone w całej narracyjnej reprezentacji wydarzeń. Prezentacja obecności JHWH staje się coraz bardziej intensywna wraz z postępem narracji, a Bóg przechodzi od nieznanego imienia i niedostrzegalnej obecności do bycia znanym w imieniu JHWH i trwale obecnym pośród Izraelitów
Depth Control for Blind Water Jet Drilling in Bone
No full textAbstract - When surgically drilling blind holes in bone using a Water Jet (WJ), control over the resulting depth is a challenging issue of paramount concern. This thesis was part of a project aimed at replacing the awl and mallet technique used in traditional microfracture procedures with an arthroscopic high-pressure WJ instrument is capable of accurately drilling 2–4 mm deep holes in subchondral bone. The focus of this paper was to develop, analyze and evaluate concepts for ensuring the depthwise accuracy of a microfracturing WJ. Research was performed on both WJ systems and the microfracture procedure, and a thorough problem analysis detailing all concerning requirements and parameters was set up. It was determined that due to the strong non-uniformity of human bone, both spatially and between subjects, a WJ capable of monitoring the depth and implementing a closed-loop control system was needed to ensure safe and accurate drilling. To measure the depth of the hole and allow for feedback control, a flexible Nickel Titanium probe concept was devised and tested. The concept featured a 3D printed nozzle with built-in WJ orifice and depth probe, which could be extended down the hole made by the WJ by an ex-vivo actuator featurimg load and displacement sensors. When the load sensor detected a sudden rise in extension resistance, bottom contact was assumed and the hole depth was calculated based on the displacement of the probe. A proof-of-concept experiment showed the viability of using a flexible probe to measure the depth. Additionally, the algorithm produced for calculating the depth was shown to be robust against the hysteresis and backlash exhibited by the setup. When probing holes with depths of 0, 1, 2, 3, 4 and 5 mm and bore diameters of 1, 1.5, and 2 mm drilled in solid PMMA, the prototype managed an error mean of 0.00 mm with a SD of 0.19 mm. To test the probe in holes shaped as expected during microfracture surgery, a virtual interference experiment was carried out using mCT scans of WJ-drilled bones and simulated probes of varying diameters. Seven scans were probed from 4 different angles each; the results suggested that a probe with a 0.2–0.3 mm diameter was optimal in terms of traversing the hole without blockages and without risking over-penetration. Moreover, this thesis produced recommendations on carrying the project further, towards a fully integrated system capable of drilling accurate blind holes in human bone, in a closed-loop depth-controlled manner.BMEBioMechanical EngineeringMechanical, Maritime and Materials Engineerin
Abstract PD4-05: Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors
No full textAbstract
Background:Cyclin D kinase inhibitors (CDK-is) have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer (MBC) when combined with aromatase inhibition or estrogen receptor (ER) antagonism. Despite the benefit of this approach, clinical resistance develops sometimes early in the treatment without any response to endocrine therapy (primary endocrine resistance) or after initial response (secondary resistance) in all patients in the metastatic setting and the molecular basis for this resistance are still largely unknown. We evaluated the pattern of genomic alterations in circulating cell-free tumor DNA (ctDNA) analysis of metastatic breast cancer patients with ER-positive tumors treated with palbociclib combined with either letrozole or fulvestrant and progressing during therapy.
Methods: We conducted a retrospective study of patients with ER-positive MBC who had longitudinal assessment of their disease by ctDNA analysis. The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes. After tabulating number of genomic alterations detected for every patient at baseline and after CDK-i therapy, analysis was performed to identify molecular profile changes in the entire population and in individuals with early progression of disease (&lt;6 months).
Results: We analyzed data of 15 ER-positive MBC patients: 8 patients received fulvestrant/palbociclib and 7 received letrozol/palpociclib. The most common mutations before CDK-i therapy were: PIK3CA (16%), TP53 (16%), ESR1 (13%), KIT (9%), EGFR (3%), APC (3%), ERBB2 (3%), MYC (3%), PTEN (3%), RB1 (3%). After therapy with CDK-i the pattern of mutations showed stable and persistent incidence of PIK3CA, TP53 and ESR1. However, new mutations where identified: FGFR1 (6%), IDH (2%), BRCA1 (2%), BRCA2 (2%), CCNE (2%), CCND1 (2%), RAF (2%), AR (2%), ALK(2%). Also, the pattern of gene amplifications presented an increased rate of MYC and FGFR1 amp. Patients with progression of disease before 6 months of CDK-i therapy presented baseline higher number and variation of mutations compared to patients with disease controlled beyond 6 months of therapy.
Conclusion: Longitudinal assessment with ctDNA analysis suggest that a genomic alteration landscape consisting of persistent detection of driver and acquired mutations along with emergent new abnormalities in regulatory genes could potentially be related to primary or secondary resistance to CDK-Is in ER+ MBC patients. Future investigation of these alterations should be conducted.
Citation Format: Cruz MR, Limentani K, Taxter T, Santa-Maria CA, Behdad A, Gradishar WJ, Nagy RJ, Cristofanilli M. Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-05.</jats:p
Mojżesz wysłannik Jahwe (Wj 1,1–14,31)
No full textThe Exodus of the Israelites from Egypt was the most important event in the history of the Chosen People. The historical and theological context of the biblical events contained in Exodus 1:1–14:31 was described.The aim of the research became the analysis and interpretation of the theological message contained in the first part of the Exodus recounting the liberation of the Israelites from Egyptian slavery (Exodus 1:1–14:31).In the analysis and exegesis of biblical texts, the intertextual method was used, as well as the historical-critical method over the issue of Moses’ mission.As a result of the study, it can be concluded that: 1) the knowledge of the God of Israel and His intentions is the key theme of the first fifteen chapters of the Exodus. Yahweh is the main protagonist of the events described in the Book of Exodus. He is their author and perpetrator; 2) the theme of the first part of the Exodus is the conflict over whom Israel is to serve; 3) the historical sources do not reflect in their entirety the facts known from the biblical account, for the reason that the Bible is not a historical chronicle, but a record of God’s revelation. Its main task is to convey theological content.The conclusions to be drawn are: 1) the revelation that was to Moses also applies to the Israelites, as well as to the Egyptians. However, the times and the manner of revelation change. God’s words are addressed to everyone, including modern people.The study conducted does not exhaust the subject of Moses’ mission to Israel. It is not a complete characterization of Moses. At the same time, it is necessary to keep in mind the further impact of the message of the Exodus on subsequent generations of Israel, as well as on modern times. The study can become a contribution to further theological reflection on the message of the Exodus.Wyjście Izraelitów z Egiptu było najważniejszym wydarzeniem w historii narodu wybranego. Został opisany kontekst historyczno-teologiczny wydarzeń biblijnych zawartych w Wj 1,1–14,31.Celem badań stała się analiza i interpretacja przesłania teologicznego zawartego w pierwszej części Księgi Wyjścia opowiadającej o wyzwoleniu Izraelitów z niewoli egipskiej (Wj 1,1–14,31).Przy analizie i egzegezie tekstów biblijnych wykorzystano metodę intertekstualną, a także historyczno-krytyczną nad zagadnieniem misji Mojżesza.W wyniku przeprowadzonych badań można stwierdzić, że: 1) poznanie Boga Izraela i Jego zamiarów jest kluczowym tematem pierwszych piętnastu rozdziałów Księgi Wyjścia. Jahwe jest głównym bohaterem wydarzeń opisanych w Księdze Wyjścia. On jest ich sprawcą i autorem; 2) tematem pierwszej części Księgi Wyjścia jest konflikt o to, komu służyć ma Izrael; 3) źródła historyczne nie odzwierciedlają w całości faktów znanych z relacji biblijnej, dlatego że Biblia nie jest kroniką historyczną, lecz zapisem objawienia Bożego. Jej głównym zadaniem jest przekaz treści teologicznej.Wnioski, jakie należy wyciągnąć to: 1) objawienie, które było do Mojżesza, dotyczą także Izraelitów, jak i do Egipcjan. Zmieniają się jednak czasy i sposób objawienia. Słowa Boga skierowane są do wszystkich, również do ludzi współczesnych.Przeprowadzone badania nie wyczerpują tematu misji Mojżesza względem Izraela. Nie jest pełną charakterystyką Mojżesza. Należy przy tym pamiętać o dalszym oddziaływaniu przesłania Księgi Wyjścia na kolejne pokolenia Izraela, a także na czasy współczesne. Badanie mogą stać się przyczynkiem do dalszej refleksji teologicznej nad przesłaniem Księgi Wyjścia
Abstract P5-03-11: Possible role for cancer stem cells: results from a pilot neoadjuvant trial of HER-2 positive breast cancer patients treated with a combination of (Nab)-paclitaxel and lapatinib.
No full textAbstract OT3-01-01: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
No full textAbstract
Background
A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PD-L1. This strategy has complementary and non-redundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit.
Methods
A single arm Phase II study was designed to determine the efficacy of PD-L1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PD-L1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ER-positive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer.
Citation Format: Santa-Maria CA, Jain S, Flaum L, Park J-H, Kato T, Gross L, Uthe R, Tellez C, Stein R, Rademaker A, Gradishar WJ, Nakamura Y, Giles FJ, Cristofanilli M. A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-01.</jats:p
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