tbuckley/cabot-search huggingface dataset:
Abstract SP083: Treatment of HER2-positive metastatic breast cancer - advances and challenges
Authors: N Lin
Journal: Cancer Research (2021)

Abstract Over the past two decades, there have been tremendous advances in treatment options for patients with HER2+ metastatic breast cancer (MBC). Median overall survival (OS) in control arm of the pivotal trastuzumab + chemotherapy study (Slamon et al, NEJM 2001) was 20.3 months. By contrast, median OS in the taxane/trastuzumab/pertuzumab arm of the CLEOPATRA trial was approximately 5 years, with an 8-year landmark OS of 37% (Wong et al, Oncologist 2019). Notably, OS improvements have also been demonstrated in the pivotal trials of ado-trastuzumab emtansine, tucatinib/capecitabine/trastuzumab, and trastuzumab deruxtecan in pre-treated patients with HER2+ MBC, such that we expect that median OS will only continue to lengthen. Indeed, with current therapies, a subset of patients can survive a decade or longer. Despite these improvements, there is still much progress to be made. First, the problem of brain metastases continues to contribute substantial morbidity and mortality in at least half of patients. While there have been advances in local therapy for brain metastases, breakthroughs in systemic therapy and prevention strategies ultimately will be needed to truly tackle this problem. Second, drug resistance nearly always appears over time, yet our understanding of HER2-resistance remains woefully incomplete. Developing a deeper understanding of therapeutic resistance may uncover novel targets that allow for more effective and durable treatment. Finally, with multiple highly active drugs now available, is it now time to pivot to testing curative-intent approaches in HER2+ MBC, particularly in those patients who present with de novo stage IV disease. Citation Format: N Lin. Treatment of HER2-positive metastatic breast cancer - advances and challenges [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP083.
Brain capillary pericytes exert a substantial but slow influence on blood flow
Authors: David A. Hartmann, Andrée-Anne Berthiaume, Roger I. Grant, Sarah A. Harrill, Tegan Koski, Taryn Tieu, Konnor P. McDowell, Anna V. Faino, Abigail L. Kelly, Andy Y. Shih
Journal: Nature Neuroscience (2021)
Abstract 6139: Flow Acceleration Time: A Novel Diagnostic Parameter for Prosthetic Aortic Valve Stenosis
Authors: Sagit Ben Zekry, Robert M Saad, Stephen H Little, William A Zoghbi
Journal: Circulation (2008)

Diagnosing prosthetic aortic valve (PAV) stenosis, especially in mechanical valves, is challenging. We postulated that ejection dynamics, particularly acceleration time (AT) and the ratio of AT to ejection time (ET) can differentiate PAV stenosis from normals and those with patient-prosthesis mismatch. Doppler echocardiographic studies were reviewed and quantitated in 74 patients with PAV (38 mechanical and 36 bioprosthetic; age 61±23.6 years; valve size range). Three groups of patients were identified: patients with normal prostheses (n=60) evaluated within 3 months of surgery patients with patient-prosthesis mismatch (n=10) and documented PAV stenosis (n=14) with surgical confirmation. Quantitative Doppler parameters included ejection dynamics (AT, ET and AT/ET) and conventional PAV parameters of effective orifice area (EOA) and gradient. Summary of the Doppler parameters is presented in Table 1 . Patient with PAV stenosis had significantly lower EOA and higher gradients compared to normals and mismatch. Flow ejection parameters (ET, AT and AT/ET) were significantly longer in the stenotic valves. Patients with prosthetic mismatch, while having a normal absolute EOA, had gradients and ejection dynamics intermediate, between normal and stenotic valves. Receiver-Operating characteristic curve analysis showed that AT discriminated best PAV stenosis from normals and patients with mismatch (area under ROC=0.97). A cut off of AT = 100 msec had a sensitivity of 93% and specificity of 88% for PAV stenosis. In prosthetic aortic valves, ejection dynamics, particular acceleration time, are reliable, angle independent diagnostic parameters for identifying prosthetic valve stenosis. Table 1: Doppler Echocardiographic parameters in normal PAV, stenotic valves and patients with mismatch.
Neuromedin U functions as an autocrine growth factor in human myeloid leukemias
Authors: Susan E. Shetzline, Nayna Aggarwal, Czarek Swider, Alan M. Gewirtz
Journal: Cancer Research (2005)

4590  Biologically active neuromedin U (NmU) is a 25-amino acid peptide expressed at moderate to high levels in tissues of the brain, gut, and bone marrow. To date, NmU has been reported to stimulate smooth muscle contraction, increase blood pressure, alter ion transport in the gut, regulate local blood flow and modulate adrenocortical function. We have found that c-Myb, a transcription factor required for normal and malignant hematopoiesis, and NmU gene expression are both elevated in primary acute myeloid leukemia cells and demonstrated that NmU promotes the growth of human myeloid leukemia cells (Shetzline S, Rallapalli R, Dowd K, Zou S, Nakata Y, Swider C, Kalota A, Choi J, Gewirtz A. 2004. Blood. 104(6): 1833-1840). Since myeloid leukemia cells express the cognate receptor of NmU, NMU1R, we hypothesized that NmU stimulates myeloid leukemia cell proliferation via a novel autocrine loop. To understand the mechanism by which NmU stimulates myeloid leukemia cell proliferation, we examined the ability of NmU to induce intracellular calcium ion (Ca+2) flux and produce inositol phosphates in K562 cells, a myeloid leukemia cell line, because signaling through NMU1R has been shown to induce these secondary messengers in Cos-7, HEK-293, and CHO cells. First, we measured the intracellular accumulation of Ca+2 in Indo-1 labeled K562 cells following NmU challenge. We observed Ca+2 mobilization within 100 seconds of adding NmU. Next, we determined the ability of NmU to induce the production of inositol phosphates in K562 cells that were labeled with myo-[3H]-inositiol. A dose-dependent increase was observed in inositol phosphate production following NmU challenge with an EC50 of 10 μM. Taken together, these data demonstrate that the NMU1R expressed on K562 cells is functional and indicate that NmU initiates its proliferation signal through a G-protein couple receptor. Studies are underway in our laboratory to define the molecular mechanism of NmU-mediated mobilization of Ca+2 and production of inositol phosophates, the results of which will hopefully provide new insights into the physiological function of NmU in myeloid leukemias.
Role of Diet in Colorectal Cancer Incidence
Authors: Sajesh K. Veettil, Tse Yee Wong, Yee Shen Loo, Mary C. Playdon, Nai Ming Lai, Edward L. Giovannucci, Nathorn Chaiyakunapruk
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Several meta-analyses have summarized evidence for the association between dietary factors and the incidence of colorectal cancer (CRC). However, to date, there has been little synthesis of the strength, precision, and quality of this evidence in aggregate. <h3>Objective</h3> To grade the evidence from published meta-analyses of prospective observational studies that assessed the association of dietary patterns, specific foods, food groups, beverages (including alcohol), macronutrients, and micronutrients with the incidence of CRC. <h3>Data Sources</h3> MEDLINE, Embase, and the Cochrane Library were searched from database inception to September 2019. <h3>Evidence Review</h3> Only meta-analyses of prospective observational studies with a cohort study design were eligible. Evidence of association was graded according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. <h3>Results</h3> From 9954 publications, 222 full-text articles (2.2%) were evaluated for eligibility, and 45 meta-analyses (20.3%) that described 109 associations between dietary factors and CRC incidence were selected. Overall, 35 of the 109 associations (32.1%) were nominally statistically significant using random-effects meta-analysis models; 17 associations (15.6%) demonstrated large heterogeneity between studies (<i>I</i><sup>2</sup> &gt; 50%), whereas small-study effects were found for 11 associations (10.1%). Excess significance bias was not detected for any association between diet and CRC. The primary analysis identified 5 (4.6%) convincing, 2 (1.8%) highly suggestive, 10 (9.2%) suggestive, and 18 (16.5%) weak associations between diet and CRC, while there was no evidence for 74 (67.9%) associations. There was convincing evidence of an association of intake of red meat (high vs low) and alcohol (≥4 drinks/d vs 0 or occasional drinks) with the incidence of CRC and an inverse association of higher vs lower intakes of dietary fiber, calcium, and yogurt with CRC risk. The evidence for convincing associations remained robust following sensitivity analyses. <h3>Conclusions and Relevance</h3> This umbrella review found convincing evidence of an association between lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat. More research is needed on specific foods for which evidence remains suggestive, including other dairy products, whole grains, processed meat, and specific dietary patterns.
Abstract OT-13-01: A phase I study of preoperative ipilimumab, nivolumab, and talimogene laherparepvec for localized breast cancer
Authors: Vina P. Nguyen, Helena R. Chang, Maggie L. DiNome, Denise K. Oseguera, Deborah J. Wong, Anthony T. Nguyen, Stephen L. Shiao, John A. Glaspy
Journal: Cancer Research (2021)

Abstract Background: Immunotherapy has emerged as a novel therapeutic strategy in many solid malignancies. In breast cancer, treatment with checkpoint inhibitors alone showed minimal response rates, likely because breast cancers are not sufficiently immunogenic to induce adequate baseline T cell activation. Talimogene laherparepvec (T-VEC) is an attenuated herpes simplex virus 1 (HSV-1) engineered to introduce the GM-CSF gene selectively into tumor cells to thereby enhance the immunogenicity of transduced tumor cells. T-VEC has been approved in the treatment of patients with advanced melanoma and injectable tumors. In a phase 1b clinical trial, T-VEC was well tolerated in combination with immunotherapy in patients with advanced melanoma. We evaluated the safety and tolerability of T-VEC, nivolumab, and ipilimumab in the preoperative treatment of early stage localized triple-negative breast cancer (TNBC) and hormone receptor (HR)-positive breast cancer. Trial design and eligibility criteria: This is a single site open-label phase 1b window of opportunity trial of neoadjuvant T-VEC in combination with nivolumab and ipilimumab in patients with localized breast cancer. Twenty patients with localized TNBC or HR-positive breast cancer with palpable tumors will be included. T-VEC is administered intratumorally in week 1 (106 plaque-forming units/mL [pfu/ml]) and then every 3 weeks (108 plaque-forming units/mL [pfu/ml]) for a total of 3 injections. Nivolumab (240 mg) is administered intravenously in week 1 and every 2 weeks for a total of 4 infusions. Ipilimumab (1 mg/kg) is administered intravenously in week 1 and week 6 for a total of 2 infusions. Breast cancer surgery will be carried out after completion of study treatment. Neoadjuvant chemotherapy could be administered before or after study treatment. Study objectives: The primary objective is to evaluate the safety and tolerability of T-VEC in combination with nivolumab and ipilimumab in this population. The secondary objectives are 1) to assess tumor response to T-VEC, nivolumab, and ipilimumab and 2) to descriptively analyze surgical specimens for evidence of tumor necrosis and inflammatory infiltration on histopathological examination. Present accrual: To date, 5 patients have been enrolled. As described above, the projected sample size is 20 patients. Clinical trials identification: NCT04185311 Citation Format: Vina P. Nguyen, Helena R. Chang, Maggie L. DiNome, Denise K. Oseguera, Deborah J. Wong, Anthony T. Nguyen, Stephen L. Shiao, John A. Glaspy. A phase I study of preoperative ipilimumab, nivolumab, and talimogene laherparepvec for localized breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-01.
Abstract 15795: Cathepsin D Mediates the Osteogenic and Fibrocalcific Responses to Soluble Matrilin-2 in Human Avics Through the Erk1/2 Pathway
Authors: Qingzhou Yao, Balachandar Nedumaran, Peng Zhao, Lihua Ao, David A Fullerton, Xianzhong Meng
Journal: Circulation (2019)

Introduction: Calcific aortic valve disease (CAVD) is a growing health problem in the elderly. Its pathobiology involves valvular calcification and fibrosis, and aortic valve interstitial cells (AV...
Abstract SP033: How and when to use immunotherapy and related toxicities
Authors: J Cortes
Journal: Cancer Research (2021)

Abstract Targeting the immune system is an active therapeutic approach for a subgroup of patients with metastatic triple negative breast cancer (TNBC). In a breast cancer subtype in which new treatment strategies are greatly needed, the medical community welcomes this progress with great excitement. Single-agent anti PD-L1 and PD1 monoclonal antibodies have been evaluated in patients with locally advanced or metastatic TNBC. Although very limited efficacy was achieved in pre-treated patients, 1 out of 4 patients achieved an objective response when treated in the first-line setting. Of interest, many of these responses were long lasting. In 2019, atezolizumab was approved in combination with nab-paclitaxel in patients with metastatic TNBC whose tumors are positive for PD-L1 expression (≥1%) on immune infiltrate, evaluated by the VENTANA PD-L1 (SP142) antibody. However, when combined with paclitaxel, atezolizumab does not improve neither progression-free survival nor overall survival. On the other hand, pembrolizumab in combination when paclitaxel, nab-paclitaxel or carboplatin + gemcitabine has improved progression-free survival when PD-L1 expression was 10 or more (CPS score) evaluated by the 22C3 antibody. Unfortunately, the optimal platform to assess PD-L1 status is unknown, as it is the optimal cut-off value. Other biomarkers, such as mutational tumour burden or tumour infiltrating lymphocytes are not ready to be used in the clinic yet. Thus, biomarkers that can identify a broader group of patients who could benefit from this approach are urgently needed. Also, the combination of different immune checkpoint inhibitors between them or with other drugs, such as targeted therapy, may expand immunotherapy indication to more patients. Immune-related toxicities are closely associated with the known mechanisms of action of both PD-1 and PD-L1 antibodies, after restarting the anticancer immune system. The overall incidence is about 22% for all grades and 4% for high grades, being more frequent for patients treated with anti-PD-1 (all grades 27%) compared with anti-PD-L1 (all grades 17%). The most frequent organ specific immune-related adverse events were the endocrine system (7%), skin (5%), pulmonary system and gastrointestinal tract (4% each). Of note, immune-related deaths were reported in 0.34% of patients, the vast majority due to pneumonitis. When combined with chemotherapy, non-immune-related toxicities were reported with the same frequency as with chemotherapy alone. Citation Format: J Cortes. How and when to use immunotherapy and related toxicities [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP033.
Abstract PS14-04: A picture worth a thousand words - “classic” inflammatory breast cancer (IBC) appearance associated with overall survival
Authors: Wintana Balema, Diane Liu, Yu Shen, Randa El-Zein, Megumi Kai, Beth Overmoyer, Kathy D Miller, Carisa Le-Petross, Naoto T Ueno, Wendy A Woodward
Journal: Cancer Research (2021)

Abstract Background: IBC is considered a clinical diagnosis characterized by rapid onset of diffuse skin changes in the setting of a breast cancer diagnosis. A wide variety of visual changes are accurately diagnosed as IBC. Here, we sought to determine whether the most subjectively “classic” appearing presentation (swollen, involved breast with nipple inversion and diffuse skin change) was associated with worse outcomes. Method: We reviewed the images and charts of patients from the prospective IBC registry from the MD Anderson IBC Clinic. Breast medical photographs were reviewed by a non-expert and the visual presentation was scored as classic (as above), not classic, and in between. Comparative analyses were used to assess differences between patient groups using Chi-squared test, or Fisher’s exact test for categorical variables. Wilcoxon rank sum test was used for continuous measures. We used the Kaplan Meier estimator and the log-rank test to investigate association between scoring and survival distributions. Cox proportional hazard regression was employed to assess the impact of important covariates on the overall survival. Results: We analyzed 245 IBC patients with median age 55 (range, 26-81), M0 vs. M1 status (157 and 88 patients, respectively), 68 TNBC vs. 177 non-TNBC patients. The classic presentation was significantly associated with smoking, post-menopausal status, and metastatic disease at presentation (P = 0.002, 0.018, and 0.004, respectively). Presentation was significantly associated with OS in univariate analysis (P &amp;lt; 0.001). 10 year overall survival was 57% vs. 33% for classic (score 3) versus non-classic or in between presentation. The multivariable Cox regression model adjusting for clinical staging (P&amp;lt;0.001) and TNBC status (P&amp;lt;0.001) demonstrated classic presentation score was significantly associated with poorer OS time (HR 2.4, CI 1.6-3.6, p&amp;lt;0.001). Conclusions: A visual inspection of presentation photograph for “classic” appearance, obvious swelling, skin change, and nipple inversion, independently predicted poorer OS in IBC. Further work is warranted to understand the differences in classic and non-classic presentations, and the relationship between smoking and breast cancer presentation. Citation Format: Wintana Balema, Diane Liu, Yu Shen, Randa El-Zein, Megumi Kai, Beth Overmoyer, Kathy D Miller, Carisa Le-Petross, Naoto T Ueno, Wendy A Woodward. A picture worth a thousand words - “classic” inflammatory breast cancer (IBC) appearance associated with overall survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-04.
Richard Anthony Hayes
Authors: Matthew Hayes
Journal: BMJ (2021)

Richard Anthony Hayes was born at home in Kingswood, Bristol, delivered by his family GP, John Ridgeway, who influenced his later life. He attended Kingswood Grammar School, where, at the age of 16, he met his childhood sweetheart, Anne, from whom he became inseparable. He developed an early interest in the natural world, in particular a love of birds, and considered pursuing a career as an ornithologist. However, he chose to read medicine at the University of Bristol in 1961, his interest encouraged by the family doctor who delivered him.

After graduating and house …
Ruling Out Sars-cov-2 Infection With a Fast-track 0/1,5-hour Molecular Testing in Patients With Acute Coronary Syndromes
Authors: C. Spaccarotella, S. Migliarino, A. Mongiardo, A. Curcio, S. De Rosa, A. Quirino, G. Barreca, A. Giancotti, C. Peronace, N. Marascio, G. Matera, C. Indolfi
Journal: Circulation (2020)
Abstract SP068: The unique epigenetic state of invasive lobular breast cancers
Authors: R Jeselsohn
Journal: Cancer Research (2021)

Abstract Although the majority of invasive lobular breast cancers (ILC) are strongly hormone receptor positive and are rarely high-grade, they present a number of unique clinical problems compared with invasive ductal cancer (IDC). These include challenges for early detection, decreased response to chemotherapy and evidence of relative resistance specifically to adjuvant tamoxifen treatment. In addition to uniform loss of e-cadherin, ILCs possess genetic alterations that are suggestive of a unique estrogen receptor axis, including an increase in the frequency of FOXA1 mutations and decrease in GATA3 mutations. In this study we performed a comprehensive analysis of the estrogen receptor axis in pre-clinical models and clinical samples of ILC and IDC. We found that ILC has a unique chromatin state that stems from gained FOXA1 chromatin binding and leads the remodeling of ER chromatin binding. We demonstrated that FOXA1 recruitment can classify primary hormone receptor positive breast cancers to ILC and IDC histological subtypes. Moreover, we show that gained FOXA1 recruitment leads to the transcription of a gene signature associated with resistance to adjuvant tamoxifen in estrogen receptor positive breast cancers and is a mechanism for the divergent pattern of response to specific endocrine treatments in ILC. Collectively, these studies unveil key insights to the fundamental biology unique to ILC, set the stage for precision endocrine treatment in estrogen receptor positive breast cancer, and offer potential treatment targets to improve outcomes for patients with ILC. Citation Format: R Jeselsohn. The unique epigenetic state of invasive lobular breast cancers [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP068.
Robust SARS-CoV-2 infection in nasal turbinates after treatment with systemic neutralizing antibodies
Authors: Dongyan Zhou, Jasper Fuk-Woo Chan, Biao Zhou, Runhong Zhou, Shuang Li, Sisi Shan, Li Liu, Anna Jinxia Zhang, Serena J. Chen, Chris Chung-Sing Chan, Haoran Xu, Vincent Kwok-Man Poon, Shuofeng Yuan, Cun Li, Kenn Ka-Heng Chik, Chris Chun-Yiu Chan, Jianli Cao, Chun-Yin Chan, Ka-Yi Kwan, Zhenglong Du, Thomas Tsz-Kan Lau, Qi Zhang, Jie Zhou, Kelvin Kai-Wang To, Linqi Zhang, David D. Ho, Kwok-Yung Yuen, Zhiwei Chen
Journal: Cell Host & Microbe (2021)