bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SP159: EMT
Authors: Yang J 
Published: February 2021

Abstract
During metastasis, epithelial tumor cells dissociate from each other, disseminate into the systemic circulation, and then establish secondary tumors in distant sites. A developmental program termed Epithelial-Mesenchymal Transition (EMT) is implicated in promoting the dissemination of single carcinoma cells during metastasis. Our recent studies aim to understand how EMT is dynamically regulated in response to signals from the tumor microenvironment and from the intracellular machineries to impact EMT and tumor metastasis. Specifically, I will present a mechanotransduction pathway that senses and transmits mechanincal cues from stiff matrix in the tumor microenvironment to promote EMT and invasion during tumor progression. Breast tumors are often detected due to their apparent “hardness” compared to normal tissues, and increasing matrix stiffness correlates with distant metastasis and poor survival in breast cancer patients. These observations raise the question of how mechanical forces generated by the rigid tumor ECM impact tumor progression and metastasis. In a hydrogel coupled with 3D Matrigel overlay culture system that recapitulates the range of physiological stiffness from normal mammary glands to breast tumors, increased ECM stiffness triggers Epithelial-Mesenchymal Transition (EMT), invasion and metastasis. We previously reported that the transcription factor Twist1 is an essential mechano-mediator that promotes EMT and metastasis in response to ECM stiffness. High matrix stiffness promotes Twist1 nuclear localization through phosphorylation-dependent regulation of its interaction with cytoplasmic anchor G3BP2. Using kinase screening and protein affinity purification, we identified a novel mechanoresponsive protein complex including an ephrin receptor and a Src-family kinase that promotes Twist1 phosphorylation and subsequent nuclear translocation in response to high matrix rigidity. Pharmacological and genetic inhibition of this mechanotransduction pathway blocks ECM stiffness-induced EMT and invasion in vitro and inhibits metastasis in human breast tumor xenografts. Our findings reveal a novel mechanotransduction pathway that responds to mechanical signals from the tumor microenvironment to drive EMT, invasion, and metastasis.
Citation Format: J Yang. EMT [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 SP159.
Abstract SP161: Context-dependent functions and inter-tumoral heterogeneity of tumor-associated myeloid cells.
Authors: Zhang X 
Published: February 2021

Abstract
Tumor-associated myeloid cells, including macrophages (TAMs) and neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this talk, we will discuss evidence supporting the mutual influence between cancer cells and TAMs/TANs. We will review the immunosuppressive roles of these myeloid cells as well as their direct interactions with cancer cells. We will stress an emerging theme in recent studies: the precise myeloid functions may be determined by multiple factors including plasticity of these cells, mutual cooperation/competition among different cell types, and co-evolution between immune microenvironment and cancer traits. These factors together contribute to the heterogeneity of immune cells across tumors, an additional layer of heterogeneity beyond tumor-intrinsic characteristics.
Citation Format: X Zhang. Context-dependent functions and inter-tumoral heterogeneity of tumor-associated myeloid cells. [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 SP161.
Abstract SP031: Mechanisms of therapeutic resistance in ER+ breast cancer
Authors: Clarke RB 
Published: February 2021

Abstract
ER+ breast cancer is often successfully treated with endocrine therapies and more recently CDK4/6 inhibitors. In order to discover resistance mechanisms, we studied the tumour cells that survive anti-estrogen therapies such as tamoxifen and fulvestrant. We found that tamoxifen and fulvestrant therapy-resistant cells have cancer stem cell (CSC) attributes such as aldehyde dehydrogenase (ALDH) enzyme activity, mammosphere colony formation ex vivo and tumour initiation in vivo. We established that these CSC activities are regulated by pathways downstream of JAGGED/NOTCH4 receptor, the interleukin (IL) 1beta/IL1 receptor, and IL6/STAT3 signalling. Emerging data implicate these signalling pathways in metastatic progression, and both endocrine and CDK4/6 inhibitor therapy resistance. Targeting them in combination with current therapies has the potential to improve clinical outcomes.
Citation Format: RB Clarke. Mechanisms of therapeutic resistance in ER+ 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 SP031.
Abstract SP033: How and when to use immunotherapy and related toxicities
Authors: Cortes J 
Published: February 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 SP054: Obesity and Breast Cancer: Body Composition, Metabolic Mediators and Inflammation
Authors: Goodwin P 
Published: February 2021

Abstract
Obesity has been associated with an increased risk of postmenopausal breast cancer (predominantly ER+), as well as triple negative premenopausal breast cancer. It has also been associated with an increased risk of breast cancer distant recurrence and death, regardless or menopausal status or IHC defined breast cancer subtype. Obesity effects on recurrence and death are modest, with HRs for either outcome approximating 1.3. Obesity is linked to metabolic alterations that include insulin resistance (with associated high insulin and reduced glucose tolerance), altered lipids and adipokines, hypertension, central obesity, inflammation and increased risks of type 2 diabetes (T2DM) and cardiovascular disease - this constellation of attributes comprises the insulin resistance or metabolic syndrome. There is growing appreciation that BMI [weight (kg)/height (m)2] ≥ 30 kg/m2 is an imperfect measure of both body composition and underlying metabolic status. Recent research has focused on body composition (e.g. central obesity/sarcopenic obesity) and metabolic health (“healthy” obese, “unhealthy” normal weight) as predictors of breast cancer outcomes. Many of the inter-related physiologic changes associated with obesity (including higher levels of insulin, glucose, altered adipokines and, less consistently, circulating inflammatory factors) have individually been associated with increased breast cancer risk and/or poor breast cancer outcomes. These circulating factors, and obesity per se, have, in turn, been associated with changes in breast tissue and tumor micro-environment, including crown-like structures (dying adipocytes surrounded by inflammatory cells) as well as increased infiltration of inflammatory cells, cytokines and chemokines - all of which have been linked to cancer risk and progression in preclinical and/or clinical research. Evidence linking obesity/body composition, circulating obesity-associated physiologic and inflammatory factors to breast cancer outcomes will be discussed as will interventions (notably weight loss, metformin) targeting these factors in breast cancer patients. Recent findings linking breast inflammation to obesity/obesity-associated physiology and breast cancer outcomes will be reviewed. The inter-relatedness of these factors and the likelihood that the breast cancer-obesity link is complex and multifactorial will be highlighted.
Citation Format: P Goodwin. Obesity and Breast Cancer: Body Composition, Metabolic Mediators and Inflammation [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 SP054.
Abstract SP083: Treatment of HER2-positive metastatic breast cancer - advances and challenges
Authors: Lin N 
Published: February 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.
Abstract SP094: DCIS - Con
Authors: McLaughlin S 
Published: February 2021

Abstract
Ductal carcinoma in situ (DCIS) represents a collection of biologically heterogenous pre-invasive breast lesions some with the potential for progression to invasive cancer. Widespread adoption of screening mammography has increased the diagnosis of DCIS and may contribute to overdiagnosis identifying some conditions that may never impact one’s overall health. Unfortunately, clinicians treating DCIS patients currently lack robust biomarkers stratifying DCIS patients into those at high or low risk for invasive progression. Further, variations in pathologic assessment and grade, intra-lesional DCIS heterogeneity, and discordance in pathologic interpretations between pathologists make it challenging for providers to further identify appropriate low risk DCIS patients for active surveillance. Guideline concordant care including excision and potentially radiation and anti-estrogen therapies should remain as the standard of care and provides a definitive treatment endpoint which patients desire. Existing evidence documents a significant upstage rate of DCIS to invasive disease at surgical excision including a small, but important population benefiting from adjuvant systemic therapy. Finally, patient anxiety and documented poor adherence rates to endocrine therapy preclude active surveillance and after all the morbidity of surgical excision is low.
Citation Format: S McLaughlin. DCIS - Con [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 SP094.
Вплив лікувально-профілактичного комплексу на показники пероксидного окиснення ліпідів та антиоксидантного захисту ротової рідини дітей із хронічним катаральним гінгівітом
Authors: Kaskova L. F. , Honcharenko V. A. 
Published: February 2021

Резюме. Дані клінічних та експериментальних досліджень свідчать про тісний зв’язок захворювань тканин пародонта з порушенням функції ендокринних залоз. Велике значення в патогенезі захворювань пародонта надають ролі вільнорадикальним процесам як універсальному стресреалізуючому механізму ушкодження клітини.
Мета дослідження – вивчити вплив запропонованого лікувально-профілактичного комплексу, який містить препарати з антиоксидантними властивостями, на стан прооксидантно-антиоксидантної системи ротової рідини у дітей із хронічним катаральним гінгівітом на тлі цукрового діабету.
Матеріали і методи. Лікувально-профілактичні заходи проводили дітям із хронічним катаральним гінгівітом, яким призначали загальноприйнятий комплекс (перша, друга групи), та запропонований нами (третя група), до складу якого входять препарати, що мають антиоксидантну дію. Визначали активність каталази, супероксиддисмутази, рівень дієнових кон’югатів, малоновий діальдегід у ротовій рідині.
Результати досліджень та їх обговорення. Результати застосування лікувально-профілактичного комплексу свідчать про позитивний вплив його складових на процеси пероксидного окинення ліпідів ротової рідини обстежуваних дітей. Спостерігали найбільш значиме зниження активності малонового діальдегіду в групі пацієнтів, яким призначали запропонований нами комплекс. Через 6 місяців показник малонового діальдегіду в пацієнтів першої та другої груп повернувся до початкових значень, а в третій групі він був вірогідно нижчий, ніж до проведеного лікування, та знаходився на рівні показника дітей першої групи. Вивчення рівня дієнових кон’югатів свідчить про те, що найкращі результати в короткі (після завершення курсу лікування) терміни спостереження отримані у дітей, яким призначали комплекс, що вміщує складові з антиоксидантами. Також у цих пацієнтів виявлена вірогідна різниця показника під час обстеження через 6 місяців відносно I обстеження (рɪ-v<0,05). Зниження процесів пероксидного окиснення ліпідів під час проведеного лікування хронічного катарального гінгівіту в пацієнтів із цукровим діабетом супроводжується підвищенням та утриманням на достатньо високому рівні протягом 6 місяців показників антиоксидантного захисту ротової рідини, про що свідчать дослідження активності ферментів супероксиддисмутази та каталази.
Висновки. Застосування запропонованого нами лікувально-профілактичного комплексу дало можливість знизити показники пероксидного окиснення ліпідів та підвищити антиоксидантні властивості ротової рідини дітей, які мають хронічний катаральний гінгівіт, та хворіють на цукровий діабет.
Hemodynamics and Clinical Implications of Occult Left Ventricular Dysfunction in Adults Undergoing Ebstein Anomaly Repair
Authors: Egbe Alexander C. , Miranda William R. , Dearani Joseph A. , Connolly Heidi M. 
Published: February 2021

Background:
Left ventricular global longitudinal strain (LVGLS) can detect early phases of LV systolic dysfunction, but its application has not been studied in Ebstein anomaly. We hypothesized that LVGLS can detect early phases of LV systolic dysfunction and that patients with occult LV systolic dysfunction will have worse hemodynamics, end-organ dysfunction, and suboptimal postoperative LV reverse remodeling after tricuspid valve surgery in comparison to patients with normal LV systolic function.

Methods:
In this retrospective cohort study, 371 Ebstein patients that underwent tricuspid valve surgery were divided into 3 groups: normal LV systolic function (normal LVGLS and LV ejection fraction; n=244, 77%), occult LV systolic dysfunction (abnormal LVGLS with normal LV ejection fraction; n=44, 14%), and overt LV systolic dysfunction (abnormal LVGLS and LV ejection fraction; n=27, 9%).

Results:

Compared with the normal LV function group, the occult group had smaller LV volume and cardiac output (2.1±0.4 versus 2.9±0.6 L/min per m
2
,
P
<0.001), worse end-organ dysfunction (glomerular filtration rate, 78±14 versus 91±18 mL/min per 1.73 m
2
,
P
=0.01), and suboptimal postoperative LV reverse remodeling. Although both the occult and overt groups had a similar degree of end-organ dysfunction (glomerular filtration rate, 78±14 versus 82±16 mL/min per 1.73 m
2
,
P
=0.3), the occult group was less likely to be on heart failure therapy (48% versus 96%,
P
<0.001).

Conclusions:
Abnormal LVGLS was associated with suboptimal postoperative LV reverse remodeling. These data suggest that LVGLS can potentially be used for risk stratification and provides a foundation for further studies to determine whether optimal heart failure therapy or tricuspid valve intervention can improve outcomes for LV systolic dysfunction in patients with Ebstein anomaly.
Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials
Authors: Lau Emily S. , Braunwald Eugene , Morrow David A. , Giugliano Robert P. , Antman Elliott M. , Gibson C. Michael , Scirica Benjamin M. , Bohula Erin A. , Wiviott Stephen D. , Bhatt Deepak L. , Bonaca Marc P. , Cannon Christopher P. , Im KyungAh , Guo Jianping , Sabatine Marc S. , O’Donoghue Michelle L. 
Published: February 2021

Background:
Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown.

Methods:
Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models.

Results:

After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR
adj
], 1.22 [95% CI, 1.16–1.28];
P
<0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (OR
adj
, 1.20 [95% CI, 1.13–1.27]) and active therapy arms (OR
adj
, 1.23 [95% CI, 1.17–1.30)]; there was some evidence for regional heterogeneity (
P
interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both;
P
=0.60). Women were also more likely to withdraw consent compared with men (OR
adj
, 1.26 [95% CI, 1.17–1.36];
P
<0.001).

Conclusions:
Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.
Association of Ischemic Evaluation and Clinical Outcomes Among Patients Admitted With New‐Onset Heart Failure
Authors: McGuinn Erin , Warsavage Theodore , Plomondon Mary E. , Valle Javier A. , Ho P. Michael , Waldo Stephen W. 
Published: February 2021

Background
The significant morbidity associated with systolic heart failure makes it imperative to identify patients with a reversible cause. We thus sought to evaluate the proportion of patients who received an ischemic evaluation after a hospitalization for new‐onset systolic heart failure.

Methods and Results

Patients admitted with a new diagnosis of heart failure and a reduction in left ventricular ejection fraction (≤40%) were identified in the VA Healthcare System from January 2006 to August 2017. Among those who survived 90 days without a readmission, we evaluated the proportion of patients who underwent an ischemic evaluation. We identified 9625 patients who were admitted with a new diagnosis of systolic heart failure with a concomitant reduction in ejection fraction. A minority of patients (3859, 40%) underwent an ischemic evaluation, with significant variation across high‐performing (90th percentile) and low‐performing (10th percentile) sites (odds ratio, 3.79; 95% CI, 2.90–4.31). Patients who underwent an evaluation were more likely to be treated with angiotensin‐converting enzyme inhibitors (75% versus 64%,
P
<0.001) or beta blockers (92% versus 82%,
P
<0.001) and subsequently undergo percutaneous (8% versus 0%,
P
<0.001) or surgical (2% versus 0%,
P
<0.001) revascularization. Patients with an ischemic evaluation also had a significantly lower adjusted hazard of all‐cause mortality (hazard ratio, 0.54; 95% CI, 0.47–0.61) compared with those without an evaluation.

Conclusions
Ischemic evaluations are underutilized in patients admitted with heart failure and a new reduction in left ventricular systolic function. A focused intervention to increase guideline‐concordant care could lead to an improvement in clinical outcomes.