A pilot randomised controlled trial of acceptance and commitment therapy for medication decision-making and quality of life in women with breast cancer: The ACTION trial.

OBJECTIVE: Non-adherence to adjuvant endocrine therapy (AET) in women with breast cancer is common and associated with medication side-effects and distress. We co-designed an Acceptance and Commitment Therapy intervention (ACTION) to enhance medication decision-making and quality of life (QoL). We undertook a pilot trial of ACTION to inform the feasibility of a phase III trial, and to examine intervention acceptability. METHODS: This was a multi-site, exploratory, two-arm, individually randomised external pilot trial. Women with early breast cancer prescribed AET were randomised (1:1) to receive usual care (UC) or UC + ACTION. The ACTION intervention comprised a remotely delivered one-to-one ACT session followed by three group sessions delivered by clinical psychologists, alongside a website containing ideas for the self-management of side effects. RESULTS: Of the 480 women screened for eligibility, 260 (54.2%) were approached and 79 (30.4%) randomised. 71 (89.9%) women provided data at 3-month and 70 (88.6%) at 6-month 40 women were randomised to receive UC + ACTION and 32 (80.0%) completed the intervention. Most (75.0%) accessed the website at least once. ACTION was acceptable to participants (Borkovec & Nau Scale: mean = 7.8 [SD = 2.7] out of 10). Signals of effectiveness in favour of the UC + ACTION arm were observed for medication adherence (Adherence Starts with Knowledge questionnaire-12), QoL (work and social adjustment scale), health-related QoL (functional assessment of cancer therapy[FACT] general and FACT-ES-19/23), distress (generalised anxiety disorder -7, patient health questionnaire-9) and psychological flexibility (valuing questionnaire). CONCLUSIONS: The ACTION intervention was acceptable to patients. There were promising signals for effectiveness on primary and secondary outcomes. A phase III randomised controlled trial is feasible. TRIAL REGISTRATION: ISRCTN12027752.

Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom.

BACKGROUND: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. METHODS: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. RESULTS: 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. CONCLUSION: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience.

Aligning patient values and code status: Choice of Diction's Effect (CODE) study.

BACKGROUND: Decisions regarding resuscitation after cardiac arrest are critical from ethical, patient satisfaction, outcome, and healthcare cost standpoints. Physician-reported discussion barriers include topic discomfort, fear of time commitment, and difficulty articulating end-of-life concepts. The influence of language used in these discussions has not been tested. This study explored whether utilizing the alternate term "allow (a) natural death" changed code status decisions in hospitalized patients versus "do not resuscitate" (DNR). METHODS: All patients age 65 and over admitted to a general medicine hospital teaching service were screened (English-speaking, not ICU-level care, no active psychiatric illness, no substance misuse, no active DNR). Participants were randomized to resuscitation discussions with either DNR or "allow natural death" as the "no code" phrasing. Outcomes included patient resuscitation decision, satisfaction with and duration of the conversation, and decision correlation with illness severity and predicted resuscitation success. RESULTS: 102 participants were randomized to the "allow natural death" (N = 49) or DNR (N = 53) arms. The overall "no code" rate for our sample of hospitalized general medicine inpatients age >65 was 16.7%, with 13% in the DNR and 20.4% in the "allow natural death" arms (p = 0.35). Discussion length was similar in the DNR and "allow natural death" arms (3.9 + 3.2 vs. 4.9 + 3.9 minutes), and not significantly different (p = 0.53). Over 90% of participants were highly satisfied with their code status decision, without difference between arms (p = 0.49). CONCLUSIONS: Participants' code status discussions did not differ in "no code" rate between "allow natural death" and DNR arms but were short in length and had high patient satisfaction. Previously reported code status discussion barriers were not encountered. It is appropriate to screen code status in all hospitalized patients regardless of phrasing used.

The development of a clinical research educational training for community health workers using the joint task force for clinical trial competency framework.

Introduction: The NYU Clinical & Translational Science Institute, in collaboration with a number of community-engaged initiatives, developed a training for community health workers (CHWs) to enhance health literacy about clinical research. This innovative research training provides CHWs with a basic level of competency in clinical research to convey the importance of research to communities and better advocate for their health needs. CHWs are an underutilized resource to engage diverse populations in clinical research. The training also addresses the need to expand and diversify the clinical research workforce-integrating CHWs into research teams and connecting underserved populations with research opportunities to enhance quality of care. Methods: Structured individual interviews and focus group sessions were held with CHWs as well as clinical research faculty and staff to identify knowledge gaps in clinical research and identify best practices for educating community members on research. Using the Joint Task Force (JTF) for Clinical Trial Competency framework, an online course was developed consisting of 28 modules offered asynchronously for internal and external audiences. Topics include the fundamentals of clinical research, scientific concepts and research design, research ethics, study management, clinical study operations, communications, and teamwork, as well as the importance of diversity and equity in research and the barriers to participation. Results: Learning was evaluated using multiple choice questions after each module to ensure the fundamental level of knowledge was obtained. A separate survey, completed at the conclusion of the course, evaluated the quality of training. Discussion: The course aims to enhance the knowledge and skills of CHWs to help promote greater understanding of clinical research within the communities they serve, including the risks and benefits of clinical research and opportunities for participation. As members of the research team, community stakeholders can help design interventions tailored to the unique needs, culture, and context of their communities. In addition, this research training equips trainees with skills to engage the community actively, involving them in the research process and ensuring community priorities are represented in research through more community engaged processes.

Single-cell transcriptomic heterogeneity between conduit and resistance mesenteric arteries in rats.

The endothelium contains morphologically similar cells throughout the vasculature, but individual cells along the length of a single vascular tree or in different regional circulations function dissimilarly. When observations made in large arteries are extrapolated to explain the function of endothelial cells (ECs) in the resistance vasculature, only a fraction of these observations are consistent between artery sizes. To what extent endothelial (EC) and vascular smooth muscle cells (VSMCs) from different arteriolar segments of the same tissue differ phenotypically at the single-cell level remains unknown. Therefore, single-cell RNA-seq (10x Genomics) was performed using a 10X Genomics Chromium system. Cells were enzymatically digested from large (>300 µm) and small (<150 µm) mesenteric arteries from nine adult male Sprague-Dawley rats, pooled to create six samples (3 rats/sample, 3 samples/group). After normalized integration, the dataset was scaled before unsupervised cell clustering and cluster visualization using UMAP plots. Differential gene expression analysis allowed us to infer the biological identity of different clusters. Our analysis revealed 630 and 641 differentially expressed genes (DEGs) between conduit and resistance arteries for ECs and VSMCs, respectively. Gene ontology analysis (GO-Biological Processes, GOBP) of scRNA-seq data discovered 562 and 270 pathways for ECs and VSMCs, respectively, that differed between large and small arteries. We identified eight and seven unique ECs and VSMCs subpopulations, respectively, with DEGs and pathways identified for each cluster. These results and this dataset allow the discovery and support of novel hypotheses needed to identify mechanisms that determine the phenotypic heterogeneity between conduit and resistance arteries.

Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation.

Acid-sensing ion channel 1a (ASIC1a) belongs to a novel family of proton-gated cation channels that are permeable to both Na+ and Ca2+. ASIC1a is expressed in vascular smooth muscle and endothelial cells in a variety of vascular beds, yet little is known regarding the potential impact of ASIC1a to regulate local vascular reactivity. Our previous studies in rat mesenteric arteries suggest ASIC1a does not contribute to agonist-induced vasoconstriction but may mediate a vasodilatory response. The objective of the current study is to determine the role of ASIC1a in systemic vasodilatory responses by testing the hypothesis that the activation of endothelial ASIC1a mediates vasodilation of mesenteric resistance arteries through an endothelium-dependent hyperpolarization (EDH)-related pathway. The selective ASIC1a antagonist psalmotoxin 1 (PcTX1) largely attenuated the sustained vasodilatory response to acetylcholine (ACh) in isolated, pressurized mesenteric resistance arteries and ACh-mediated Ca2+ influx in freshly isolated mesenteric endothelial tubes. Similarly, basal tone was enhanced and ACh-induced vasodilation blunted in mesenteric arteries from Asic1a knockout mice. ASIC1a colocalizes with intermediate- and small-conductance Ca2+-activated K+ channels (IKCa and SKCa, respectively), and the IKCa/SKCa-sensitive component of the ACh-mediated vasodilation was blocked by ASIC1a inhibition. To determine the role of ASIC1a to activate IKCa/SKCa channels, we measured whole-cell K+ currents using the perforated-patch clamp technique in freshly isolated mesenteric endothelial cells. Inhibition of ASIC1a prevented ACh-induced activation of IKCa/SKCa channels. The ASIC1 agonist, α/ß-MitTx, activated IKCa/SKCa channels and induced an IKCa/SKCa-dependent vasodilation. Together, the present study demonstrates that ASIC1a couples to IKCa/SKCa channels in mesenteric resistance arteries to mediate endothelium-dependent vasodilation.

Role of Cholesterol in the Regulation of Hydrogen Sulfide Signaling within the Vascular Endothelium.

H2S is a gaseous signaling molecule enzymatically produced in mammals and H2S-producing enzymes are expressed throughout the vascular wall. We previously reported that H2S-induced vasodilation is mediated through transient receptor potential cation channel subfamily V member 4 (TRPV4) and large conductance (BKCa) potassium channels; however, regulators of this pathway have not been defined. Previous reports have shown that membrane cholesterol limits activity of TRPV4 and BKCa potassium channels. The current study examined the ability of endothelial cell (EC) plasma membrane (PM) cholesterol to regulate H2S-induced vasodilation. We hypothesized that EC PM cholesterol hinders H2S-mediated vasodilation in large mesenteric arteries. In pressurized, U46619 pre-constricted mesenteric arteries, decreasing EC PM cholesterol in large arteries using methyl-ß-cyclodextrin (MBCD, 100 µM) increased H2S-induced dilation (NaHS 10, 100 µM) but MBCD treatment had no effect in small arteries. Enface fluorescence showed EC PM cholesterol content is higher in large mesenteric arteries than in smaller arteries. The NaHS-induced vasodilation following MBCD treatment in large arteries was blocked by TRPV4 and BKCa channel inhibitors (GSK219384A, 300 nM and iberiotoxin, 100 nM, respectively). Immunohistochemistry of mesenteric artery cross-sections show that TRPV4 and BKCa are both present in EC of large and small arteries. Cholesterol supplementation into EC PM of small arteries abolished NaHS-induced vasodilation but the cholesterol enantiomer, epicholesterol, had no effect. Proximity ligation assay studies did not show a correlation between EC PM cholesterol content and the association of TRPV4 and BK. Collectively, these results demonstrate that EC PM cholesterol limits H2S-induced vasodilation through effects on EC TRPV4 and BKCa channels.

Endothelial cell membrane cholesterol content regulates the contribution of TRPV4 channels in ACh-induced vasodilation in rat gracilis arteries.

OBJECTIVE: Our previous work demonstrated that endothelial cell (EC) membrane cholesterol is reduced following 48 h of chronic hypoxia (CH). CH couples endothelial transient receptor potential subfamily V member 4 (TRPV4) channels to muscarinic receptor signaling through an endothelium-dependent hyperpolarization (EDH) pathway does not present in control animals. TRVPV4 channel activity has been shown to be regulated by membrane cholesterol. Hence, we hypothesize that acute manipulation of endothelial cell membrane cholesterol inversely determines the contribution of TRPV4 channels to endothelium-dependent vasodilation. METHODS: Male Sprague-Dawley rats were exposed to ambient atmospheric (atm.) pressure or 48-h of hypoxia (0.5 atm). Vasodilation to acetylcholine (ACh) was determined using pressure myography in gracilis arteries. EC membrane cholesterol was depleted using methyl-ß-cyclodextrin (MßCD) and supplemented with MßCD-cholesterol. RESULTS: Inhibiting TRPV4 did not affect ACh-induced vasodilation in normoxic controls. However, TRPV4 inhibition reduced resting diameter in control arteries suggesting basal activity. TRPV4 contributes to ACh-induced vasodilation in these arteries when EC membrane cholesterol is depleted. Inhibiting TRPV4 attenuated ACh-induced vasodilation in arteries from CH animals that exhibit lower EC membrane cholesterol than normoxic controls. EC cholesterol repletion in arteries from CH animals abolished the contribution of TRPV4 to ACh-induced vasodilation. CONCLUSION: Endothelial cell membrane cholesterol impedes the contribution of TRPV4 channels in EDH-mediated dilation. These results provide additional evidence for the importance of plasma membrane cholesterol content in regulating intracellular signaling and vascular function.

Acceptance and Commitment Therapy to support medication decision-making and quality of life in women with breast cancer: protocol for a pilot randomised controlled trial.

BACKGROUND: Adherence to adjuvant endocrine therapy is affected by medication side-effects and associated distress. Previous interventions focused on educating women to enhance adherence have proved minimally effective. We co-designed an Acceptance and Commitment Therapy (ACT) intervention to enhance medication decision-making and quality of life by targeting a broader range of factors, including side-effect management and psychological flexibility. This study aims to establish key trial parameters, assess the acceptability of the intervention and the extent to which it can be delivered with fidelity, and to demonstrate "proof of principle" regarding its efficacy on primary and process outcomes. METHODS: The ACTION intervention includes an individual 1:1 ACT session followed by three group sessions involving 8-10 women and two practitioner psychologists. Participants are also provided with access to a website containing evidence-based methods for self-managing side-effects. The ACT sessions were adapted during the COVID-19 pandemic to be remotely delivered via video conferencing software. To evaluate the feasibility and acceptability of this intervention, a multi-site, exploratory, two-arm, individually randomised external pilot trial with a nested qualitative study will be undertaken. Eighty women with early stage breast cancer prescribed adjuvant endocrine therapy will be randomised (1:1) to receive treatment as usual or treatment as usual plus the ACTION intervention. The planned future primary outcome is medication adherence assessed by the ASK-12 measure. Progression to a phase III RCT will be based on criteria related to recruitment and follow-up rates, acceptability to patients, competency and fidelity of delivery, and proof of principle for change in medication adherence. DISCUSSION: This external pilot trial will be used to ascertain the feasibility of undertaking a future phase III RCT to definitively evaluate an ACT-based intervention to support medication taking behaviour and quality of life in women with early stage breast cancer on adjuvant endocrine therapy. TRIAL REGISTRATION: ISRCTN: 12027752. Registered 24 December 2020, https://doi.org/10.1186/ISRCTN12027752.

Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results.

PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.

Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K+ channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na+ and Ca2+ , is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na+ influx contributes to PASMC Em regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K+ currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced Em depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 (Asic1-/- ) prevents CH-induced Em depolarization and largely inhibits whole-cell NSCC currents, without affecting whole-cell K+ currents. Our results show a combination of factors, including inhibition of K+ efflux and augmented Na+ influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of Em in PASMCs during CH-induced pulmonary hypertension. KEY POINTS: In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential (Em ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well-established reduction of K+ conductance, we show that non-selective cation channel currents are increased and essential to the persistent Em depolarization in PASMCs following chronic hypoxia (CH)-induced pulmonary hypertension. The current study provides novel evidence that acid-sensing ion channel 1 (ASIC1)-mediated Na+ influx induces membrane depolarization and regulates Em in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.

Hydrogen Sulfide Actions in the Vasculature.

Hydrogen sulfide (H2 S) is a small, gaseous molecule with poor solubility in water that is generated by multiple pathways in many species including humans. It acts as a signaling molecule in many tissues with both beneficial and pathological effects. This article discusses its many actions in the vascular system and the growing evidence of its role to regulate vascular tone, angiogenesis, endothelial barrier function, redox, and inflammation. Alterations in some disease states are also discussed including potential roles in promoting tumor growth and contributions to the development of metabolic disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.

Short-term high fat diet alters genes associated with metabolic and vascular dysfunction during adolescence in rats: a pilot study.

BACKGROUND: Diet-induced metabolic dysfunction precedes multiple disease states including diabetes, heart disease, and vascular dysfunction. The critical role of the vasculature in disease progression is established, yet the details of how gene expression changes in early cardiovascular disease remain an enigma. The objective of the current pilot project was to evaluate whether a quantitative assessment of gene expression within the aorta of six-week old healthy male Sprague-Dawley rats compared to those exhibiting symptoms of metabolic dysfunction could reveal potential mediators of vascular dysfunction. METHODS: RNA was extracted from the aorta of eight rats from a larger experiment; four animals fed a high-fat diet (HFD) known to induce symptoms of metabolic dysfunction (hypertension, increased adiposity, fasting hyperglycemia) and four age-matched healthy animals fed a standard chow diet (CHOW). The bioinformatic workflow included Gene Ontology (GO) biological process enrichment and network analyses. RESULTS: The resulting network contained genes relevant to physiological processes including fat and protein metabolism, oxygen transport, hormone regulation, vascular regulation, thermoregulation, and circadian rhythm. The majority of differentially regulated genes were downregulated, including several associated with circadian clock function. In contrast, leptin and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) were notably upregulated. Leptin is involved in several major energy balance signaling pathways and Hmgcs2 is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis. CONCLUSION: Together, these data describe changes in gene expression within the aortic wall of HFD rats with early metabolic dysfunction and highlight potential pathways and signaling intermediates that may impact the development of early vascular dysfunction.

Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality.

BACKGROUND: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL). METHODS: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires. RESULTS: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months. CONCLUSION: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient.

Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer.

BACKGROUND: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. METHODS: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. RESULTS: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed. CONCLUSIONS: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. TRIAL REGISTRATION: ISRCTN 46099296.

Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life.

BACKGROUND: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. METHODS: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. FINDINGS: A total of 3416 women (median age 77, range 69-102) were recruited from 56 breast units-2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23-0.33, P < 0.001). Unmatched breast cancer-specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29-0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53-0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40-1.37, P = 0.34) although at 4-5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. INTERPRETATION: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4-5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). TRIAL REGISTRATION NUMBER: ISRCTN: 46099296.

Bridging the Age Gap in breast cancer: Impact of chemotherapy on quality of life in older women with early breast cancer.

INTRODUCTION: Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study. MATERIALS AND METHODS: A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013-2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching. RESULTS: Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18-24 months in unmatched and matched cohorts. CONCLUSIONS: The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy. TRIAL REGISTRATION NUMBER ISRCTN: 46099296.

Simulated sleep apnea alters hydrogen sulfide regulation of blood flow and pressure.

In sleep apnea, airway obstruction causes intermittent hypoxia (IH). In animal studies, IH-dependent hypertension is associated with loss of vasodilator hydrogen sulfide (H2S), and increased H2S activation of sympathetic nervous system (SNS) activity in the carotid body. We previously reported that inhibiting cystathionine γ-lyase (CSE) to prevent H2S synthesis augments vascular resistance in control rats. The goal of this study was to evaluate the contribution of IH-induced changes in CSE signaling to increased blood pressure and vascular resistance. We hypothesized that chronic IH exposure eliminates CSE regulation of blood pressure (BP) and vascular resistance. In rats instrumented with venous catheters, arterial telemeters, and flow probes on the main mesenteric artery, the CSE inhibitor dl-propargylglycine (PAG, 50 mg/kg/day i.v. for 5 days) increased BP in Sham rats but decreased BP in IH rats [in mmHg, Sham (n = 11): 114 ± 4 to 131 ± 6; IH (n = 8): 131 ± 8 to 115 ± 7 mmHg, P < 0.05]. PAG treatment increased mesenteric vascular resistance in Sham rats but decreased it in IH rats (day 5/day 1: Sham: 1.50 ± 0.07; IH: 0.85 ± 0.19, P < 0.05). Administration of the ganglionic blocker hexamethonium (to evaluate SNS activity) decreased mesenteric resistance in PAG-treated Sham rats more than in saline-treated Sham rats or PAG-treated IH rats. CSE immunoreactivity in IH carotid bodies compared with those from Sham rats. However, CSE staining in small mesenteric arteries was less in arteries from IH than in Sham rats but not different in larger arteries (inner diameter > 200 µm). These results suggest endogenous H2S regulates blood pressure and vascular resistance, but this control is lost after IH exposure with decreased CSE expression in resistance size arteries. IH exposure concurrently increases carotid body CSE expression and relative SNS control of blood pressure, suggesting both vascular and carotid body H2S generation contribute to blood pressure regulation.NEW & NOTEWORTHY These results suggest that CSE's protective role in the vasculature is impaired by simulated sleep apnea, which also upregulates CSE in the carotid body. Thus, this enzyme system can exert both pro- and antihypertensive effects and may contribute to elevated SNS outflow in sleep apnea.

Altered Lipid Domains Facilitate Enhanced Pulmonary Vasoconstriction after Chronic Hypoxia.

Chronic hypoxia (CH) augments depolarization-induced pulmonary vasoconstriction through superoxide-dependent, Rho kinase-mediated Ca2+ sensitization. Nicotinamide adenine dinucleotide phosphate oxidase and EGFR (epidermal growth factor receptor) signaling contributes to this response. Caveolin-1 regulates the activity of a variety of proteins, including EGFR and nicotinamide adenine dinucleotide phosphate oxidase, and membrane cholesterol is an important regulator of caveolin-1 protein interactions. We hypothesized that derangement of these membrane lipid domain components augments depolarization-induced Ca2+ sensitization and resultant vasoconstriction after CH. Although exposure of rats to CH (4 wk, ∼380 mm Hg) did not alter caveolin-1 expression in intrapulmonary arteries or the incidence of caveolae in arterial smooth muscle, CH markedly reduced smooth muscle membrane cholesterol content as assessed by filipin fluorescence. Effects of CH on vasoreactivity and superoxide generation were examined using pressurized, Ca2+-permeabilized, endothelium-disrupted pulmonary arteries (∼150 µm inner diameter) from CH and control rats. Depolarizing concentrations of KCl evoked greater constriction in arteries from CH rats than in those obtained from control rats, and increased superoxide production as assessed by dihydroethidium fluorescence only in arteries from CH rats. Both cholesterol supplementation and the caveolin-1 scaffolding domain peptide antennapedia-Cav prevented these effects of CH, with each treatment restoring membrane cholesterol in CH arteries to control levels. Enhanced EGF-dependent vasoconstriction after CH similarly required reduced membrane cholesterol. However, these responses to CH were not associated with changes in EGFR expression or activity, suggesting that cholesterol regulates this signaling pathway downstream of EGFR. We conclude that alterations in membrane lipid domain signaling resulting from reduced cholesterol content facilitate enhanced depolarization- and EGF-induced pulmonary vasoconstriction after CH.