Prescriber Acceptability of a Direct-to-Patient Intervention for Benzodiazepine Receptor Agonist Deprescribing and Behavioural Management of Insomnia in Older Adults.

Behavioural treatments are recommended first-line for insomnia, but long-term benzodiazepine receptor agonist (BZRA) use remains common and engaging patients in a deprescribing consultation is challenging. Few deprescribing interventions directly target patients. Prescribers' support of patient-targeted interventions may facilitate their uptake. Recently assessed in the Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study, Sleepwell (mysleepwell.ca) was developed as a direct-to-patient behaviour change intervention promoting BZRA deprescribing and non-pharmacological insomnia management. BZRA prescribers of YAWNS NB participants were invited to complete an online survey assessing the acceptability of Sleepwell as a direct-to-patient intervention. The survey was developed using the seven construct components of the theoretical framework of acceptability (TFA) framework. Respondents (40/250, 17.2%) indicated high acceptability, with positive responses per TFA construct averaging 32.3/40 (80.7%). Perceived as an ethical, credible, and useful tool, Sleepwell also promoted prescriber-patient BZRA deprescribing engagements (11/19, 58%). Prescribers were accepting of Sleepwell and supported its application as a direct-to-patient intervention.

Effectiveness and cost analysis of methods used to recruit older adult sedative users to a deprescribing randomized controlled trial during the COVID-19 pandemic.

Background: Recruitment to clinical trials is a challenge for researchers that became more pronounced because of COVID-19 public health protective measures, especially with respect to studies enrolling older adults. We completed an effectiveness and cost analysis of the recruitment methods used in The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study, a randomized controlled trial of a deprescribing intervention that recruited older adults with chronic use of sedatives during the pandemic. Methods: Study recruitment began during the COVID-19 pandemic. Strategies included random digit dialing (RDD), a targeted mail campaign and advertising through newspapers, online platforms (Google and Facebook), and television. Other awareness raising and recruitment strategies involved seniors' organizations, pharmacies, television news stories, and referrals. Recruitment effectiveness and cost analysis involved enrollment rate (ER), cost per randomized participant (CPRP), fractional cost (FC), fractional enrollment (FE), fractional enrollment-cost ratio (FEC), and efficacy index (EI) calculations. Results: There were 1295 interested older adults with 594 randomized into the study for an enrollment rate of 46%. The efficacy index (EI) was highest for Facebook ads (EI = 0.683) followed by television (EI = 0.426), and newsprint ads (EI = 0.298). The cost of RDD was highest per randomized participant at $1117.90 and produced the lowest EI (0.013). Conclusion: Facebook ads had the best efficacy index for recruiting older adults to the YAWNS NB study during the COVID-19 pandemic and television ads produced the most enrollments. RDD was expensive and yielded few recruits. Recruitment costs can be significant for recruiting community-dwelling older adults. This experience can inform recruitment strategy and budget development for future community studies enrolling older adults, especially in the context of the COVID-19 pandemic.

A protocol for a randomized controlled trial comparing Sleepwell, EMPOWER, and treatment-as-usual for benzodiazepine receptor agonist discontinuation in older adults: the your answers when needing sleep in New Brunswick (YAWNS NB) study.

Background: Chronic benzodiazepine receptor agonist (BZRA) use among older adults is a public health concern given cognitive and physical risks. One in four older adults in New Brunswick, Canada, is a long-term user of BZRAs. Previous studies using a direct-to-patient approach as the primary intervention target have shown promise in reducing BZRA use. The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study aims to reduce the long-term use of BZRAs in older adults and increase the use of cognitive behavioural therapy for insomnia (CBTi), which is the recommended first line treatment. Methods: The trial (ClinicalTrials.gov registration NCT04406103) is a three arm, open-label, parallel randomized controlled trial in NB, Canada. Eligible participants 65 years and older using BZRAs long-term will be randomly allocated to: the Eliminating Medications through Patient Ownership of End Results (EMPOWER) information package group; the Sleepwell information package group; or treatment-as-usual (TAU). Information packages will be mailed via Canada Post. The primary outcome of BZRA discontinuation at 6 months will be compared across groups. Secondary outcomes include participants with ≥25% BZRA dose reduction, and switching to newly prescribed alternate sedative-hypnotics. Several exploratory outcomes will also be examined. Discussion: Targeting participants with information packages informing them of appropriate use, dangers, and approaches to reducing BZRA use and increasing CBTi use may be beneficial in a region of Canada with the highest rate of chronic BZRA use in older adults. Comparing information packages and TAU will provide insights into the effectiveness of direct-to-patient interventions for BZRA reduction.

Increased Risk for Ipsilateral Breast Tumor Recurrence in Invasive Lobular Carcinoma after Accelerated Partial Breast Irradiation Brachytherapy.

BACKGROUND: The suitability criteria for accelerated partial breast irradiation (APBI) from the American Brachytherapy Society (ABS), American Society for Radiation Oncology (ASTRO), and The Groupe Européende Curiethérapie European SocieTy for Radiotherapy & Oncology (GEC-ESTRO) have significant differences. MATERIALS AND METHODS: This is a single institution retrospective review of 946 consecutive patients with invasive breast cancer who underwent lumpectomy and APBI intracavitary brachytherapy from 2003 to 2018. Overall survival (OS), breast cancer-specific survival (BCSS), relapse-free survival (RFS), and ipsilateral breast tumor recurrence (IBTR) were estimated with Kaplan-Meier method. RESULTS: Median follow-up time was 60.2 months. Median age was 68 years (46-94 years). The majority of patients had estrogen receptor (ER)-positive disease (94%). There were 821 (87%) cases of invasive ductal carcinoma and 68 cases (7%) of invasive lobular carcinoma (ILC). The 5-year OS, BCSS, RFS, and IBTR were 93%, 99%, 90%, and 1.5%, respectively. Upon univariate analysis, ILC (hazard ratio [HR], 4.6; p = .008) and lack of nodal evaluation (HR, 6.9; p = .01) were risk factors for IBTR. The 10-year IBTR was 2.5% for IDC and 14% for ILC. While the ABS and ASTRO criteria could not predict IBTR, the GEC-ESTRO intermediate risk group was associated with inferior IBTR (p = .04) when compared to both low risk and high risk groups. None of the suitability criteria was able to predict RFS. CONCLUSION: These results show that APBI is an effective treatment for patients with invasive breast cancer. Expansion of the current eligibility criteria should be considered, although prospective validation is needed. Caution is required when considering APBI for patients with ILC. IMPLICATIONS FOR PRACTICE: In a large retrospective review of 946 patients with early breast cancer treated with partial mastectomy and accelerated partial breast irradiation (APBI) intracavitary brachytherapy, this study demonstrates durable local control. Patients deemed unsuitable or high risk by the American Brachytherapy Society, American Society for Radiation Oncology, and European Society for Radiotherapy and Oncology guidelines were not at increased risk for ipsilateral breast tumor recurrence (IBTR), suggesting that expansion of the current criteria should be considered. Importantly, however, these results demonstrate that caution should be taken when considering APBI for patients with invasive lobular carcinoma, as these patients had relatively high risk for IBTR (10-year IBTR, 14%).

Management of ductal carcinoma in situ with accelerated partial breast irradiation brachytherapy: Implications for guideline expansion.

PURPOSE: Accelerated partial breast irradiation (APBI) for patients with ductal carcinoma in situ (DCIS) is controversial, and the suitability criteria from the American Brachytherapy Society (ABS), American Society of Therapeutic Radiology and Oncology (ASTRO), and the European Society for Radiotherapy and Oncology (GEC-ESTRO) have important differences. METHODS AND MATERIALS: This is a single-institution retrospective review of 169 consecutive patients with DCIS who underwent lumpectomy followed by APBI intracavitary brachytherapy from 2003 to 2018. Outcomes, including overall survival, recurrence-free survival (RFS), ipsilateral breast tumor recurrence, and distant metastasis, were estimated with the Kaplan-Meier method. RESULTS: The median followup time was 62.5 months. Median age was 66 years (47-89 years). The majority of patients had estrogen receptor-positive disease (89%). Fifty patients (30%) had Grade 3 disease. Of the 142 patients with adequate pathology interpretation, 91 and 108 cases had margins ≥ 3 mm and ≥2 mm, respectively. Most patients (72%) were prescribed and started endocrine therapy. Of the patients evaluable for ABS criteria (N = 130), 97 met the suitability criteria. Of the patients evaluable for ASTRO criteria (N = 129), 42 were deemed cautionary and 33 were deemed unsuitable. Of the patients evaluable for GEC-ESTRO criteria (N = 143), 141 cases were at intermediate risk and two were at high risk. Five-year ipsilateral breast tumor recurrence, RFS, and overall survival were 0.6%, 97.7%, and 97.2%, respectively. The ABS, ASTRO, and GEC-ESTRO criteria failed to significantly predict for RFS. CONCLUSIONS: These results, although limited by short-term followup, indicate that expansion of the eligibility criteria of APBI for patients with DCIS should be considered.

Molecular analysis of breast sentinel lymph nodes.

Lymphatic mapping and sentinel lymph node (SLN) biopsy have become the standard of care for staging the axilla in patients with invasive breast cancer. Current histologic methods for SLN evaluation have limitations, including subjectivity, limited sensitivity, and lack of standardization. The discovery of molecular markers to detect metastases has been reported over the last 2 decades. The authors review the historical development of these markers and the clinical use of one of the molecular platforms in 478 patients at their institution. Controversies and future directions are discussed.

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone.

BACKGROUND: Increased use of breast cancer screening has led to an increase in the number of diagnosed cases of ductal carcinoma in situ (DCIS). However, there is no definite way to predict progression or recurrence of DCIS. We analyzed the significance of biological markers and tumor characteristics in predicting recurrence in a large series of DCIS patients with long-term follow-up treated with breast conservation surgery (BCS) alone. METHODS: Clinical and pathological data were analyzed for 141 patients who underwent BCS for DCIS. All had negative surgical margins. Using local disease recurrence as an endpoint, we sought to determine the prognostic significance of several histopathological characteristics (tumor size, presence of necrosis, and subtype) and biological markers (estrogen receptor, progesterone receptor, and Her-2/neu.) RESULTS: At a median follow-up of 122 months (maximum follow-up, 294 months), 60 recurrences occurred, with a median time to recurrence of 191 months. On multivariate analysis, Her-2 positivity (3+) was found to be significantly associated with reduced time to tumor recurrence (P = .028). Tumor size and higher grade were marginally statistically significant (P = .099, P = .070). Neither necrosis nor tumor pathological characteristics were found to be significantly related to time to disease recurrence. CONCLUSIONS: Our results suggested that status of Her-2/neu, larger tumor size, and higher nuclear grade were significantly correlated with time to tumor recurrence in patients treated with BCS alone. Using logistical analyses, no significant correlation was found between tumor pathological characteristics and disease recurrence.

Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.

It is becoming increasingly apparent that the tumor microenvironment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic downregulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA microarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.

ErbB2 induces Notch1 activity and function in breast cancer cells.

The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed Notch (Notch(fl/fl)) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.