Citations

Abstract Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors. Concurrent use of luteinizing hormone-releasing hormone agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy and the disease is incurable in these cases. New therapies are needed to combat endocrine therapy resistance, maintain patient health-related quality-of-life, and delay the need for chemotherapy. AZD9833 (camizestrant) is a highly potent, next-generation selective ER degrader and pure ER antagonist that has demonstrated anticancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, AACR 2020). A Phase I dose-escalation and expansion study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor activity when administered alone or in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, Phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+/HER2− ABC who have not received systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1342 patients with de novo or recurrent ER+/HER2− ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive oral treatment with either (a) AZD9833 75 mg once daily, palbociclib 125 mg once daily for 21 days followed by 7 days off treatment and a placebo for anastrozole 1 mg once daily or (b) anastrozole 1 mg once daily, palbociclib (same as active arm) and a placebo for AZD9833 75 mg once daily. Men and premenopausal women will also receive a luteinizing hormone-releasing hormone agonist. The primary endpoint is progression-free survival (PFS; up to 5 years). Secondary endpoints include overall survival (up to 8 years), second PFS, time to chemotherapy, objective response rate, and changes in health-related quality-of-life measures. Enrollment began in January 2021. As of 02 July 2021, the number of open sites is 57 across 15 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, for providing medical writing support funded by AstraZeneca Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Citation Format: Fabrice André, Seock-Ah Im, Patrick Neven, Richard D Baird, Johannes Ettl, Matthew P Goetz, Erika Hamilton, Hiroji Iwata, Zefei Jiang, Anil Abraham Joy, Vincent Haddad, Andrew Walding, Manuel Selvi Miralles, Cynthia Huang Bartlett, Antonio Llombart-Cussac. SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-06.

Background Hypotension with endotracheal intubation (ETI) is common and associated with adverse outcomes. We sought to evaluate whether a previously described hypotension prediction score (HYPS) for ETI is associated with worse patient outcomes and/or clinical conditions. Methods This study is a post hoc analysis of a prospective observational multicenter study involving adult (age ≥18 years) intensive care unit (ICU) patients undergoing ETI in which the HYPS was derived and validated on the entire cohort and a stable subset (ie, patients in stable condition). We evaluated the association between increasing HYPSs in both subsets and several patient-centered outcomes and clinical conditions. Results Complete data for HYPS calculations were available for 783 of 934 patients (84%). Logistic regression analysis showed increasing odds ratios (ORs) for the highest risk category for new-onset acute kidney injury (OR, 7.37; 95% CI, 2.58-21.08); new dialysis need (OR, 8.13; 95% CI, 1.74-37.91); ICU mortality (OR, 16.39; 95% CI, 5.99-44.87); and hospital mortality (OR, 18.65; 95% CI, 6.81-51.11). Although not increasing progressively, the OR for the highest risk group was significantly associated with new-onset hypovolemic shock (OR, 6.06; 95% CI, 1.47-25.00). With increasing HYPSs, median values (interquartile ranges) decreased progressively (lowest risk vs. highest risk) for ventilator-free days (23 [18-26] vs. 1 [0-21], P < .001) and ICU-free days (20 [11-24] vs. 0 [0-13], P < .001). Of the 729 patients in the stable subset, 598 (82%) had complete data for HYPS calculations. Logistic regression analysis showed significantly increasing ORs for the highest risk category for new-onset hypovolemic shock (OR, 7.41; 95% CI, 2.06-26.62); ICU mortality (OR, 5.08; 95% CI, 1.87-13.85); and hospital mortality (OR, 7.08; 95% CI, 2.63-19.07). Conclusions As the risk for peri-intubation hypotension increases, according to a validated hypotension prediction tool, so does the risk for adverse clinical events and certain clinical conditions. Trial Registration The study was registered at ClinicalTrials.gov (NCT02508948).

Abstract Background: Despite widespread efforts to create wellness programming in medical schools, there is a paucity of literature examining students’ perception of wellness and perceptions of these programs. With the inaugural class at the Arizona campus of Mayo Clinic Alix School of Medicine (MCASOM-AZ), an opportunity arose to establish an empirically evaluated wellness curriculum that most inclusively and effectively enables medical students to flourish for years to come. The initial wellness offerings included mental health, academic success, and disability services, curriculum-embedded seminars, wellness committee driven programming, and student-proposed wellness activities. We aimed to improve the relevance and impact of medical school wellness curricula by soliciting in-depth and longitudinal perspectives of medical students themselves. As MCASOM-AZ opened in 2017, the student body at the time of study consisted of first- and second-year medical students. Methods: Employing a mixed methods analysis of qualitative and longitudinal quantitative data,first- and second-year students at a MCASOM-AZ were invited to respond to an anonymous, online year-long survey (baseline, six months and 12 months) during the 2018-2019 academic year and participate in a structured, in-depth and in-person, peer-to-peer interview about their conceptions of wellness and the MCASOM-AZ wellness curriculum and resources. Qualitative data was coded for themes using thematic analysis strategies by independent raters. Results: Nearly half of eligible students completed the baseline survey,1/3 completed all 3 time-points, and 1/5 participated in an in-depth interview. Participant age, gender, and year of school were representative of the larger student body. Although individual conceptions varied, Wellness was consistently highly valued. Family, Academic Performance, and Friends emerged as most important to well-being across time-points. Academic work arose as the largest barrier to wellness. Analysis of qualitative data revealed five themes. Despite individual differences in approaches to wellness, wellbeing was interrelated to the learning environment; mandatory wellness efforts that didn’t address the medical culture met with skepticism.Conclusions: Interview responses provided understanding and context by which to interpret questionnaire responses. Academics was critical to students’ identity and wellness, while also the largest barrier. Suggested curricular improvements include restructuring academic work, seamlessly integrating wellness within coursework, and offering optional individualized approaches.

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993–1998) through 2018. We conducted a mediation analysis to examine depressive symptoms as a potential mediator and further examined effect modification by age and race and ethnicity. Incident HF requiring hospitalization was the main outcome. Social isolation was a composite variable based on marital/partner status, religious ties, and community ties. Depressive symptoms were assessed using CES‐D (Center for Epidemiology Studies‐Depression). Over a median follow‐up of 15.0 years, we analyzed data from 36 457 women, and 2364 (6.5%) incident HF cases occurred; 2510 (6.9%) participants were socially isolated. In multivariable analyses adjusted for sociodemographic, behavioral, clinical, and general health/functioning; socially isolated women had a higher risk of incident HF than nonisolated women (HR, 1.23; 95% CI, 1.08–1.41). Adding depressive symptoms in the model did not change this association (HR, 1.22; 95% CI, 1.07–1.40). Neither race and ethnicity nor age moderated the association between social isolation and incident HF. Conclusions Socially isolated older women are at increased risk for developing HF, independent of traditional HF risk factors. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

Objective To determine the association of allergic conditions with incident rheumatoid arthritis (RA), especially in relation to smoking history and anti-citrullinated peptide antibody (ACPA) status. Methods This case–control study included 3515 incident RA cases and 5429 matched controls from the Epidemiological Investigation of Rheumatoid Arthritis study 1995 to 2016, including questionnaire-based information on eight allergic conditions composed from a list of 59 unique allergies. We used logistic regression and adjusted ORs (aOR) to assess the association between allergic conditions and risk of RA, adjusting for age, sex, residential area, body mass index, education, and smoking, and stratified by smoking and ACPA. Results A history of any reported allergy was equally common in RA (n=1047, 30%) as among population controls (n=1540, 29%), aOR 1.04, 95% CI 0.95 to 1.15. Metal, respiratory, food, plant/pollen and chemical allergies were not associated with risk of RA. By contrast, statistically significant associations were observed for animal dander allergy (6% vs 5%, aOR 1.37, 95% CI 1.03 to 1.82), especially in ACPA-positive RA (aOR 1.46 95% CI 1.06 to 2.01) and for atopic dermatitis, in particular for older and ACPA-negative RA (aOR 2.33, 95% CI 1.37 to 3.96 at age 80). Never smokers with allergic rhinitis also had increased risk of developing RA (aOR 1.30, 95% CI 1.00 to 1.68). Conclusion Most common allergies do not increase risk of RA, nor do they protect against RA. However, some allergic conditions, notably animal dander allergy, atopic dermatitis and allergic rhinitis, were associated with an increased risk for RA.

(1) Background: The objective of this study was to determine the long-term efficacy of fractional CO2 laser therapy in breast cancer survivors. (2) Methods: This was a single-arm study of breast cancer survivors. Participants received three treatments of fractional CO2 laser therapy and returned for a 4 week follow-up. Participants were contacted for follow-up at annual intervals. The Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Female Sexual Distress Scare Revised (FSDS-R), the Urinary Distress Inventory (UDI), and adverse events were collected and reported for the two-year follow-up. The changes in scores were compared between the four-week and two-year and the one-year and two-year follow-ups using paired t-tests. (3) Results: In total, 67 BC survivors were enrolled, 59 completed treatments and the four week follow-up, 39 participated in the one-year follow-up, and 33 participated in the two-year follow-up. After initial improvement in the VAS from baseline to the four week follow-up, there was no statistically significant difference in the VAS score (mean Δ 0.23; 95% CI [−0.05, 0.51], p = 0.150) between the four week follow-up and the two-year follow-up. At the two-year follow-up, the FSFI and FSDS-R scores remained improved from baseline and there was no statistically significant change in the FSFI score (mean Δ −0.83; 95% CI [−3.07, 2.38] p = 0.794) or the FSDS-R score (mean Δ −2.85; 95% CI [−1.88, 7.59] p = 0.227) from the one to two-year follow-up. The UDI scores approached baseline at the two-year follow-up; however, the change between the one- and two-year follow-ups was not statistically significant (mean Δ 4.76; 95% CI [−1.89, 11.41], p = 0.15). (4) Conclusions: Breast cancer survivors treated with fractional CO2 laser therapy have sustained improvement in sexual function two years after treatment completion, suggesting potential long-term benefit.

Background: Functional movement disorders (FMD, aka psychogenic movement disorders) are very common and frequently chronic and disabling. Despite this, there is a paucity of evidence-based treatment to manage and alleviate these conditions. Specialized physical therapy (PT), involving sequential motor relearning and redirecting attention, has shown promise as a therapeutic intervention for motor symptoms. Methods: The objective of this study was to critically assess current evidence regarding specialized PT compared with usual care in improving motor symptoms among patients with FMD. This was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of physical medicine and rehabilitation, physical and occupational therapy, psychiatry, and psychology. Results: A randomized controlled feasibility trial was identified and selected for critical appraisal. This study randomized 60 patients with FMD to a 5-day specialized outpatient PT program or to general outpatient PT referral, and measured patient-reported and clinician-measured outcomes. At 6 months, 72% of patients in the intervention group had a good outcome compared with 18% of control group patients. Patients in the specialized outpatient PT program had significantly better outcomes in 3 Short-Form 36 (SF36) domains (d=0.46 to 0.79) and multiple other scales of physical and social function as well as clinician-measured outcomes. The intervention resulted in 0.08 additional quality-adjusted life years in a cost-effective manner. Conclusions: Current evidence suggests that in patients with FMD, specialized PT improves motor symptoms in a clinically significant, sustained, and cost-effective manner. This promising intervention warrants further investigation and replication.

292 Background: Despite recent approval of anti-PD-1 antibodies as 1L therapy in HER2(-) advanced GEA, benefit remains modest and limited largely to PD-L1(+) patients (pts), primarily those with combined positive scores (CPS) ≥5. Thus novel therapeutic approaches are needed for this pt population. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated improved clinical outcomes in pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Methods: DisTinGuish (NCT04363801) is a Phase 2a single arm 2-part trial; Part A investigated DKN-01 (D) + tislelizumab (TS) + CAPOX as 1L therapy for pts with advanced HER2(-) GEA regardless of DKK1 status; Part B investigated two dosing cohorts of D (300 mg and 600 mg) + TS as 2L therapy for DKK1-high advanced GEA pts. Primary objective was to examine safety and tolerability and secondary objectives evaluated multiple efficacy endpoints including overall response rate (ORR) in a modified intent to treat (mITT) population (>1 dose D). Results: Forty-nine pts enrolled between 01 Sept 2020 and 15 Sept 2021; 25 pts in Part A and 24 pts in Part B (D-300 mg). Key clinicopathologic features and efficacy outcomes are shown in Table. The most common D-related AEs were low grade (G1/2) fatigue, nausea, and diarrhea. Nine pts had D-related ≥G3 toxicities, elevated AST/ALT, elevated alkaline phosphatase, hypophosphatemia, hyponatremia, lymphopenia, neutropenia, diarrhea, vomiting, fatigue all occurring in 1 pt and pulmonary embolism in 2 pts (one G5 event). No new safety signals were observed in Part A or B1. Duration of response (DoR), median PFS and median OS have not been reached for Part A. Last pt enrolled in Part B1 on 15 Sept 2021. Conclusions: The combination of D/TS + CAPOX represents a well-tolerated, active 1L combination, particularly for DKK1-high patients consistent with the proposed mechanism of action. Activity appears to be independent of PD-L1 status. Part B1 is aligned with biomarker enrichment and efficacy and biomarker data will be presented along with updated Part A efficacy data. Clinical trial information: NCT04363801. [Table: see text]