Sudden Shift to Telehealth in COVID-19: A Retrospective Cohort Study of Disparities in Use of Telehealth for Prenatal Care in a Large Midwifery Service.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic created disruption in health care delivery, including a sudden transition to telehealth use in mid-March 2020. The purpose of this study was to examine changes in the mode of prenatal care visits and predictors of telehealth use (provider-patient messaging, telephone visits, and video visits) during the COVID-19 pandemic among those receiving care in a large, academic nurse-midwifery service. METHODS: We conducted a retrospective cohort study of those enrolled for prenatal care in 2 nurse-midwifery clinics between 2019 and 2021 (n = 3172). Use outcomes included number and type of encounter: in-person and telehealth (primary outcome). Comparisons were made in frequency and types of encounters before and during COVID-19. A negative binomial regression was fit on the outcome of telehealth encounter count, with race/ethnicity, age, language, parity, hypertension, diabetes, and depression as predictors. RESULTS: When comparing pre-COVID-19 (before March 2020) with during COVID-19 (after March 2020), overall encounters increased from 15.9 to 19.5 mean number of encounters per person (P < .001). The increase was driven by telehealth encounters; there were no significant differences for in-person prenatal visit counts before and during the pandemic period. Direct patient-provider messaging was the most common type of telehealth encounter. Predictors of telehealth encounters included English as primary language and diagnoses of diabetes or depression. DISCUSSION: No differences in the frequency of in-person prenatal care visits suggests that telehealth encounters led to more contact with midwives and did not replace in-person encounters. Spanish-speaking patients were least likely to use telehealth-delivered prenatal care during the pandemic; a small, but significant, proportion of patients had no or few telehealth encounters, and a significant proportion had high use of telehealth. Integration of telehealth in future delivery of prenatal care should consider questions of equity, patient and provider satisfaction, access, redundancies, and provider workload.

Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis.

Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 ( Hmox1 ) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis. Ferroptosis culminates in excessive lipid peroxidation that is constrained by the antioxidative glutathione pathway. We observed increased mucosal markers of ferroptosis and glutathione metabolism in the setting of murine and human colitis, as well as murine colonic neoplasia. We obtained similar results in murine and human colonic epithelial organoids exposed to heme and the ferroptosis activator erastin, especially induction of Hmox1 . RNA sequencing of colonic organoids from mice with deletion of intestinal epithelial Hmox1 (Hmox1 ΔIEC ) revealed increased ferroptosis and activated glutathione metabolism after heme exposure. In a colitis-associated cancer model we observed significantly fewer and smaller tumors in Hmox1 ΔIEC mice compared to littermate controls. Transcriptional profiling of Hmox1 ΔIEC tumors and tumor organoids revealed increased ferroptosis and oxidative stress markers in tumor epithelial cells. In total, our findings reveal ferroptosis as an important colitis-associated cancer signature pathway, and Hmox1 as a key regulator in the tumor microenvironment.

Clinical and immune responses to neoadjuvant fulvestrant with or without enzalutamide in ER+/Her2- breast cancer.

Most ER+ breast cancers (BC) express androgen receptors (AR). This randomized phase II trial of 4 months of neoadjuvant fulvestrant (Fulv) alone or with enzalutamide (Combo) assessed whether adding AR blockade to Fulv would limit residual tumor at the time of surgery, as measured by modified preoperative endocrine predictive index (PEPI) score. Eligible patients were women with ER+/HER2- primary BC cT2 or greater. Stratification factors were clinical node and T-stage. Fresh tumor biopsies were required at study entry, after 4 weeks on therapy (W5), and at surgery. Laboratory analyses on tumors included immunochemistry (IHC) for ER/PR/AR/GR and Ki67 protein, evaluation of gene expression, multiplex for myeloid lineage immune cells, reverse-phase protein array, and plasma metabolomic analyses. Of 69 consented patients, 59 were evaluable. Toxicity was as expected with endocrine therapy. Combo achieved PEPI = 0 more frequently (24%: 8/33) than Fulv (8%: 2/26). Ki67 was ≤10% across arms by W5 in 76% of tumors. Activation of mTOR pathway proteins was elevated in tumors with poor Ki67 response. Tumors in both arms showed decreased estrogen-regulated and cell division gene sets, while Combo arm tumors uniquely exhibited enrichment of immune activation gene sets, including interferon gamma, complement, inflammation, antigen processing, and B and T cell activation. Multiplex IHC showed significantly reduced tumor-associated macrophages and CD14+/HLADR-/CD68- MDSCs in Combo tumors at W5. In summary, Combo tumors showed a higher PEPI = 0 response, Ki67 response, and more activated tumor immune microenvironment than Fulv. The odds of response were 4.6-fold higher for patients with ILC versus IDC. (Trial registration: This trial is registered at Clinicaltrials.gov ( https://www.clinicaltrials.gov/study/NCT02955394?id=16-1042&rank=1 ). The trial registration number is NCT02955394. The full trial protocol is available under Study Details at the Clinicaltrials.gov link provided).

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Characterization of a Jumping Stereotypy in Gerbils (Meriones unguiculatus) and Assessment of Opaque Tubing Enrichment on Stereotypies and Breeding.

Mongolian gerbils can develop stereotypic behaviors, including corner digging. At our institution, gerbils also engage in repetitive corner jumping, which we sought to characterize as a potentially novel stereotypy in gerbils. We then attempted to mitigate this behavior by mimicking the natural habitat by adding intracage environmental complexity. Seventeen gerbil breeding pairs were video recorded in their home cages during the light cycle. Repetitive corner jumping and digging were compared between different times of day to assess when the behaviors occurred and whether they were temporally associated. To determine whether we could reduce the incidence of stereotypic behaviors, we tested a straight tube or 1 of 3 angled opaque tubes in different orientations, which were fitted to the gerbils' preexisting opaque nesting box. Behavior was assessed at baseline and at 1, 4, 8, and 12 wk to evaluate opaque tube placement as an intervention. In addition, breeding efficiency, valuated as the number of gerbil pups born and weaned per breeder pair, was compared with pre- and poststudy data. The number of corner jumps was highest at the end of the light cycle and the majority were associated with corner digging. After placement of the enrichment tubes, an initial increase in corner digging behavior was observed and persisted throughout the study period. The opaque tubes were not associated with significant changes in corner jumping. After adjusting for age, the addition of opaque tubing to gerbil breeding cages was not associated with significant changes in breeding efficiency. The addition of opaque tubing did not effectively address concerns about stereotypic behaviors and was associated with a chronic increase in stereotypic corner digging among breeding gerbil pairs.