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.

The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC.

Introduction: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

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.

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.

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.

Pediatric Small Renal Masses: Can Tumor Size Predict Histology and the Potential for Nephron-sparing Surgery?

PURPOSE: The majority of children with unilateral renal masses suspicious for malignancy undergo radical nephrectomy, while nephron-sparing surgery is reserved for select cases. We investigated the impact of tumor size on the probability of histology. We hypothesized that pediatric small renal masses are more likely benign or non-Wilms tumor, thus potentially appropriate for nephron-sparing surgery. MATERIALS AND METHODS: The SEER (Surveillance, Epidemiology, and End Results) database was analyzed for patients aged 0-18 years diagnosed with a unilateral renal mass from 2000-2016. Statistical analysis was performed to help determine a tumor size cut point to predict Wilms tumor and assess the predictive value of tumor size on Wilms tumor histology. Additionally, a retrospective review was performed of patients 0-18 years old who underwent surgery for a unilateral renal mass at a single institution from 2005-2019. Statistical analysis was performed to assess the predictive value of tumor size on final histology. RESULTS: From the SEER analysis, 2,016 patients were included. A total of 1,672 tumors (82.9%) were Wilms tumor. Analysis revealed 4 cm to be a suitable cut point to distinguish non-Wilms tumor. Tumors ≥4 cm were more likely Wilms tumor (OR 2.67, P ≤ .001), but this was driven by the statistical significance in children 5-9 years old. From the institutional analysis, 134 patients were included. Ninety-seven tumors (72.3%) were Wilms tumor. Tumors ≥4 cm had higher odds of being Wilms tumor (OR 30.85, P = .001), malignant (OR 6.75, P = .005), and having radical nephrectomy-appropriate histology (OR 46.79, P < .001). CONCLUSIONS: The probability that a pediatric unilateral renal mass is Wilms tumor increases with tumor size. Four centimeters is a logical cut point to start the conversation around defining pediatric small renal masses and may help predict nephron-sparing surgery-appropriate histology.

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.