Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors.

PURPOSE: Many human breast tumors become resistant to endocrine therapies and recur due to estrogen receptor (ERα) mutations that convey constitutive activity and a more aggressive phenotype. Here, we examined the effectiveness of a novel adamantyl antiestrogen, K-07, in suppressing the growth of breast cancer metastases containing the two most frequent ER-activating mutations, Y537S and D538G, and in extending survival in a preclinical metastatic cancer model. METHODS: MCF7 breast cancer cells expressing luciferase and Y537S or D538G ER were injected into NOD-SCID-gamma female mice, and animals were treated orally with the antiestrogen K-07 or control vehicle. Comparisons were also made with the antiestrogen Fulvestrant. The development of metastases was monitored by in vivo bioluminescence imaging with phenotypic characterization of the metastases in liver and lung by immunohistochemical and biochemical analyses. RESULTS: These breast cancer cells established metastases in liver and lung, and K-07 treatment reduced the metastatic burden. Mice treated with K-07 also survived much longer. By day 70, only 28% of vehicle-treated mice with mutant ER metastases were alive, whereas all K-07-treated D538G and Y537S mice were still alive. K-07 also markedly reduced the level of metastatic cell ER and the expression of ER-regulated genes. CONCLUSION: The antiestrogen K-07 can reduce in vivo metastasis of breast cancers and extend host survival in this preclinical model driven by constitutively active mutant ERs, suggesting that this compound may be suitable for further translational examination of its efficacy in suppression of metastasis in breast cancers containing constitutively active mutant ERs.

No-Show Rates in an Academic Otolaryngology Practice Before and During the COVID-19 Pandemic.

OBJECTIVE: Our objectives were to determine the no-show and nonattendance rate for an outpatient academic otolaryngology practice, to identify patient and systemic factors associated with nonattendance, and to evaluate the impact that the COVID-19 pandemic had on the rate of nonattendance. METHODS: This is a retrospective review of the Epic practice management and billing reports from all scheduled outpatient visits at a multi-physician, academic, general, and sub-specialty otolaryngology practice from January 2019 to December 2021. RESULTS: Over three years, 121,347 clinic visits were scheduled in the otolaryngology practice. The overall nonattendance rate was 18.3%. A statistically significant increase in nonattendance was noted during the COVID-19 pandemic (16.8% vs. 19.8%, p < 0.001). The rate of nonattendance in patients of younger age (under 18 years) (p <0.001), female gender (p=0.03), afternoon appointments (p=0.04), and extended time between the day of scheduling and the day of appointment (p <0.001) increased. Head and neck clinics were found to have the lowest nonattendance rates, while pediatric otolaryngology clinics had the highest (12.6% vs. 21.3%). On multivariate regression, younger age (p < 0.001), female gender (p=0.01), afternoon appointments (p< 0.001), and online self-scheduling (p< 0.001) were significantly associated with nonattendance. CONCLUSIONS: Both patient and appointment-related factors were found to impact rates of nonattendance in this academic otolaryngology practice. In this study, young age, female gender, afternoon appointments, and online self-scheduling were associated with increased nonattendance. In addition, the COVID-19 pandemic significantly impacted no-show rates across all otolaryngologic subspecialties.

IgG4-RD in a Unilateral Parotid Mass: A Rare Manifestation and Review of the Literature.

IgG4 related disease (IgG4-RD) is a rare, immune-mediated inflammatory disease that varies widely in its presentation because it can affect nearly any organ. We present a case of a 73-year-old male who presented with an ill-defined mass of the parotid gland, found to be IgG4-RD, after several months of work up and tissue sampling. Most cases of salivary gland involvement in IgG4-RD present as bilateral swelling of the submandibular glands. We present this case as a unique manifestation of salivary gland disease in IgG4-RD as a persistent, non-discrete unilateral mass in the parotid gland. It is critical that clinicians who regularly treat salivary gland pathologies are familiar with this rare disease and its potential manifestations in the oral cavity.

Relationship Between Worst Pattern of Invasion and Extranodal Extension in Oral Tongue Squamous Cell Carcinomas.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy of the oral cavity with poor survival rates. The aim of this project is to investigate the relationship between certain histopathological factors such as Worst Pattern of Invasion (WPOI) and Extranodal Extension (ENE) in patients with oral tongue squamous cell carcinoma (OTSCC) who underwent surgical resection at Loyola University Medical Center. METHODS: This was a retrospective cohort study at a tertiary care academic medical center. All patients that underwent primary surgical resection of OTSCC between 1/1/2015 and 1/1/2022 were reviewed. Patients were identified using the Cerner CoPath Laboratory Information System. RESULTS: A total of 82 patients met inclusion criteria and were included in the study. Higher grades of WPOI (WPOI 5) were not significantly associated with the presence of ENE in our study (P = 0.82), regardless of the presence of major or minor ENE. WPOI 5 was associated with a higher incidence of local recurrence (P = 0.011). CONCLUSIONS: Higher grades of WPOI were not found to correlate with the presence of ENE, a common histopathological factor that is used as an important prognostic indicator in OTSCC. It is important for clinicians to consider these factors separately when determining whether a patient is high-risk and would benefit from aggressive multimodal treatment.

Health-Related Quality of Life and Toxicity After Definitive High-Dose-Rate Brachytherapy Among Veterans With Prostate Cancer.

PURPOSE: High-dose-rate (HDR) brachytherapy (BT) is a well-tolerated and effective treatment for prostate cancer. There is limited research, however, investigating toxicity outcomes with HDRBT treatment among veterans. The objective of this study is to assess the impact on health-related quality of life (hrQOL) and physician-graded toxicities associated with HDRBT as monotherapy among veterans treated at Edward Hines, Jr. Veterans Affairs Hospital in Hines, Illinois. METHODS: Between 2016 and 2019, 74 veterans with low- or intermediate-risk prostate cancer were treated with HDRBT as monotherapy with 27 Gy in 2 fractions, delivered over 2 implants. Veteran-reported hrQOL in the genitourinary (GU), gastrointestinal (GI), and sexual domains was assessed using the International Prostate Symptoms Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire. Mixed linear effect models were used to assess differences in the hrQOL scores at follow-up compared with baseline scores. Statistically significant differences in hrQOL scores from baseline were further assessed for clinical significance, using minimal clinically important difference (MCID) evaluations. RESULTS: Median follow-up was 18 months. Veterans reported declines in GU, GI, and sexual hrQOL scores immediately after treatment, with the IPSS and EPIC-26 hrQOL scores all displaying significant decrease from baseline over time. The majority of the declines in hrQOL scores met criteria for MCID. These hrQOL scores trended toward a return to baseline, with the EPIC-26 urinary obstruction score returning to baseline at the 18-month follow-up assessment and the EPIC-26 bowel score returning to baseline at the 12-month follow-up. The IPSS, urinary incontinence, and sexual scores did not return to baseline at 18 months. The grade 2 maximum physician-graded GU, GI, and sexual toxicity rates were 65%, 5%, and 53%, respectively. There was 1 incidence of grade 3 GU toxicity but no grade 3 GI or sexual toxicity. CONCLUSIONS: HDRBT as monotherapy is a well-tolerated treatment option for veterans with low- or intermediate-risk prostate cancer, with favorable veteran-reported and physician-graded toxicities. Veterans should be educated about HDRBT as an option when counseled regarding treatment for localized prostate cancer.

Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds.

The transcription factor FOXM1 is upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome- dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.