Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study.

OBJECTIVES: Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN: In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS: A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS: During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS: In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.

PURPOSE: Increased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial. EXPERIMENTAL DESIGN: HNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed. RESULTS: Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line-derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation. CONCLUSIONS: Ruxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.

Rethinking Disparities in Minimally Invasive Myomectomy: Identifying Drivers of Disparate Surgical Approach to Myomectomy Between African American and White Women.

STUDY OBJECTIVE: To identify drivers of disparities among patients undergoing surgical management of myomas when stratified by self-identified patient race. DESIGN: This is a retrospective institutional review board-approved chart review of all patients who underwent a myomectomy at a large academic center. Surgical approach to myomectomy was classified as abdominal, laparoscopic, or robotic-assisted laparoscopic. Myoma burden was quantified preoperatively using uterine volume, intraoperatively by number of myomas listed on operative report, and postoperatively by myoma weight from pathology reports. SETTING: A large tertiary care hospital containing a comprehensive myoma treatment center. PATIENTS: A total of 265 white patients and 121 African American patients who underwent a myomectomy between January 2012 and October 2018 were included in the study population. INTERVENTIONS: Abdominal, laparoscopic, and robotic-assisted myomectomy. Laparoscopic and robotic-assisted myomectomy were classified as minimally invasive myomectomy. Multivariable logistic regression models and a propensity score matching algorithm were used to match African American (AA) women and white women for myoma burden. MEASUREMENTS AND MAIN RESULTS: A total of 386 women were included in the study. AA women (31%; n = 121) had higher myoma burden than white women by preoperative imaging (AA: 36% with 3 or more myomas; white: 19% with 3 or more myomas; p <.01) and operative report (>8 AA: 31% vs white 13%; p <.01). Despite this, AA women underwent minimally invasive myomectomy at similar rates as compared with white women when adjusted for myoma burden, body mass index, preoperative hematocrit, hypertension, and surgical indication (adjusted odds ratio 1.3; 95% confidence interval, 0.8-2.2 myomas; p <.01). Sensitivity analysis using propensity score matching found similar results. CONCLUSION: In this population, AA women had a higher myoma burden than white women. When matched for myoma burden, however, there was no statistically significant difference between rates of minimally invasive myomectomy and abdominal myomectomy. This finding was consistent when controlling for myoma burden measured by preoperative, intraoperative, or postoperative methods of measurement. Further studies are needed to better characterize this disparity at other hospitals and to investigate ways to increase access and equity among patients undergoing minimally invasive myomectomy.

Targeting the JAK/STAT pathway in solid tumors.

Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in in vivo models, they also inhibit tumor growth. JAK inhibitors, particularly the JAK1/2 inhibitor ruxolitinib, sensitize cell lines and murine models to chemotherapy, immunotherapy, and oncolytic viral therapy. Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors; two of these inhibitors are already Food and Drug Administration (FDA) approved for the treatment of myeloproliferative disorders and rheumatoid arthritis, making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated. Four JAK inhibitors (two of which are FDA approved for other indications) have exhibited promising anti-cancer effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.