Xiao Xu

Glucose Deprivation‐Induced Disulfidptosis via the SLC7A11‐INF2 Axis: Pan‐Cancer Prognostic Exploration and Therapeutic Validation

Abstract Disulfidptosis, a novel form of regulated cell death, involves cytoskeletal collapse due to excessive disulfide bond formation, linking metabolism and reactive oxygen species to potential cancer therapy targets. Recent multi‐omics studies highlight the prognostic value of disulfidptosis‐related gene (DRG) signatures in pan‐cancers; however, the molecular mechanisms underlying their biological functions and therapeutic relevance remain poorly defined. Herein, a DRG score model is constructed using LASSO Cox regression across 33 cancer types, and a nomogram incorporating the DRG score is developed for prognostic prediction. The tumor microenvironment, mutation profiles, and immunotherapy responses are analyzed. The DRG score serves as an independent prognostic factor across cancers, correlating with poor outcomes and malignant features. Glucose deprivation induces disulfidptosis in SLC7A11 high cells (high SLC7A11 expression), especially in cancers with a high DRG score, such as ovarian cancer. Silencing INF2 prevents disulfidptosis and decreases susceptibility to irofulven, which can be reversed by GLUT inhibitors. SLC7A11 knockdown reduces disulfidptosis, restores ATP/NADPH levels, and protects the cytoskeleton under glucose deprivation, whereas INF2 knockdown impairs cell migration. Moreover, the DRG scores predict prognosis and therapeutic responses. The SLC7A11‐INF2 axis regulates disulfidptosis, migration, and drug sensitivity, highlighting its potential as a marker of metabolic vulnerability in ovarian cancer.

Endometrial Sampling for Preoperative Diagnosis of Uterine Leiomyosarcoma

To examine the effectiveness of endometrial sampling for preoperative detection of uterine leiomyosarcoma in women undergoing hysterectomy, identify factors associated with missed diagnosis, and compare the outcomes of patients who had a preoperative diagnosis with those of patients who had a missed diagnosis. Retrospective cohort study using linked data from the New York Statewide Planning and Research Cooperative System and New York State Cancer Registry from 2003 to 2015. Inpatient and outpatient encounters at civilian hospitals and ambulatory surgery centers in New York State. Women with uterine leiomyosarcoma who underwent a hysterectomy and a preoperative endometrial sampling within 90 days before the hysterectomy. Endometrial sampling. A total of 79 patients with uterine leiomyosarcoma met the sample eligibility criteria. Of these patients, 46 (58.2%) were diagnosed preoperatively, and 33 (41.8%) were diagnosed postoperatively. Patients in the 2 groups did not differ significantly in age, race/ethnicity, bleeding symptoms, or comorbidities assessed. In multivariable regression analysis, women who had endometrial sampling performed with hysteroscopy (compared with women who had endeometrial sampling performed without hysteroscopy) had a higher likelihood of preoperative diagnosis (adjusted risk ratio [aRR] 3.03; 95% confidence interval [CI], 1.43-6.42). Patients with localized stage (vs distant stage) or tumor size >11 cm (vs <8 cm) were less likely to be diagnosed preoperatively (aRR 0.50; 95% CI, 0.28-0.89, and aRR 0.54; 95% CI, 0.30-0.99, respectively). Supracervical hysterectomy was not performed in any of the patients whose leiomyosarcoma was diagnosed preoperatively compared with 21.2% of the patients who were diagnosed postoperatively (p = .002). Endometrial sampling detected leiomyosarcoma preoperatively in 58.2% of the patients. The use of hysteroscopy with endometrial sampling improved preoperative detection of leiomyosarcoma by threefold. Patients with a missed diagnosis had a higher risk of undergoing suboptimal surgical management at the time of their index surgery.

Physician-level variability in adopting opportunistic salpingectomy for ovarian cancer prevention at the time of hysterectomy

Opportunistic salpingectomy reduces ovarian cancer risk. To examine heterogeneity among physicians in their adoption of opportunistic salpingectomy in hysterectomy practice, we identified 33,401 non-pregnant patients aged 18 to 49 years in the Premier Healthcare Database who underwent inpatient hysterectomy for benign indications without oophorectomy in 2011-2021 (operated on by 1297 physicians). Opportunistic salpingectomy was measured by procedure codes reflecting bilateral complete removal of fallopian tubes. Even after adjusting for patient age, surgical route, indication, overweight/obesity, smoking status, and co-morbidities, opportunistic salpingectomy use varied widely among physicians. A finite mixture model identified 2 distinct adoption patterns among physicians: 1 exhibiting low adoption (average risk-adjusted rate of opportunistic salpingectomy increased from 0.01% in 2011 to 43.3% in 2021) and the other exhibiting high adoption (10.5% in 2011 to 81.3% in 2021). They accounted for 39.3% and 60.7% of the physicians, respectively. Physicians at teaching hospitals or in the northeast or west were more likely, whereas physicians having more Medicaid patients were less likely, to follow a high-adoption pattern. Physicians' adoption patterns did not differ by hysterectomy volume, hospital size, urban/rural location, or composition of their patients' race/ethnicity and marital status. These results highlight variation among physicians in their level and speed of adopting opportunistic salpingectomy.

Peer influence on physicians in adopting opportunistic salpingectomy at the time of hysterectomy

Since professional societies recommended counseling patients about opportunistic salpingectomy for ovarian cancer risk reduction, use of opportunistic salpingectomy has increased overall. However, physicians varied in their adoption of this new cancer prevention strategy. To examine peer influence among physicians as a possible factor affecting their adoption of opportunistic salpingectomy at the time of hysterectomy. Using insurance claims data from the Blue Cross Blue Shield Axis database across the United States, we identified female patients aged 18 to 49 who underwent an inpatient hysterectomy in 2019 to 2022. The outcome of interest was opportunistic salpingectomy, defined as complete removal of both (or the remaining) fallopian tubes without concurrent removal of the ovaries. We identified peer relationships among physicians based on whether 2 physicians billed for at least 2 of the same patients among insurance claims in 2017 to 2018. Then for each index physician performing inpatient hysterectomy in the 2019 to 2022 sample, we measured the rate of opportunistic salpingectomy among inpatient hysterectomies performed by all of their peer physicians in 2017 to 2018 (baseline). A multivariable regression analysis was used to examine whether an index physician's baseline exposure to peer physicians' opportunistic salpingectomy rate was associated with the subsequent use of opportunistic salpingectomy among their own patients in 2019 to 2022. Among 3373 patients who underwent inpatient hysterectomy in 2019 to 2022 (operated on by 1528 index physicians), 1871 (55.5%) received opportunistic salpingectomy. The rate of opportunistic salpingectomy was higher among patients whose index physician had exposure to peer physicians with the highest or second highest quartile of baseline opportunistic salpingectomy rate (64.5% and 59.6%, respectively), compared to those with peer physicians in the lowest quartile of baseline opportunistic salpingectomy rate (44.0%) (P<.001). After adjusting for surgical indication, surgical route, and other patient/physician characteristics, having peer physicians in the highest and second highest quartile of baseline opportunistic salpingectomy rate was associated with a 1.99 (95% confidence interval, 1.46-2.71) times and 1.64 (95% confidence interval, 1.21-2.22) times higher odds of receiving opportunistic salpingectomy, respectively. Sharing patients with other physicians who had high utilization of opportunistic salpingectomy was associated with an increased likelihood of an index physician subsequently using opportunistic salpingectomy at the time of hysterectomy. Future efforts to promote opportunistic salpingectomy use may explore the potential benefit of strategies leveraging physician peer influence.

Trends in uterine cancer incidence and mortality: insights from a natural history model

Abstract Background Uterine cancer incidence and mortality are increasing, with concomitant disparities in outcomes between racial groups. Natural history modeling can evaluate risk factors, predict future trends, and simulate approaches to reducing mortality and disparities. Methods We designed a natural history model of uterine cancer using a multistage clonal expansion design. The model is informed by National Health and Nutrition Examination Survey, National Health Examination Survey, age, time period, birth cohort, and birth certificate data on reproductive histories and body mass index (BMI). We fit and calibrated the model to Surveillance, Epidemiology, and End Results data by race and ethnicity as well as histologic subgroup. We projected future incidence and estimated the degree of contribution of BMI, reproductive history, and competing hysterectomy to excess uterine cancer incidence. Results The model accurately replicated Surveillance, Epidemiology, and End Results incidence for endometrioid, nonendometrioid, and sarcoma subgroups for non-Hispanic Black and non-Hispanic White patients. For endometrioid, nonendometrioid, and sarcomas, BMI-attributable risks are greater for non-Hispanic White than for non-Hispanic Black patients; reproductive history–attributable risks are greater for non-Hispanic Black patients. Between 2018 and 2050, endometrioid incidence is projected to rise by 64.9% in non-Hispanic Black individuals and17.5% in non-Hispanic White individuals; the projected rise for the nonendometrioid subgroup is 41.4% in non-Hispanic Black individuals and 22.5% in non-Hispanic White individuals; the sarcoma incidence projected increase is 36% in non-Hispanic Black individuals and 29.2% in non-Hispanic White individuals. Conclusions Uterine cancer risk is substantially explained by reproductive history and BMI, with differences observed between non-Hispanic Black and non-Hispanic White individuals and future projections indicating perpetuation of disparities. Lower rates of hysterectomy and rising obesity rates will likely contribute to continued increases in uterine cancer incidence.

Dihydrotanshinone I inhibits ovarian cancer cell proliferation and migration by transcriptional repression of PIK3CA gene

Abstract Dihydrotanshinone I (DHTS), extracted from Salvia miltiorrhiza, was found to be the most effective compound of tanshen extracts against cancer cells in our previous studies. However, the therapeutic benefits and underlying mechanisms of DHTS on ovarian cancer remain uncertain. In this study, we demonstrated the cytocidal effects of DHTS on chemosensitive ovarian cancer cells with or without platinum‐based chemotherapy. DHTS was able to inhibit proliferation and migration of ovarian cancer cells in vitro and in vivo through modulation of the PI3K/AKT signalling pathways. Combinatorial treatment of DHTS and cisplatin exhibited enhanced DNA damage in ovarian cancer cells. Overall, these findings suggest that DHTS induces ovarian cancer cells death via induction of DNA damage and inhibits ovarian cancer cell proliferation and migration.

Use and outcomes of hormonal therapy for advanced-stage, low-grade serous ovarian cancer.

To examine trends in the use of hormonal therapy for advanced-stage, low-grade serous ovarian carcinoma and to compare survival outcomes of patients who received traditional chemotherapy, hormonal therapy alone, or the combination of both. Women with stage II to IV low-grade serous ovarian cancer diagnosed between 2011 and 2020 were identified from the National Cancer Data Base. Patients undergoing primary surgery followed by adjuvant chemotherapy, hormonal therapy, or both were included. A multinomial logistic regression model was used to examine factors associated with treatment. Propensity score-weighted Cox proportional hazards models (via inverse probability of treatment weighting) were applied to compare overall survival across the treatment groups. Among 1532 women, 68.0% received chemotherapy alone, 12.3% received hormonal therapy alone, and 19.8% received combination therapy. Use of hormonal monotherapy increased from 0.8% in 2011 to 27.4% in 2020, and use of combination therapy increased from 0.8% to 32.6% (p 70 years) (p = .001) and those with Medicare insurance (p < .001), while combination therapy was more common in women with stage III to IV disease (p = .001). After applying propensity score weighing, 5-year survival was 76.6% (95% CI 73.2% to 79.7%) for chemotherapy alone, 85.5% (95% CI 66.1% to 94.3%) for hormonal therapy alone, and 75.8% (95% CI 59.7% to 86.2%) for combination therapy. Compared to chemotherapy alone, the HR for all-cause mortality was 0.74 (95% CI 0.46 to 1.19) for hormonal therapy alone and 0.88 (95% CI 0.63 to 1.24) for combination therapy. In advanced-stage low-grade serous ovarian cancer, the use of hormonal therapy increased substantially over time. Comparable survival outcomes across modalities suggest hormonal therapy may be a viable treatment option, particularly for patients who will not tolerate the side effects of cytotoxic chemotherapy.

Projected Trends in the Incidence and Mortality of Uterine Cancer in the United States

Abstract Background: To develop a natural history model for uterine cancer calibrated to population-based incidence and mortality data to project future trends in the disease through 2050. Methods: We developed a state-transition microsimulation model of uterine cancer. The model begins at 18 years of age and simulates Black and White patients, includes transition states for precursor lesions, and separately models endometrioid and nonendometrioid tumors. The model was calibrated to population-based incidence and mortality data using parameter extrapolation. Results: The model closely fit population-based incidence and mortality data of uterine cancer. From 2020 to 2050, the incidence of uterine cancer is projected to increase in White women to 74.2 cases per 100,000 (compared with 57.7 cases per 100,000 in 2018) and increase to 86.9 per 100,000 (compared with 56.8 cases per 100,000 in 2018) in Black women. Among White women, incidence-based mortality will increase from 6.1 per 100,000 in 2018 to 11.2 per 100,000 in 2050, whereas incidence-based mortality in Black women will increase from 14.1 per 100,000 to 27.9 per 100,000. Endometrioid tumors are expected to increase considerably in both White and Black women; White women will experience only a slight increase in nonendometrioid tumors, whereas the incidence of these tumors will increase substantially in Black women. Conclusions: The incidence and mortality of uterine cancer are projected to increase substantially over the next three decades. Black women will experience a disproportionate increase in the disease. Impact: Projecting the incidence and mortality of uterine cancer can facilitate future cancer control efforts.