Dermal repeated dose toxicity study of the anti-breast cancer drug Formestane cream in Bama minipig.

Formestane (4-OHA) has been proven to be highly effective with high systemic tolerability in treating ER+ breast cancer. However, its intramuscular administration and associated side effects make it unsuitable for adjuvant treatment, leading to its withdrawal from the market. In contrast, Formestane cream may offer a solution by providing a more convenient route of administration and retaining its tumor-shrinking effects. This suggests that 4-OHA cream could have promising clinical applications. However, before clinical application, it is necessary to evaluate the potential toxicity of the cream in animals. This study evaluated the toxicity of 4-OHA cream on female Bama minipigs in vivo by analyzing hematology, biochemistry, and histopathology. The results showed that there was no significant difference between the cream-treated group and the control normal group for each parameter analyzed, indicating that 4-OHA cream was non-dermal toxic to minipigs. This finding provides a basis for the safe clinical use of the cream.

The transdermal cream of Formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment.

Background: Treatment of ER+ breast cancer with intramuscular formulation of Formestane (4-OHA) shrinks the tumor within weeks. Since the tedious way of intramuscular administration and side effects are not suited for adjuvant treatment, Formestane was withdrawn from the market. A new transdermal formulation of 4-OHA cream may overcome the defects and retain the effect of shrinking the breast cancer tumor. However, the effects of 4-OHA cream on breast cancer need further confirmatory studies. Methods: In this work, in vivo, the influence of 4-OHA cream on breast cancer was evaluated using the mode of 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary cancer. We explored the common molecule mechanisms of action of 4-OHA cream and its injection formulation on breast cancer through RNA- sequencing-based transcriptome analysis and several biochemical experiments. Results: The results showed that the cream substantially reduced the entire quantity, size, and volum of tumors in DMBA-treated rats consistent with 4-OHA injection, and indicated that there were comprehensive signals involved in 4-OHA antitumor activity, such as ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and proteoglycans in cancer. In addition, we observed that both 4-OHA formulations could enhance immune infiltration, especially CD8+ T cells, B cells, natural killer cells, and macrophages infiltration, in the DMBA-induced mammary tumor tissues. The antitumor effects of 4-OHA partly depended on these immune cells. Conclusion: 4-OHA cream could inhibit breast cancer growth as its injection formulation and may provide a new way for neoadjuvant treatment of ER+ breast cancer.

The effectiveness of single ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation in managing placenta accreta spectrum (PAS) disorder.

OBJECTIVE: To evaluate the feasibility and effectiveness of single ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation in managing placenta accreta spectrum (PAS) disorder. MATERIALS AND METHODS: We retrospectively analyzed 40 PAS patients between April 2017 and October 2021. All the patients received one session of HIFU treatment. Regular follow-up was done after HIFU treatment until normal menstruation returned and placental tissue disappeared. The patient's reproductive-related outcomes were obtained through telephone interviews. RESULTS: The median follow-up time for the 40 patients was 30.50 (15.75-44.00) months and the mean placental tissue elimination time was 45.29 ± 33.32 days. The mean duration of bloody lochia was 13.43 ± 10.01 days, with no incidences of severe bleeding. Notably, Linear regression analysis showed that the residual placenta volume before HIFU was a factor affecting the duration of bloody lochia after HIFU (R2 = 0.284, B = 0.062, P = 0.000). The normal menstrual return time was 58.71 ± 31.14 days. One (2.50%) patient developed an infection. Two (5.00%) patients were subjected to ultrasound-guided suction curettage for persistent vaginal discharge for more than one month without infection. Notably, 7 of the 18 patients who expressed reproductive plans became pregnant during the 4 to 53 months of follow-up without placental abnormalities. The remaining 11 patients were on contraceptives. CONCLUSIONS: Single HIFU is an effective treatment option for managing PAS. However, future studies on further treatment strategies to reduce complications and promote patient recovery after HIFU ablation are desirable.

Focused Ultrasound Ablation Surgery combined with ultrasound-guided suction curettage in the treatment and management of Cesarean Scar Pregnancy.

OBJECTIVE: To evaluate the feasibility, safety, and effectiveness of Focused Ultrasound Ablation Surgery (FUAS) combined with ultrasound-guided suction curettage in the management of Cesarean Scar Pregnancy (CSP). STUDY DESIGN: We retrospectively analyzed 52 patients with CSP from April, 2017, to December, 2019. All the patients received one session of FUAS, and suction curettage under ultrasound guidance was performed 1-3 days after FUAS. The intraoperative blood loss in suction curettage, duration of vaginal bleeding after curettage, reproductive outcomes, and adverse effects were recorded and analyzed. RESULTS: All the 52 patients completed one session of FUAS combined with suction curettage without serious adverse effects. The mean intraoperative blood loss was 32.81 ± 53.83 mL. 47 (90.38 %) patients had a successful suction curettage with a blood loss of less than 80 mL. 5 (9.62 %) patients had an active bleeding of ≥80 mL; however, the bleeding was stopped effectively by Foley's urinary catheter and no evident bleeding presented when the catheter was removed 24 h later. The mean duration of vaginal bleeding was 7.88 ± 4.24 days. 48 (92.30 %) patients recovered with little vaginal bleeding after curettage. 4 (7.69 %) type III CSP patients experienced late-onset severe bleeding and required UAE or surgery. During 6-36 months of the follow-up period, 12 patients expressed reproductive plan, in which 4 patients delivered by cesarean section, 3 patients had an ongoing pregnancy and 1 patient had an abortion in the early pregnancy. CONCLUSIONS: FUAS combined with ultrasound-guided suction curettage is a safe and effective treatment strategy in the management of CSP type I and CSP type II and is particularly advantageous for CSP patients with reproductive requirements. However, further studies are warranted to determine the meticulous inclusion criteria for patients with type III CSP.

The beneficial androgenic action of steroidal aromatase inactivators in estrogen-dependent breast cancer after failure of nonsteroidal drugs.

Direct treatment of ER (+) breast cancer with Formestane diminishes the tumor within weeks. This is unlikely due to lack of estrogens alone. We proposed that it is the negative influence of androgens on the growth of ER(+) breast cancer. We investigated the influence of Formestane and Exemestane and of their major androgenic metabolites 4-hydroxytestosterone and 17-hydroexemestane on the proliferation of MCF-7 cells and ZR-75-1 cells. Inhibitory effects could be prevented by antiandrogens and siRNA. Activation of the AR in MCF-7 and U2-OS cells was tested by reporter gene assays. In vivo androgenicity was evaluated using the Hershberger assay. Influence on the cell cycle was demonstrated by flow-cytometry. Influence of androgens on the activity of CCND1 was demonstrated by Chip-qPCR. Antitumor activity was determined by topical treatment of DMBA tumors. We found that breast cancer cells can metabolize Formestane and Exemestane to androgenic compounds which inhibit proliferation. This can be explained by hindering the accessibility of CCND1 by histone modification. Androgenic metabolites can abolish the growth of DMBA-tumors and prevent the appearance of new tumors. The lack of cross-resistance between steroidal and nonsteroidal aromatase inhibitors is due to inhibitory effects of androgenic steroidal metabolites on the production of cyclin D1. These sterols not only inhibit proliferation of cancer cells but can also stop the growth of DMBA cancers upon direct absorption into the tumor. The quick and considerable effect on ER(+) tumors may open a new avenue for neodjuvant treatment.

Double-blind, randomized study comparing the effects of two monophasic oral contraceptives containing ethinylestradiol (20 microg or 30 microg) and levonorgestrel (100 microg or 150 microg) on lipoprotein metabolism.

The effects of two monophasic oral contraceptives containing ethinylestradiol 20 microg in combination with levonorgestrel 100 microg (EE20/LNG100) or 30 microg and 150 microg (EE30/LNG150), respectively, on lipoprotein metabolism was investigated in a double-blind, randomized study of 12 treatment cycles in healthy female volunteers. Total triglycerides (+32% to +46%, p < 0.05 in comparison to baseline) increased significantly. Triglycerides were highest after six cycles of treatment, decreasing thereafter. Total cholesterol (+1% to +7%), apolipoprotein (apo) B (+21% to +29%) and low-density lipoprotein (LDL) cholesterol (+7% to +17%) increased slightly. High-density lipoprotein (HDL) cholesterol decreased slightly (-11% and -5%), HDL triglycerides increased (+16% and +26%). Apo AI did not change during the study, suggesting that the molar concentration of HDL particles did not change. Apo E (-23% to -14%) decreased, and there was a transitory decrease of lipoprotein (a). Essentially, there was no difference regarding the changes in lipoprotein metabolism between the two treatment groups. The effects of the two combinations of ethinylestradiol and levonorgestrel on triglyceride-rich lipoproteins appear less pronounced than those produced by preparations containing third-generation progestins. It is not likely that the changes in lipoprotein metabolism brought about by the two preparations will alter the risk of future cardiovascular disease in a clinically relevant fashion.