This study aimed to evaluate the efficacy and safety of computed tomography-magnetic resonance imaging (CT-MRI)-guided multi-catheter interstitial brachytherapy for patients with bulky (≥4 cm) and high-risk, stage IIB–IVB advanced cervical cancer. Eighteen patients who underwent concurrent chemoradiotherapy with multi-catheter interstitial brachytherapy between September 2014 and August 2020 were enrolled. The prescribed dose of external beam radiotherapy was 45–50.4 Gy, and the brachytherapy high-dose-rate aim was 25–30 Gy per 5 fractions. The endpoints were four-year local and pelvic control rates, four-year disease-free and overall survival rates, and the adverse events rate. The median follow-up period was 48.4 months (9.1–87.5 months). Fifteen patients received concurrent cisplatin therapy (40 mg/m², q1week). Four (22.2%), seven (38.9%), and seven (38.9%) patients had stage II, III, and IV cervical cancer, respectively. Pelvic and para-aortic lymph node metastases were observed in 11 (61.1%) and 2 (11.1%) patients, respectively. The median pre-treatment volume was 87.5 cm³. The four-year local control, pelvic control, disease-free survival, and overall survival rates were 100%, 100%, 81.6%, and 87.8%, respectively. Three (16.7%) patients experienced grade 3 adverse events, and none experienced grade 4–5 adverse events. CT-MRI-guided multi-catheter interstitial brachytherapy could be a promising treatment strategy for locally advanced cervical cancer.

Menstrual blood, containing high iron levels, can undergo retrograde transport into the abdominal cavity. Excess iron causes oxidative stress and inflammation. Iron metabolism is regulated by hepcidin, and serum hepcidin levels are increased in patients with endometriosis; however, the functions of hepcidin in normal endometrium remain unclear. We therefore aimed to examine hepcidin concentrations in patients with endometriosis and to determine if iron accumulation and hepcidin increased the production of reactive oxygen species (ROS) and inflammation in normal endometrial cells. We determined hepcidin levels in peritoneal fluid and menstrual blood from patients with and without endometriosis (25/16 and 15/15 patients, respectively). We also examined the effects of hepcidin on ferroportin expression, iron accumulation, and ROS generation in normal endometrial stromal cells (NESCs) from 20 women who underwent surgery for uterine leiomyoma, using immunohistochemistry and immunofluorescence analyses and analyzed its effect on the expression of inflammatory cytokines by real-time polymerase chain reaction. There was no significant difference in iron concentrations in menstrual blood or peritoneal fluid between women with and without endometriosis; however, women with endometriosis had significantly higher hepcidin levels in menstrual blood. Hepcidin reduced the expression of ferroportin in NESCs and promoted the accumulation of ferrous iron. Hepcidin plus ferrous iron increased the production of ROS and inflammatory cytokines compared with ferrous iron alone. These results indicate that women with endometriosis have high hepcidin levels in menstrual blood, leading to increased iron production, oxidative stress, and inflammation, which may, in turn, promote the development of endometriosis.

STUDY QUESTION: Does the restoration of regulatory T cells (Tregs) suppress the progression of endometriosis? SUMMARY ANSWER: Adoptive transfer of Tregs suppresses the progression of endometriosis and reduces the levels of helper T (Th)-cell-related and proinflammatory cytokines in mice. WHAT IS KNOWN ALREADY: Endometriosis is a chronic inflammatory gynecological disease, which involves multiple immune components. Activated Treg counts decrease in the endometrioma and endometrium of patients with endometriosis, and depletion of Tregs exacerbates endometriosis in mice. STUDY DESIGN, SIZE, DURATION: We evaluated the effects of adoptive transfer of Tregs on the progression of endometriosis in mice. We used Foxp3tm3Ayr/J (Foxp3DTR) mice with temporarily ablated Tregs by injecting diphtheria toxin to develop an endometriosis model, which was generated by ovariectomy, estradiol administration and transplantation of uterine fragments from donor mice. Foxp3DTR mice were randomly divided into Treg adoptive transfer (n = 12) and control (n = 11) groups. Tregs were isolated from lymph nodes and spleens of wild-type (WT) mice and were adoptively transferred into mice that were temporarily Treg-depleted. Control mice were injected with vehicle. Treg adoptive transfer was performed on the day of uterine implantation, and a second adoptive transfer was performed after 14 days. Mice were euthanized 28 days after uterine implantation, and blood, peritoneal fluid, spleen, and endometriosis-like lesion samples were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Foxp3DTR mice were intravenously injected with Tregs isolated from WT mice. The number, total weight, and total volume of the endometriosis-like lesions were evaluated on Day 28 following implantation of uterine fragments. The proportion of Tregs in endometriosis-like lesions, ascites, and peripheral blood was analyzed by flow cytometry. Inflammation in lesions and serum was examined using real-time PCR and ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Injection of Tregs increased their total count and decreased the number (P < 0.0001), weight (P = 0.0021), and volume (P = 0.0010) of endometriosis-like lesions in Foxp3DTR Treg-depleted mice. Furthermore, injection of Tregs decreased the mRNA expression of Th 1-, 2-, and 17-related cytokines, including interferon gamma (P = 0.0101), interleukin (IL)-4 (P = 0.0051), and IL-17 (P = 0.0177), as well as the levels of the proinflammatory cytokine IL-6 (P = 0.0002), in endometriosis-like lesions of Foxp3DTR Treg-depleted mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Treg-related immune mechanisms in mice may not precisely reflect those in humans. WIDER IMPLICATIONS OF THE FINDINGS: Restoration of Tregs may be a useful therapeutic strategy for inhibiting the progression of endometriosis in cases where the decrease in the Treg population is an exacerbating factor. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by the Grants-in-Aid for Scientific Research (grant numbers 18K16808 and 20K22983) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The sponsor had no role in the study design, collection, analysis and interpretation of data, writing of the report, and decision to submit the article for publication. The authors have no conflicts of interest to disclose.

The clinical outcomes in patients with ovarian cancer have been significantly improved by Poly(adenosine diphosphate–ribose) polymerase inhibitors (PARP-is). However, the best therapeutic strategy for recurrence during PARP-i maintenance therapy remains unknown. Herein, we elucidated the efficacy of platinum-based chemotherapy after PARP-i treatment in recurrent ovarian cancer. Eligible patients had experienced relapses during PARP-i maintenance therapy lasting at least 6 months and had received subsequent platinum-based chemotherapy at our institution between January 2019 and March 2024. Progression-free survival (PFS), overall survival (OS), and risk factors for PFS were evaluated. Sixty-six patients were assessed for eligibility and eighteen were enrolled. The median follow-up period was 14.5 months. The PFS and OS of all patients were 6.5 and 17.6 months, respectively. The evaluation of the risk factors for PFS revealed that age, pathological type, duration of PARP-i maintenance therapy, prior lines of chemotherapy, and PARP-i dose reduction were not significant prognostic markers. However, bevacizumab use in subsequent therapies significantly extended the PFS. The median PFS was 3.1 months in the chemotherapy-alone group and 8.9 months in the chemotherapy with bevacizumab group (log-rank p = 0.022). Platinum-based chemotherapy with bevacizumab in subsequent therapies would provide substantial benefits in the PFS of patients with recurrent ovarian cancer.

Cisplatin resistance poses a substantial barrier to the successful treatment of advanced endometrial cancer. Glucose deprivation in the tumor microenvironment, resulting from inadequate vascularization and rapid proliferation of cancer cells, may promote chemoresistance by modifying cellular metabolism and survival pathways. This study aimed to elucidate how glucose deprivation induces cisplatin resistance in endometrial cancer cells, focusing on the role of solute carrier family 7 member 11 (SLC7A11, xCT). The endometrial cancer cell lines HEC-1A and AN3CA were cultured under glucose-deprived and glucose-supplemented conditions. Cisplatin half-maximal inhibitory concentration (IC50) values, SLC7A11 expression, and reactive oxygen species (ROS) levels were assessed using cell proliferation assays, real-time PCR, Western blotting, and fluorescence assays. SLC7A11 was inhibited using small interfering RNA (siRNA) knockdown and the selective inhibitor HG106. Cisplatin-resistant cell lines were generated to evaluate the effect of SLC7A11 inhibition. Glucose deprivation significantly decreased cisplatin sensitivity and increased cisplatin IC50 values (P < 0.05). This reduction in sensitivity was accompanied by upregulation of SLC7A11 expression and decreased ROS levels (P < 0.05). Inhibition of SLC7A11, either by siRNA or HG106, increased cisplatin sensitivity and ROS production, even in cisplatin-resistant cells (P < 0.05). This effect was reversible with the antioxidant N-acetylcysteine. These findings demonstrate that glucose deprivation induces cisplatin resistance in endometrial cancer cells by upregulating SLC7A11, leading to reduced ROS levels and enhanced cell survival. Targeting SLC7A11 restores cisplatin sensitivity by elevating ROS production, even in cisplatin-resistant cells. The findings suggest that SLC7A11 is a promising therapeutic target for overcoming chemoresistance in endometrial cancer, potentially improving treatment outcomes and patient survival.