Mana Taki

Live Birth Outcomes After Extended or Repeated High‐Dose Medroxyprogesterone Acetate Therapy for Fertility‐Sparing Management of Endometrial Neoplasia: A Single‐Center Retrospective Case Series

ABSTRACT Aim To clarify live birth outcomes among women receiving extended or repeated high‐dose medroxyprogesterone acetate (MPA) therapy for fertility‐sparing management of atypical endometrial hyperplasia or endometrioid carcinoma grade 1. Methods We conducted a single‐center retrospective case series of 53 patients undergoing MPA therapy between 2005 and 2023. Patients were stratified into three groups: (i) complete response (CR) within 6 months (standard group), (ii) CR after extended treatment beyond 6 months (extended group), and (iii) CR after MPA retreatment for first intrauterine recurrence (retreatment group). Primary outcome was the live birth rate (LBR). Secondary outcomes included the effect of initial reproductive intentions, interval from CR to conception, recurrence rates, and recurrence‐free interval (RFI). Results LBRs were 33% (10/30) in the standard group, 8% (1/12) in the extended group, and 17% (2/12) in the retreatment group. Among eight patients undergoing MPA retreatment for a second or subsequent recurrence, none achieved live birth. Patients with an initial desire for prompt conception had significantly higher LBRs than those without (38% vs. 5%, p < 0.01). Median time from CR to conception leading to live birth was 12 months. Patients achieving live birth had significantly longer RFIs than those without ( p < 0.01). Conclusions Live birth is most likely when CR is achieved within 6 months of MPA therapy; nonetheless, extended or repeated MPA treatment may still result in live birth. These findings suggest the importance of appropriate patient selection and careful monitoring during extended or repeated therapy and attempting conception promptly in fertility‐sparing management of endometrial neoplasia.

YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma

Abstract Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.

A Deep Learning–Based Assessment Pipeline for Intraepithelial and Stromal Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Carcinoma

Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with epithelial ovarian cancer. However, TIL evaluation has not been used in routine clinical practice because of reproducibility issues. The current study developed two convolutional neural network models to detect TILs and to determine their spatial location in whole slide images, and established a spatial assessment pipeline to objectively quantify intraepithelial and stromal TILs in patients with high-grade serous ovarian carcinoma. The predictions of the established models showed a significant positive correlation with the number of CD8

Therapeutic impact of neoadjuvant chemotherapy on lymph node metastasis in locally advanced cervical cancer

Abstract Background Cervical cancer remains a global health concern. Lymph node (LN) metastasis, especially para‐aortic LN (PAN) involvement, is a critical prognostic factor. While neoadjuvant chemotherapy (NAC) followed by radical hysterectomy (RH) is used for locally advanced cervical cancer, its therapeutic effect on LN metastases remains uncertain. Method This retrospective study analyzed 110 patients treated with NAC followed by RH. Patients were grouped into nine cIIIC2 cases with PAN metastasis, 81 non‐cIIIC2 squamous cell carcinoma (SCC) cases, and 20 non‐squamous cell carcinoma (non‐SCC) cases. Non‐cIIIC2 SCC cases were further divided into four subgroups by LN status: cN1ypN1 ( n  = 16), cN1ypN0 ( n  = 24), cN0ypN1 ( n  = 10), and cN0ypN0 ( n  = 31). Tumor and LN size changes by NAC and survival outcomes were analyzed. Results In cIIIC2 cases, ypPAN‐negative patients showed significantly better 5‐year progression‐free survival (PFS) compared to ypPAN‐positive cases (100% vs. 0%, p  < 0.0001). Among non‐SCC cases, ypN1 patients ( n  = 9) had poorer outcomes than ypN0 cases ( n  = 11) (5‐year PFS: 25% vs. 90%, p  = 0.0005). As for non‐cIIIC2 SCC cases, tumor shrinkage rates varied among SCC subgroups: cN0ypN0 (−58.3%), cN1ypN0 (−45.5%), cN1ypN1 (−36.4%), and cN0ypN1 (−29.6%). cN0ypN1 cases also showed distinct recurrence patterns, with 66.7% experiencing distant metastases; however, prognosis did not differ among four LN‐related groups. Conclusion NAC can significantly improve prognosis in selected cases where LN metastases are eliminated, particularly in PAN and non‐SCC pelvic region metastasis cases. However, such cases are rare, emphasizing the need for better candidate selection and enhanced treatment strategies.

Investigation of the clinical implications of anterior cervical invasion in locally advanced cervical squamous cell carcinoma

Abstract Purposes This study investigates the clinical significance of the anterior parametrical invasion in surgically treated patients with cervical squamous cell carcinoma (SCC). Methods We included patients diagnosed with cervical SCC with local lesions classified as T2b, who were treated at our department between January 2006 and December 2020. We evaluated the degree of anterior invasion using pretreatment magnetic resonance imaging and divided patients into three groups: partial, equivocal, and full invasion. The frequency of recurrence within 3 years (early recurrence) and overall prognosis were assessed. Results There were 12, 24, and 46 cases in the partial equivocal, and full invasion groups, respectively. Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy was the mainstay of treatment across all groups (7, 17, and 27 cases, respectively). Although the frequency of early recurrence tended to be worse in the full group (partial; 2/7 cases, equivocal; 3/17 cases and full; 9/27 cases), all early local recurrence cases in the full group (four cases) responded well to the subsequent treatment. As for overall survival, the full invasion group had the best prognosis among the three groups. Conclusions In surgical treatment, although full anterior invasion may increase the risk of early local recurrence, it was considered to have little prognostic impact.

Mini‐review: Immunology in ovarian cancer

AbstractImmunotherapy for ovarian cancer has been studied for many years and programmed cell death protein 1 ligand/programmed cell death protein 1 (PD‐L1/PD‐1) blockade has been attempted in several clinical trials; however, the expected therapeutic effect has not been achieved. In contrast, the PD‐L1/PD‐1 blockade has been clinically applied to endometrial and cervical cancers, and a certain therapeutic effect has been observed. In endometrial cancer, promising outcomes have been achieved with a combination of an anti‐PD‐1 antibody and lenvatinib, regardless of the number of regimens, even in cases of recurrence after platinum administration. Therefore, immunotherapy is expected to have a therapeutic effect on ovarian cancer regardless of platinum resistance. In this review, considering immunotherapy for ovarian cancer, we discuss the immune mechanisms that exist in ovarian cancer and the immunotherapeutic strategies that should be developed.

High‐grade vaginal intraepithelial neoplasia after hysterectomy for high‐grade cervical intraepithelial neoplasia: Is hysterectomy a “definitive” treatment compared to conization?

AbstractAimWe investigated the frequency of early recurrence of vaginal intraepithelial neoplasia grade 2/3 (VaIN 2/3) (within 2 years) after hysterectomy for cervical intraepithelial neoplasia grade 3 (CIN3). The characteristics of the clinicopathological factors common to them were explored including different surgical methods.MethodsAs a retrospective observational study, a total of 647 CIN3 patients were divided into a conization and hysterectomy group (C group, n = 492; H group, n = 155), and HSIL (CIN2/3 or VaIN2/3) recurrence within 2 years after surgery was evaluated. A stratified analyses was performed. Surgical methods were divided into trans‐abdominal, trans‐vaginal, and laparoscopic.ResultsThe recurrence of VaIN3 was detected in four cases (2.6%) in the H group, which was similar to that of CIN2/3 in the C group, 12 out of 491 patients (2.4%). The patients who developed VaIN3 were significantly older than those who did not (median, VaIN3: 71.0; VaIN1 and less: 48.0; p < 0.0001). All VaIN3 cases were detected within 5 months, although majority of cases were negative in the margin (3/4 cases; margin negative). The method of hysterectomy was not related to the VaIN3 recurrence.ConclusionFor CIN3 patients for whom hysterectomy is the main treatment, VaIN3 can develop in 2.6% within very shortly after operation even if surgical margin was negative. The elder the age, the higher the risk of early recurrence could be. Laparoscopic surgery is considered to be acceptable methods of hysterectomy.

Defecation disorder after anterior pelvic exenteration

Abstract Aim Anterior pelvic exenteration preserves rectal function. However, we observed postoperative defecation disorders, mainly frequent, divided, and watery stools, that are not transient and persist even after hospital discharge. No reports of defecation problems after anterior pelvic exenteration for gynecological malignancies exist. Therefore, we evaluated defecation status after anterior pelvic exenteration for gynecological malignancies. Methods Sixteen patients who underwent anterior pelvic exenteration in our department between 2012 and 2022 were included. For comparison, 132 radical hysterectomy and 13 radical cystectomy cases were also included. The postoperative defecation frequency and stool form were retrospectively evaluated. Results Patients who underwent rectal mobilization, laparoscopy, and prior hysterectomy had more frequent defecation 8–14 days postoperatively than those who did not. Laparoscopy and rectal mobilization were plausible causes of increased defecation frequency after anterior pelvic exenteration. Anterior pelvic exenteration with rectal mobilization was associated with more frequent defecation than radical hysterectomy and radical cystectomy, and laparoscopic‐anterior pelvic exenteration was associated with more frequent stools than laparoscopic‐ radical hysterectomy and laparoscopic‐radical cystectomy. However, there was no difference in defecation frequency among laparotomic‐anterior pelvic exenteration, laparotomic‐radical hysterectomy, and laparotomic‐radical cystectomy. Anterior pelvic exenteration with rectal mobilization and laparoscopic‐anterior pelvic exenteration had higher Bristol Stool Form Scale scores than radical hysterectomy and laparoscopic‐radical hysterectomy, respectively. Conclusions In anterior pelvic exenteration requiring the preservation of defecatory function, patients can experience postoperative frequent watery stools. Prospective studies are needed to validate these findings in larger cohorts.