Akihito Horie

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 Survey of Current Practice and Perspectives on Lymphadenectomy in Minimally Invasive Surgery for Endometrial Cancer in Japan

ABSTRACT Objective This study investigated the reasons behind the decreasing trend of lymph node dissection for endometrial cancer (EC) in Japan, focusing on the impact of minimally invasive surgery (MIS) adoption, evolving clinical guidelines, and physician work‐style reform. Methods A cross‐sectional survey of the Japan Society of Gynecologic Oncology and Endoscopy (JSGOE) members was conducted to investigate facility demographics, MIS adoption, lymphadenectomy practices, factors influencing omission, impact of work‐style reform, and perspectives on future EC management, such as molecular classification and sentinel lymph node biopsy (SLNB). Results In total, 424 responses were received, representing a response rate of 67.8%. MIS adoption for EC is widespread in Japan, with laparoscopy preferred over robotic surgery. Lymphadenectomy is commonly performed; however, the criteria for omission varied among institutions, with clinical guidelines published by the Japanese Society of Gynecologic Oncology having the greatest impact. Physician work‐style reform significantly affected surgical practices such as surgical scheduling, adherence to time limits, and the number of surgeons participating in surgeries, while it had little impact on the criteria for lymphadenectomy omission. The adoption of molecular classifications is increasing with approximately half of the institutions planning to implement or having partially implemented them, while SLNBs remained relatively low. Conclusion This study highlights the significant impact of evolving clinical guidelines on lymphadenectomy practices for MIS for EC in Japan, and the limited impact of physician work‐style reform.

Efficacy of Sentinel Lymph Node Sampling for Early Cervical Cancer: A Single Institute Study

ABSTRACT Aim Radioisotope (RI) tracers were approved for use in gynecological cancers in Japan in 2023, and their application in sentinel lymph node (SLN) biopsy for cervical cancer is expected to expand. Our institution has been performing SLN biopsies for cervical cancer since 2009. This study aimed to evaluate the efficacy and safety of SLN biopsy in patients with early‐stage cervical cancer. Methods This study included 136 patients with FIGO 2008 stage IA1 to IB1 cervical cancer who underwent hysterectomy with SLN mapping between January 2009 and December 2023. The SLNs were identified using a combination of RI and dye (patent blue) methods. Systematic pelvic lymph node dissection (PLND) was performed during the initial introduction period. Patients were divided into two groups: the PLND group ( n  = 50), who underwent systematic dissection until August 2012, and the sentinel node navigation surgery (SNNS) group ( n  = 86), who underwent SLN biopsy with systematic dissection only when SLN metastasis was detected. Recurrence, prognosis, and complications were compared between the groups. Results In the PLND group, the SLN detection rate was 84%, and the sensitivity for detecting lymph node metastasis was 100%. Lymphedema occurred in 5.8% and 20.0% of patients in the SNNS and PLND groups, respectively. The 5‐year progression‐free survival rates in the SNNS and PLND groups were 88.6% and 92.2% respectively. The 5‐year overall survival rates were 95.5% and 97.8%, respectively, with no significant differences observed. Conclusion SLN biopsy can improve the quality of life without compromising oncologic outcomes in early‐stage cervical cancer.

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.

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy

To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy. Demonstration of the laparoscopic technique with narrated video footage. Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein. Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures. Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.

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.

Current trends and challenges in minimally invasive surgical treatment for gynecologic cancers in Japan: a cancer statistics report

Minimally invasive surgery (MIS) for gynecologic cancers, which includes laparoscopic and robotic approaches, has seen significant growth in Japan over the past decade. While offering numerous benefits, including reduced postoperative pain and shorter hospital stays, its rapid adoption has also highlighted several challenges, particularly in the management of severe surgical adverse events and disparities in training and access to technology. This article explores the current trends in MIS adoption in Japan, focusing on laparoscopy and robotic surgery, their benefits and limitations, the regulatory and certification frameworks established by the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy, and future directions for ensuring safety and efficacy in gynecologic oncology surgery.