Koji Yamanoi

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.

Real-world application of comprehensive genomic profiling for gynecological malignancies: a multicenter observational study

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.

Origin of Peritoneal Cancer With Features of High-grade Serous Carcinoma: A Detailed Molecular Analysis

Primary peritoneal cancer has characteristics similar to high-grade serous carcinomas of ovarian and fallopian tube origin. However, the relationship between endometriosis and primary peritoneal cancer is not well understood. This study focuses on a case of peritoneal cancer in a patient who had undergone hysterectomy and bilateral salpingo-oophorectomy 5 yr before. In addition to morphology, there was a positive for TP53 in immunohistochemistry and homologous recombination deficiency test, which were similar to high-grade serous carcinomas. However, WT1 was negative in the tumor, and extensive endometriosis coexisted. To reveal the clonal relationship between tumor and endometriosis, we dissected 3 sites each from the tumor and endometriosis and performed whole-exome sequencing analysis. As a result, we found that the tumors were of identical origin. Contrarily, no shared mutations were found in the 3 endometriosis sites. Furthermore, several shared mutations were found between the tumor and 1 endometriosis tissue, showing that the tumor and 1 ectopic endometrial gland originated from the same clone. This study indicates that several peritoneal cancers may be derived from endometriosis. We should consider the possibility of more diverse origins of peritoneal cancer than we speculated before.

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

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

Real-world multicenter study of immune checkpoint inhibitors in advanced cervical cancer across HPV-associated and HPV-independent subtypes

Cervical cancer remains a major health problem, and HPV-independent subtypes such as gastric-type adenocarcinoma carry dismal outcomes. Although immune checkpoint inhibitors (ICIs) have improved survival in large trials, their real-world effectiveness including HPV-independent tumors is not well established. We conducted a retrospective multicenter study of two surrogate cohorts representing refractory cervical cancer: patients treated with bevacizumab (Bev-cohort, n = 65) and those undergoing comprehensive genomic profiling (CGP-cohort, n = 42). Early ICI administration was evaluated using landmark analysis (Bev: 180 days; CGP: 6 months), with differences in restricted mean survival time (ΔRMST) as the primary endpoint. Multivariable Cox models adjusting for stage, histology, and treatment interval were performed as secondary analyses. Exploratory analyses assessed HPV and molecular status for associations with ICI response. In the Bev-cohort, 14 ICI-treated patients achieved significantly longer survival than 48 non-ICI patients (ΔRMST + 19.4 days at 180 days; + 56.2 days at 360 days). Multivariable Cox confirmed ICI as an independent predictor of survival (HR 0.15, 95%CI 0.01-0.69). In the CGP-cohort, 11 ICI-treated patients also experienced superior survival compared with 20 non-ICI patients (ΔRMST + 1.05 months at 6 months; + 2.33 months at 12 months). Among 36 ICI-treated cases overall, efficacy was not clearly associated with PD-L1 or tumor mutation burden status. Importantly, HPV-independent tumors, including gastric-type adenocarcinoma, demonstrated progression-free survival comparable to HPV-associated tumors. ICIs improved survival in advanced refractory cervical cancer across two real-world cohorts. HPVI may respond favorably, but further studies are needed.

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.

Re-evaluating prognostic factors for cervical cancer with lymph node metastasis: a Japanese multicenter cohort study based on FIGO 2018

In 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised its cervical cancer staging system to enhance clinical relevance, notably by categorizing lymph node metastases (LNM) as an independent stage IIIC. This multicenter study evaluates the prognostic implications of the FIGO 2018 classification within a Japanese cohort. This study included 1468 patients with cervical cancer. Initial FIGO 2009 stages were restaged under FIGO 2018. Stage IIIC was further compared based on the location of LNM (pelvic or para-aortic, i.e., IIIC1 and IIIC2, respectively), local tumor stage, and histology. A total of 345 cases (27.4%) were upstaged to stage IIIC, which exhibited a poorer prognosis compared to stage II (HR, 2.12; 95% CI 1.29 - 3.48; p = 0.004) and better than stage IIIAB (HR, 0.46; 95% CI 0.27 - 0.78; p = 0.004). Notably, stage IIIC2 showed a significantly worse prognosis than IIIC1 (HR, 2.32; 95% CI 1.37 - 3.93; p = 0.003). Subdivisions of stage IIIC1 (T1, T2, and T3AB) displayed significantly varied prognoses, with the prognosis for IIIC1-T3AB similar to that of stage IIIAB. In contrast, all subdivisions of IIIC2 showed uniformly poor outcomes. Multivariate analysis of stage IIIC patients revealed that para-aortic LNM, adenocarcinoma and adenosquamous carcinoma histology, and local T3AB tumor remained significant. The classification of para-aortic LNM as stage IIIC2 has proven to be of critical relevance in the Japanese cohort. However, the prognostic impact of stage IIIC1 remains influenced by local tumor factors and histological subtypes.

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.

Neuroendocrine carcinoma of the uterine cervix with extensive pagetoid spread pattern

AbstractThere have been no reported cases of neuroendocrine carcinoma (NEC) of the cervix with pagetoid spread (Pag‐S). A 44‐year‐old woman came to our department because of abnormal cytology that persisted immediately after a radical hysterectomy for NEC of the cervix. A mapping biopsy in a large area from the vaginal wall to the vulva revealed that synaptophysin/Ki‐67‐positive tumor cells were scattered within the epithelium in multiple areas, suggesting a wide Pag‐S of NEC. Because tumor cells were found beyond the vaginal wall, the anterior pelvic exenteration was performed. Since we could pathologically confirm the complete resection and no distant metastases were detected, no adjuvant therapy was performed. Four years have passed since the initial treatment without any tumor recurrence. It is known that the prognosis of NEC of the cervix that invades beyond the cervix is poor; however, if there is a Pag‐S pattern, a radical surgical treatment can be considered.

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.

Differentiation of uterine fibroids and sarcomas by MRI and serum LDH levels: a multicenter study of the KAMOGAWA study

In the differential diagnosis between uterine fibroids and uterine sarcomas, real-world magnetic resonance imaging (MRI) diagnostic information is scarce; furthermore, high diagnostic sensitivity is important in clinical practice. We previously developed a diagnostic algorithm to detect uterine sarcoma with high sensitivity using simple MRI images and serum lactate dehydrogenase (LDH) levels. In this multicenter study, we investigated the preoperative diagnosis of sarcoma in the real world and further validated the usefulness of our diagnostic algorithm. Of 154 uterine sarcomas and 154 uterine fibroids treated at 15 centers between January 2006 and December 2020, 139 sarcomas (16 smooth muscle tumors of uncertain malignant potential) and 141 fibroids with diffusion-weighted imaging information were included in the analysis. The diagnostic algorithm was validated by 3 radiologists who were blinded to the clinical information and pathologic diagnoses and who read the MRIs. The sensitivity/specificity of preoperative diagnosis was 77.7%/92.9% for the preoperative report; 92.1%/72.3% for algorithm A; and 82.0%/85.8% for algorithm B (McNemar's test p<0.05). Comparison of overall survival rates among 3 groups (Group 1: negative A, Group 2: positive A and negative B; Group 3: positive B) using algorithms A and B showed p=0.012. On multivariate analysis, stage, and serum LDH level were independent prognostic factors. MRI is useful for preoperative diagnosis of uterine sarcoma, and the sarcoma diagnostic algorithm presented in this study is an option for diagnosing sarcoma with greater sensitivity. This information should be shared with patients.