Ken Yamaguchi

A Rare Case of Ovarian Serous Borderline Tumor Recurrence with Muscle Metastasis

BACKGROUND Ovarian serous borderline tumors (SBTs) generally have a favorable prognosis, with a very low recurrence rate. However, in rare cases, they can recur as invasive low-grade serous carcinoma (LGSC) after a prolonged follow-up period. Here, we report a case of LGSC originating from SBT that recurred 23 years after the initial surgery, with metastasis to the quadratus lumborum muscle - an exceptionally rare site of metastasis. CASE REPORT A 50-year-old woman, initially diagnosed with stage IIIC SBT and treated with complete tumor resection 23 years prior, presented with an asymptomatic recurrence detected by an elevated serum cancer antigen 125 (CA125) level. Contrast-enhanced computed tomography (CT) revealed multiple nodules suspected of peritoneal dissemination and a tumor infiltrating the quadratus lumborum muscle, suggesting recurrent SBT. A CT-guided needle biopsy confirmed that the tumor within the quadratus lumborum was a recurrence of SBT. Complete cytoreductive surgery was performed with the assistance of an orthopedic surgeon. Histopathological examination revealed progression to LGSC with cytoplasmic expression of the BRAF proto-oncogene (BRAF) V600E, indicating the presence of the BRAF V600E mutation, which is a characteristic feature of both SBT and LGSC. A retrospective review of CT images taken 10 years prior to the recurrence diagnosis showed a peritoneal tumor with calcification attached to the ileocecum, suggesting that the patient had remained asymptomatic for more than a decade after the actual onset of recurrence. CONCLUSIONS This case illustrates a rare instance of recurrent SBT with metastasis to the quadratus lumborum muscle. Given the exceptionally slow progression of recurrent SBT, long-term follow-up with CT imaging and serum CA125 monitoring is crucial for timely intervention and appropriate management upon recurrence.

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.

Visceral-to-subcutaneous fat ratio is a possible prognostic factor for type 1 endometrial cancer

Abstract Background Associations have been observed between obesity defined by the body mass index (BMI) and the incidence of endometrial cancer. However, the impact of obesity on the prognosis of endometrial cancer is not yet clear. Recently, visceral fat has been considered to have a greater impact on malignant disease in obese patients than subcutaneous fat. In this study, we investigated the association between prognostic factors of type 1 and type 2 endometrial cancer and obesity parameters. Methods The impacts of clinical factors on the progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in 145 primary endometrial cancer patients. The factors included age, BMI, pathological findings, Federation of Gynecology and Obstetrics (FIGO) stage, status of lymph node metastasis, and the amounts of visceral and subcutaneous fat obtained from computed tomography (CT) data. Results Only the visceral-to-subcutaneous fat ratio (V/S ratio) (cutoff value 0.5) corresponded to a significant difference in OS and PFS in type 1 endometrial cancer (p = 0.0080, p = 0.0053) according to the results of log-rank tests of Kaplan–Meier curves. The COX regression univariate analysis revealed that only the V/S ratio was a significant prognostic factor for PFS, but not OS (p = 0.033 and p = 0.270, respectively). Conclusion A V/S ratio > 0.5 is a possible factor for poor prognosis in type 1 endometrial cancer. Further research is needed to investigate the preventive and therapeutic effects of reducing visceral fat on the prognosis of this type of cancer.

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.

Comparison of nedaplatin and cisplatin in concurrent chemoradiotherapy for cervical cancer: a systematic review and meta-analysis

Abstract Background Cisplatin-based concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer; however, its nephrotoxicity and gastrointestinal toxicity often limit treatment eligibility and completion. Nedaplatin, a cisplatin analogue with reduced renal and gastrointestinal toxicity, has been increasingly used in East Asia, but its comparative efficacy and safety in cervical cancer have not been comprehensively evaluated. Methods We systematically searched MEDLINE, Embase, CENTRAL, CNKI, Ichushi Web, ICTRP, and ClinicalTrials.gov for randomized controlled trials comparing nedaplatin versus cisplatin-based CCRT. The primary efficacy outcome was all-cause mortality at 3 years, and the primary safety outcome was renal toxicity. Secondary outcomes included mortality at 1 and 5 years, progression or mortality, hematologic and gastrointestinal toxicities, liver dysfunction, and quality of life. Random-effects meta-analyses were performed using risk ratios. Results Seventeen trials met the eligibility criteria. All-cause mortality at 3 years did not differ significantly between the groups (RR 0.88; 95% CI 0.51–1.51; I 2  = 0%). Nedaplatin significantly reduced renal toxicity (RR 0.25; 95% CI 0.20–0.31; I 2  = 0%). Short-term outcomes favored nedaplatin, including lower 1 year mortality (RR 0.61; 95% CI 0.40–0.93) and fewer 1 year progression or mortality events (RR 0.63; 95% CI 0.44–0.91). The incidences of anemia and severe nausea/vomiting were also lower with nedaplatin. No eligible study assessed quality of life. Conclusion Nedaplatin showed fewer adverse effects and comparable or improved short-term outcomes compared with cisplatin. These findings support nedaplatin as a potential alternative for patients who are cisplatin-intolerant or frail. Confirmation in large, high-quality trials with long-term follow-up and patient-reported outcomes is warranted.

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.

Prognostic significance of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in uterine carcinosarcoma

Uterine carcinosarcoma (UCS) and uterine sarcomas (US) are rare but aggressive cancer with poor prognoses. The prognostic value of systemic inflammatory response (SIR) indicators, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), in predicting outcomes of UCS and US remains unclear. This study investigated the prognostic significance of SIR indicators for UCS and US. Clinicopathological data from 237 patients diagnosed with UCS or US across 14 hospitals from January 2008 to December 2017 were retrospectively analyzed. NLR, PLR, and MLR values were calculated from preoperative blood counts. Prognostic impact was evaluated using Kaplan-Meier survival analysis, Cox regression models, and receiver operating characteristic (ROC) curve analysis. Elevated NLR, PLR, and MLR were associated with poorer progression-free survival (PFS) in UCS. Additionally, a high NLR also indicated worse overall survival (OS) in UCS. In patients with US, only PLR was significantly associated with poorer PFS. Combining SIR indicators provided a stronger prognostic prediction for UCS compared to individual indicators. Multivariate analysis revealed that high levels of SIR indicators were an independent poor prognostic factor for both PFS and OS in UCS. SIR indicators, particularly when combined, are valuable prognostic markers in UCS, reflecting the inflammatory status and aiding in stratifying patients for tailored therapeutic strategies. These findings support the incorporation of SIR indicators into clinical practice for better management of patients with UCS.

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.

B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression

Abstract New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2–CCR2–M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1–low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFNγ signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2–CCR2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3–high tumors had fewer tumoral IFNγ+CD8+ T cells and poorer prognosis than patients with B7-H3–low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2–CCR2–M2 macrophage axis–mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma

AbstractOvarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum‐based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21‐24 (chr.17q21‐24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21‐24 amplification, and mitochondrion‐related genes were enriched in patients with chr.17q21‐24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.

CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high-grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and it was a favorable prognostic factor for patients with HGSC. Coexistence of CD8+ T cells and B cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLS. CXCL13 expression was predominantly coincident with CD4+ T cells in TLS and CD8+ T cells in TILs, and it shifted from CD4+ T cells to CD21+ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.

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.

Possible overestimation of treatment effects of pelvic and para-aortic lymphadenectomy for early-stage ovarian clear cell carcinoma: a retrospective propensity-score weighted multi-center cohort study

The treatment effects of lymphadenectomy in early-stage ovarian clear cell carcinoma (OCCC) reported in previous studies may have been overestimated owing to confounding factors. This study aimed to investigate the treatment effect of pelvic and para-aortic lymphadenectomy (PeNPAN) in early-stage OCCC, with careful adjustment for potential confounders. This retrospective multi-center cohort study involved women with preoperatively suspected stage I OCCC. We included patients who underwent surgery for OCCC between 2005 and 2019 at 11 affiliated institutions. The exposure (PeNPAN) group comprised patients who underwent PeNPAN. The primary outcome was disease-free survival (DFS). Additionally, hazard ratios (HRs) of lymphadenectomy for DFS were estimated using unadjusted and propensity score-weighted Cox regression models and biased models applied in previous studies. To identify strong confounders, we further examined factors associated with recurrence that differed between the groups. We analyzed 304 women who underwent surgery for preoperatively suspected stage I OCCC. The unadjusted HR for DFS was 0.63 (95% confidence interval [CI]=0.36-1.09; p=0.10), and the propensity-score adjusted HR was 0.82 (95% CI=0.42-1.58; p=0.55). The biased model showed a statistically significant HR of 0.59 (95% CI=0.36-1.00; p=0.048). Adhesions in the Douglas' pouch and cardiovascular disease were associated with recurrence and were more prevalent in the control group, suggesting potential confounders. After adjusting for potential confounders, the observed treatment effects of lymphadenectomy in the biased models were no longer statistically significant. Future investigations should carefully account for possible confounders, including intraoperative adhesions and comorbidities.

Awareness and attitude toward cardio‐oncology among Japanese gynecologic oncologists in managing patients with endometrial cancer: The Japanese Gynecologic Oncology Group (JGOG) questionnaire surveys

AbstractAimThis study aimed to assess the awareness of the concept of “cardio‐oncology” and cardiovascular disease (CVD) in patients with endometrial cancer (EC) among the Japanese Gynecologic Oncology Group members.MethodsAn online anonymous survey, which consisted of questions about respondent attributes and cardio‐oncology, was conducted twice, in 2022 and 2024. During these surveys, guidelines for the treatment of uterine body neoplasm were published in July 2023.ResultsIn 2022, significantly numerous physicians were unaware of cardio‐oncology or the increased risk of developing CVD in patients with EC, and 25.3% of them answered that they had no idea about cardio‐oncology at all. However, in 2024, the percentage significantly dropped to 8.7%. The number of physicians who were aware that CVD is more common as the cause of death in patients with low‐grade EC than the cancer itself was significantly higher in 2024 than in 2022. Similarly, the number of physicians who were aware that the usage of platinum agents could become a risk factor for CVD was significantly higher in 2024. Furthermore, this study reported challenges in the collaboration between oncologists and primary care physicians in the region and in the provision of guidance for preventing metabolic syndrome.ConclusionJapanese Gynecologic Oncology Group members' awareness of cardio‐oncology was inadequate, but it seemed to be improving, especially after publishing the guideline for the treatment of uterine body neoplasm. Thus, raising awareness of cardio‐oncology and managing CVD risk in patients with EC are necessary to improve long‐term survival after cancer diagnosis.