Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers.

OBJECTIVE: The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: MLH1 hypermethylated, Lynch-like syndrome (LLS)-associated, and Lynch syndrome (LS)-associated cancers. This study aimed to investigate whether the efficacy of pembrolizumab differs among these 3 groups, and if so, whether EPM2AIP1 immunohistochemistry (IHC), which correlates with MLH1 promoter methylation, can be used to rule out MLH1 methylation cases. METHODS: This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on MLH1 methylation analysis and the Amsterdam Criteria: MLH1 hypermethylated (sporadic [SP]), LLS-associated, and LS-associated. Patients' medical records were retrospectively reviewed, and the efficacy of treatment was evaluated based on the response rate using the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for MLH1 methylation were 100% and 66.7%, respectively. CONCLUSION: Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than MLH1 methylation analysis; however, it may be useful for ruling out MLH1 methylation cases due to its high sensitivity. Further studies are needed to determine whether EPM2AIP1 IHC can predict pembrolizumab efficacy.

Comparison of postoperative adjuvant platinum-based chemotherapy and no further therapy after radical surgery in intermediate-risk early-stage cervical cancer.

OBJECTIVE: To identify a relatively high-risk population in postoperative intermediate-risk cervical cancer and evaluate the effect of platinum-based adjuvant chemotherapy (CT). METHODS: We retrospectively reviewed the medical records of patients with stage IA2-IIA cervical cancer who had been treated with radical hysterectomy and pelvic lymphadenectomy and classified as the intermediate-risk group for recurrence by postoperative pathological examination from January 2007 to December 2018 at 3 medical centers in Japan. First, patients with intermediate-risk were stratified by histological type and the number of intermediate-risk factors (IRF; large tumor diameter, lymph vascular space invasion, and deep cervical stromal invasion) and then divided into 2 groups: high and low-risk population (estimated 5-year recurrence-free survival [RFS] rate with no further therapy [NFT] <90% and ≥90%, respectively). Second, the efficacy of CT for the high-risk population was evaluated by comparing RFS and overall survival (OS) between the patients receiving CT and those with NFT. RESULTS: In total, 133 patients were included in the analysis. Among patients with squamous cell carcinoma (SCC) with all IRF or those with non-SCC with 2 to 3 IRF, the 5-year estimated RFS was <90% when treated with NFT. In this population, adjuvant CT was significantly superior to NFT regarding RFS (log-rank, p=0.014), although there was no statistical difference in OS. CONCLUSION: Patients with SCC with all 3 IRFs and those with non-SCC with 2 to 3 IRFs were at high risk for recurrence. Adjuvant CT is a valid treatment option for these populations.

Trop-2 expression and the tumor immune microenvironment in cervical cancer.

OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.

Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a unique clinicopathological subtype of epithelial ovarian cancer that is resistant to standard chemotherapy. Eribulin, a microtubule dynamics inhibitor of halichondrin class, has unique effects in the cancer microenvironment such as induction of epithelization and reduction in metastatic potential in breast cancer cells; however, nothing is known about the effect of eribulin and the detailed mechanisms in OCCC. This study aimed to investigate the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in OCCC cells and a mouse xenograft model. We found that eribulin-induced cell death was reduced by ferroptosis inhibitors; deferoxamine, an iron chelator and ferrostatin-1, a lipid peroxidation inhibitor. Eribulin increased the levels of intracellular iron, reactive oxygen species (ROS), and lipid peroxides, and increased the mitochondrial membrane potential. Eribulin downregulated the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and superoxide dismutase (SOD) activity. The combination of eribulin and ML210, a glutathione peroxidase 4-inhibiting ferroptosis inducer, had a synergistic effect on ferroptosis. Taken together, our findings show firstly that eribulin triggers ferroptosis in OCCC and this effect occurs via the suppression of the Nrf2-HO-1 signaling pathway, SOD activity and the promotion of lipid peroxidation. These findings suggest that eribulin-induced ferroptosis is associated with its anti-tumor effect and also could be a potential therapeutic target in OCCC.

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer.

The clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5-year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. METHODS: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. RESULTS: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. CONCLUSION: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

Prevention of symptomatic pulmonary embolism for gynecologic malignancies with preoperative asymptomatic venous thromboembolism: GOTIC-VTE trial.

OBJECTIVE: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. METHODS: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. RESULTS: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). CONCLUSION: The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE. TRIAL REGISTRATION: JRCT Identifier: jRCTs031180124.

Gynecological technical notes for appropriate spacer injections.

BACKGROUND: Despite its efficacy, if adherence to dose constraints for surrounding normal tissues proves unattainable, the risk of late radiation-related adverse events after primary radiotherapy involving brachytherapy remains a noteworthy concern. Some studies suggest that similar to prostate radiotherapy, spacers may potentially reduce doses to surrounding healthy rectal or bladder tissues. However, guidance on spacer injections for gynecologic brachytherapy is scarce, and the optimal anatomical location for spacer placement remains undefined. We discuss maximizing the effects of spacers from an anatomical perspective. FINDINGS: As vesicovaginal and rectovaginal septa form part of the endopelvic fascia and are not uniform tissues, spacer injection resistance varies. In pelvic organ prolapse surgery, saline is injected into the anterior and posterior vaginal walls as a spacer, and the vagina, vesicovaginal septum, and bladder can be fluidly dissected. Relatively firm vesicovaginal septum tissue is used as a reconstructive organ, whereas rectovaginal septum tissue is less dense. Cervical cancer is invasive, involving surrounding fascia and ligaments. Ideally, the vesicovaginal and rectovaginal septa should be resected in radical hysterectomy. Here, spacer adaptation and the technical details of injection are described. When using ultrasound guidance for spacer injection, the target site should be adequately magnified, and the spacer ideally injected into the incision layer during radical hysterectomy. Finally, posthysterectomy, the intestinal tract may adhere to the vaginal cuffs. Therefore, artificial ascites may be useful; however, the spread depends on perioperative manipulation. CONCLUSIONS: Anatomical and surgical viewpoints are advantageous for safe, therapeutic, and replicable spacer injection administration.

Use of clinical variables for preoperative prediction of lymph node metastasis in endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynaecological cancer, and most patients are identified during early disease stages. Noninvasive evaluation of lymph node metastasis likely will improve the quality of clinical treatment, for example, by omitting unnecessary lymphadenectomy. METHODS: The study population comprised 611 patients with endometrial cancer who underwent lymphadenectomy at four types of institutions, comprising seven hospitals in total. We systematically assessed the association of 18 preoperative clinical variables with postoperative lymph node metastasis. We then constructed statistical models for preoperative lymph node metastasis prediction and assessed their performance with a previously proposed system, in which the score was determined by counting the number of high-risk variables among the four predefined ones. RESULTS: Of the preoperative 18 variables evaluated, 10 were significantly associated with postoperative lymph node metastasis. A logistic regression model achieved an area under the curve of 0.85 in predicting lymph node metastasis; this value is significantly higher than that from the previous system (area under the curve, 0.74). When we set the false-negative rate to ~1%, the new predictive model increased the rate of true negatives to 21%, compared with 6.8% from the previous one. We also provide a spreadsheet-based tool for further evaluation of its ability to predict lymph node metastasis in endometrial cancer. CONCLUSIONS: Our new lymph node metastasis prediction method, which was based solely on preoperative clinical variables, performed significantly better than the previous method. Although additional evaluation is necessary for its clinical use, our noninvasive system may help improve the clinical treatment of endometrial cancer, complementing minimally invasive sentinel lymph node biopsy.

Ovarian Mucinous Tumor Presenting Atypical Lobular Endocervical Glandular Hyperplasia-Like Appearance in a Patient With Germline STK11 p.F354L Variant: A Case Report.

Peutz-Jeghers syndrome (PJS) is associated with female genital lesions, such as cervical gastric-type adenocarcinoma and lobular endocervical glandular hyperplasia (LEGH). However, ovarian mucinous borderline tumors (OMBT) with atypical LEGH-like histology have not been described. The patient was a 60-year-old female with PJS clinically diagnosed at 23 years old with gastrointestinal polyposis. Abdominal distension was noted, and computed tomography scan revealed bilateral breast masses, multiple lung nodules, and a multicystic ovarian tumor. A needle biopsy revealed invasive ductal carcinoma of the breast. For the ovarian tumor, simple hysterectomy and bilateral salpingo-oophorectomy were performed. The left ovarian tumor was 25 × 20 × 12 cm in size and a multicystic tumor containing yellowish mucus without a solid part. Histologically, the cyst wall was covered with mucus cells with focal mild-to-moderate cellular atypia, forming LEGH-like architectures. The glandular cells were immunohistochemically positive for MUC5AC, MUC6 (focal), HIK1083 (focal), and HNF4α. Stromal invasion was not observed. Cervical lesions were not observed. The final pathological diagnosis was OMBT showing atypical LEGH morphology. Targeted sequencing of nontumor tissues revealed the germline STK11 p.F354L variant. Six months later, peritoneal dissemination of adenocarcinoma showing features similar to those of the ovarian tumor was observed, and the patient died of the disease. In summary, we report a case of OMBT with an atypical LEGH-like appearance in a patient with germline STK11 p.F354L variant. This case provides us with unresolved questions regarding the pathogenicity of this STK11 variant and the malignant potential of OMBT with this unusual morphology.

Ovarian Mesonephric-Like Adenocarcinoma With Recurrent Liver Metastases: A Case Report with Analysis of Therapeutic Molecular Targets.

Ovarian mesonephric-like adenocarcinoma (MLA) is a rare cancer subtype. We describe a patient with ovarian MLA wherein liver metastases developed 1 month after surgery. A phenotypic analysis of the tumor was performed to identify molecular therapeutic targets. A 53-year-old woman, without any symptoms, underwent uterine cancer screening. Transvaginal ultrasonography revealed an ovarian mass, and subsequent pelvic magnetic resonance imaging showed a 13 × 10 cm multicystic ovarian lesion with a solid part. No extra ovarian lesions were observed and a staging laparotomy was performed. Pathological examination revealed an MLA of the left ovary (stage IC1). The tumor comprised tumor cells in a tubular pattern with intraluminal eosinophilic material, as well as mixed glandular and papillary, cord-like, and solid patterns. Endometriosis was also observed. Immunohistochemically, the tumor cells were positive for PAX8, GATA3 (focal), TTF1 (focal), and CD10 (luminal) and negative for the estrogen receptor, progesterone receptor, and WT1. One month after surgery, computed tomography revealed multiple liver metastases. Additional immunohistochemistry for therapeutic targets revealed that the tumor cells were weakly positive for human epidermal growth factor receptor 2 (focal; score 1+), pan-tropomyosin receptor kinase-negative, programmed death-ligand 1-negative, and PMS2 and MSH6 intact. The companion homologous recombination deficiency test (MyChoice®) showed homologous recombination repair proficiency. These findings suggest that poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors may not be effective treatment options. A literature review revealed that data on therapeutic targets in MLA are scarce. In summary, we report a patient with ovarian MLA showing an aggressive clinical course and the phenotypic analysis of the tumor may contribute to the identification of therapeutic targets for MLA.

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression.

OBJECTIVE: This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. METHODS: We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. RESULTS: A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. CONCLUSION: MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

Therapeutic target biomarkers of patient-derived xenograft models of gastric-type cervical adenocarcinoma.

Background: Most cervical adenocarcinomas are associated with human papillomavirus (HPV). Gastric-type cervical adenocarcinoma (GAS), an HPV-independent adenocarcinoma, shows an aggressive clinical feature, resulting in a poor prognosis. Resistance to chemotherapy poses a difficulty in managing patients with metastatic GAS. We aimed to establish patient-derived xenografts (PDXs) of tumors from two patients with GAS and evaluated protein biomarkers for drug development using immunohistochemistry. Methods: Two PDXs were established 78 and 48 days after transplanting the patient's tumor tissues into immunodeficient mice, respectively. PDX and patient's tumor samples were stained for HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A to evaluate biomarkers for therapeutic targets. In addition, whole exome sequencing and RNA sequencing were performed on available samples. Results: The pathological findings in morphological features and immunohistochemical profiles from the established PDXs were similar to those from the patients' surgical tumor specimens. HER3 was overexpressed in the patient's tumors, and the corresponding PDX tumors and HER2 was weakly stained in both types of tumor samples. In all PDX and patient tumor samples, PMS2, MSH6, and ARID1A were retained, and PanTrk was not expressed. In addition, a total of 10 samples, including tumor tissue samples from 8 other GAS patients, were evaluated for HER3 expression scores, all of which were 2 + or higher. Conclusions: In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2.

Integrative analysis reveals early epigenetic alterations in high-grade serous ovarian carcinomas.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. To date, the profiles of gene mutations and copy number alterations in HGSOC have been well characterized. However, the patterns of epigenetic alterations and transcription factor dysregulation in HGSOC have not yet been fully elucidated. In this study, we performed integrative omics analyses of a series of stepwise HGSOC model cells originating from human fallopian tube secretory epithelial cells (HFTSECs) to investigate early epigenetic alterations in HGSOC tumorigenesis. Assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq) methods were used to analyze HGSOC samples. Additionally, protein expression changes in target genes were confirmed using normal HFTSECs, serous tubal intraepithelial carcinomas (STICs), and HGSOC tissues. Transcription factor motif analysis revealed that the DNA-binding activity of the AP-1 complex and GATA family proteins was dysregulated during early tumorigenesis. The protein expression levels of JUN and FOSL2 were increased, and those of GATA6 and DAB2 were decreased in STIC lesions, which were associated with epithelial-mesenchymal transition (EMT) and proteasome downregulation. The genomic region around the FRA16D site, containing a cadherin cluster region, was epigenetically suppressed by oncogenic signaling. Proteasome inhibition caused the upregulation of chemokine genes, which may facilitate immune evasion during HGSOC tumorigenesis. Importantly, MEK inhibitor treatment reversed these oncogenic alterations, indicating its clinical effectiveness in a subgroup of patients with HGSOC. This result suggests that MEK inhibitor therapy may be an effective treatment option for chemotherapy-resistant HGSOC.

Nodal infiltration in endometrial cancer: a prediction model using best subset regression.

OBJECTIVES: To build preoperative prediction models with and without MRI for regional lymph node metastasis (r-LNM, pelvic and/or para-aortic LNM (PENM/PANM)) and for PANM in endometrial cancer using established risk factors. METHODS: In this retrospective two-center study, 364 patients with endometrial cancer were included: 253 in the model development and 111 in the external validation. For r-LNM and PANM, respectively, best subset regression with ten-time fivefold cross validation was conducted using ten established risk factors (4 clinical and 6 imaging factors). Models with the top 10 percentile of area under the curve (AUC) and with the fewest variables in the model development were subjected to the external validation (11 and 4 candidates, respectively, for r-LNM and PANM). Then, the models with the highest AUC were selected as the final models. Models without MRI findings were developed similarly, assuming the cases where MRI was not available. RESULTS: The final r-LNM model consisted of pelvic lymph node (PEN) ≥ 6 mm, deep myometrial invasion (DMI) on MRI, CA125, para-aortic lymph node (PAN) ≥ 6 mm, and biopsy; PANM model consisted of DMI, PAN, PEN, and CA125 (in order of correlation coefficient ß values). The AUCs were 0.85 (95%CI: 0.77-0.92) and 0.86 (0.75-0.94) for the external validation, respectively. The model without MRI for r-LNM and PANM showed AUC of 0.79 (0.68-0.89) and 0.87 (0.76-0.96), respectively. CONCLUSIONS: The prediction models created by best subset regression with cross validation showed high diagnostic performance for predicting LNM in endometrial cancer, which may avoid unnecessary lymphadenectomies. CLINICAL RELEVANCE STATEMENT: The prediction risks of lymph node metastasis (LNM) and para-aortic LNM can be easily obtained for all patients with endometrial cancer by inputting the conventional clinical information into our models. They help in the decision-making for optimal lymphadenectomy and personalized treatment. KEY POINTS: •Diagnostic performance of lymph node metastases (LNM) in endometrial cancer is low based on size criteria and can be improved by combining with other clinical information. •The optimized logistic regression model for regional LNM consists of lymph node ≥ 6 mm, deep myometrial invasion, cancer antigen-125, and biopsy, showing high diagnostic performance. •Our model predicts the preoperative risk of LNM, which may avoid unnecessary lymphadenectomies.

Utility of the revised FIGO2023 staging with molecular classification in endometrial cancer.

OBJECTIVES: Molecular classification was introduced in endometrial cancer staging following the transition of the International Federation of Gynecology and Obstetrics (FIGO) 2008 to FIGO2023. In the early stages, p53 abnormal endometrial carcinoma with myometrial involvement was upstaged to stage IICm, in addition to the downstaging of POLE mutation endometrial cancer to stage IAm. This study compared the goodness of fit and discriminatory ability of FIGO2008, FIGO2023 without molecular classification (FIGO2023), and FIGO2023 with molecular classification (FIGO2023m); no study has been externally validated to date. METHODS: The study included 265 patients who underwent initial surgery at the National Cancer Center Hospital between 1997 and 2019 and were pathologically diagnosed with endometrial cancer. The three classification systems were compared using Harrell's concordance index (C-index), Akaike information criterion (AIC), and time-dependent receiver operating characteristic (ROC) curves. A higher C-index score and a lower AIC value indicated a more accurate model. RESULTS: Among the three classification systems, FIGO2023m had the lowest AIC value (FIGO2023m: 455.925; FIGO2023: 459.162; FIGO2008: 457.901), highest C-index (FIGO2023m: 0.768; FIGO2023: 0.743; FIGO2008: 0.740), and superior time-dependent ROC curves within 1 year after surgical resection. In the stage IIIC, patients with p53 abnormalities had considerably lower 5-year overall survival than those with a p53 wild-type pattern (24.3% vs. 83.7%, p = 0.0005). CONCLUSIONS: FIGO2023m had the best discriminatory ability compared with FIGO2008 and FIGO2023. Even in advanced stages, p53 status was a poor prognostic factor. When feasible, molecular subtypes can be added to the staging criteria to allow better prognostic prediction in all stages.

Potential diagnostic value of quantitative superb microvascular imaging in premalignant and malignant cervical lesions.

Objective: The purpose of this study was to assess the diagnostic efficacy of the vascular index (VI) on superb microvascular imaging (SMI) in distinguishing normal uterine cervical epithelium, high-grade cervical intraepithelial neoplasia (CIN), and cervical cancer. Methods: The retrospective study included women with pathology-confirmed CIN or cervical cancer, who underwent transvaginal ultrasound and SMI between April 2021 and October 2022. The SIM manifestations of normal cervix and cervical lesions were reviewed. SIM were measured and converted into vascular index (VI) which compared between cervical lesions and control groups. We have retrospectively compared ultrasound features of cervical lesions and characteristics of patients. Measurement reliability was evaluated by intra class correlation coefficient (ICC). Results: A total of 235 consecutive females were enrolled, comprising 38 with high-grade CIN, 96 with cervical cancer, and 101 with a normal uterine cervix. The microvascular architecture exhibited significant variations between premalignant and malignant cervical lesions. Branch-like patterns were predominantly observed in high-grade CIN, while crab claw-like and fireball-like patterns were more commonly associated with cervical cancer. The median VI of cervical cancer (34.7 ± 10.3) was significantly higher than that of high-grade CIN (17.6 ± 4.2) (P < 0.001). Moreover, the VI values of cervical cancer differed significantly among different FIGO stages and pathological types (P < 0.001 and P = 0.003, respectively). The VI demonstrated superior diagnostic performance for cervical lesions compared to vascular patterns (AUC = 0.974 and 0.969, respectively). Using a cut-off value of 25.5, the VI yielded a sensitivity of 82.3% and a specificity of 99.3% for cervical lesion detection. Conclusions: The SMI parameter (VI) exhibited a significantly higher value in cervical cancer compared to high-grade CIN, with a high level of agreement among observers. These findings suggest that quantitative SMI holds promise as an imaging technique for the detection and characterization of cervical lesions.

Rare FGFR fusion genes in cervical cancer and transcriptome-based subgrouping of patients with a poor prognosis.

BACKGROUND: Although cervical cancer is often characterized as preventable, its incidence continues to increase in low- and middle-income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed the distribution of fusion genes across cancer types and used an RNA-based classification to divide cervical cancer patients with a poor prognosis into subgroups. MATERIAL AND METHODS: RNA sequencing of 116 patients with cervical cancer was conducted. Fusion genes were extracted using StarFusion program. To identify a high-risk group for recurrence, 65 patients who received postoperative adjuvant therapy were subjected to non-negative matrix factorization to identify differentially expressed genes between recurrent and nonrecurrent groups. RESULTS: We identified three cases with FGFR3-TACC3 and one with GOPC-ROS1 fusion genes as potential targets. A search of publicly available data from cBioPortal (21,789 cases) and the Center for Cancer Genomics and Advanced Therapeutics (32,608 cases) showed that the FGFR3 fusion is present in 1.5% and 0.6% of patients with cervical cancer, respectively. The frequency of the FGFR3 fusion gene was higher in cervical cancer than in other cancers, regardless of ethnicity. Non-negative matrix factorization identified that the patients were classified into four Basis groups. Pathway enrichment analysis identified more extracellular matrix kinetics dysregulation in Basis 3 and more immune system dysregulation in Basis 4 than in the good prognosis group. CIBERSORT analysis showed that the fraction of M1 macrophages was lower in the poor prognosis group than in the good prognosis group. CONCLUSIONS: The distribution of FGFR fusion genes in patients with cervical cancer was determined by RNA-based analysis and used to classify patients into clinically relevant subgroups.

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma.

OBJECTIVE: Folate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. METHODS: This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. RESULTS: A total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. CONCLUSIONS: FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

Reconsideration of Sharp Dissection in Gynecological Surgery.

In surgical fields, sharp dissection is a basic surgical technique, and the prognosis and oncological outcomes are known to be affected by the technique of dissection. Even in gynecologic surgery, we believe that the basic surgical technique is sharp dissection. We herein present our technique and discuss its significance. Sharp dissection should entail the removal of a single thin line between the residual tissue and the excised tissue. If this line becomes multiple or thicker, it is not sharp dissection but blunt dissection. The accumulation of this thin line of sharp dissection can form surgical layers. What is important is moderate tissue tension and how to use monopolar. One can sharply cut the loose connective tissue assisted by moderate tissue tension. With regard to the use of monopolar, it is essential that it not be applied directly to the tissue, but rather be used with or without touching the tissue. Inadvertent blunt dissection should be minimized, as most surgical procedures can be performed with sharp dissection. We usually perform sharp dissection for open surgery as well as minimally invasive surgery. We obstetricians and gynecologists should reconsider the significance of sharp dissection and practice it in gynecological surgery.