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.

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.

Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

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.

Utility of molecular subtypes and genetic alterations for evaluating clinical outcomes in 1029 patients with endometrial cancer.

BACKGROUND: We investigated the utility of a molecular classifier tool and genetic alterations for predicting prognosis in Japanese patients with endometrial cancer. METHODS: A total of 1029 patients with endometrial cancer from two independent cohorts were classified into four molecular subtype groups. The primary and secondary endpoints were relapse-free survival (RFS) and overall survival (OS), respectively. RESULTS: Among the 265 patients who underwent initial surgery, classified according to immunohistochemistry, patients with DNA polymerase epsilon exonuclease domain mutation had an excellent prognosis (RFS and OS), patients with no specific molecular profile (NSMP) and mismatch repair protein deficiency had an intermediate prognosis, and those with protein 53 abnormal expression (p53abn) had the worst prognosis (P < 0.001). In the NSMP group, mutant KRAS and wild-type ARID1A were associated with significantly poorer 5-year RFS (41.2%) than other genomic characteristics (P < 0.001). The distribution of the subtypes differed significantly between patients with recurrence/progression and classified by sequencing (n = 764) and patients who underwent initial surgery (P < 0.001). Among patients with recurrence/progression, 51.4% had the opportunity to receive molecular targeted therapy. CONCLUSIONS: A molecular classifier is a useful tool for determining prognosis and eligibility for molecularly targeted therapy in patients with endometrial cancer.

Changes in HER3 expression profiles between primary and recurrent gynecological cancers.

BACKGROUND: Human epidermal growth factor receptor-3 (HER3) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases, and its overexpression is associated with inferior prognosis in several cancers. However, it is unclear whether HER3 expression status changes in tumor tissue at recurrence. Therefore, this study aimed to evaluate the changes in HER3 expression between primary and recurrent status in gynecological cancers. METHODS: This retrospective study used matched-pair tissues of gynecological cancer patients at initial diagnosis and at recurrence. Immunohistochemical (IHC) scores of 3 + or 2 + were termed "HER3-high", while IHC scores of 1 + or 0 were designated as "HER3-low/zero". RESULTS: A total of 86 patients (40 with ovarian cancers, 32 with endometrial cancers, and 14 with cervical cancers) were included in this study. In ovarian cancer, 67.5% and 80.0% of the patients received a HER3-high at initial and recurrent diagnosis, respectively. The H-score was significantly increased at recurrence (p = 0.004). The proportion of HER3-high endometrial cancer patients increased from 46.9% at initial diagnosis to 68.8% at recurrence, and the H-score tended to increase at recurrence (p = 0.08). The fraction of HER3-high-rated cervical cancer patients remained unchanged at 85.7% both at initial and recurrent diagnosis. The discordance rate of HER3 expression detection in initial and recurrent diagnosis samples was 27.5%, 53.1%, and 14.3% for ovarian, endometrial, and cervical cancers, respectively. Ovarian and endometrial cancers with a HER3-high recurrent score tended to show shorter median survival time than those with a HER3-low/zero recurrent rating. CONCLUSION: Our findings suggest that, in main types of gynecological cancers, the proportion of patients having a HER3-high score increased from initial to recurrent diagnosis.

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.

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.

Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group.

OBJECTIVES: Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. METHODS: We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1-SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. RESULTS: The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. CONCLUSIONS: Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.

Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

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.

Endometrioid Endometrial Carcinoma With NKX3.1 Expression in a Transgender Man: A Case Report.

Endometrial cancer in transgender men is rare, and its histopathologic features remain unknown. A 30-yr-old transgender man with an intrauterine tumor, an ovarian mass, and a 2-yr history of testosterone use was referred to us for treatment. The presence of the tumors was confirmed via imaging, and the intrauterine tumor was identified as an endometrial endometrioid carcinoma via endometrial biopsy. The patient underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection. Pathologic examination revealed grade 3 endometrioid endometrial carcinoma, and the synchronous endometrial and ovarian tumors were collectively characterized as primary endometrial carcinoma. Metastatic carcinomas were discovered in both ovaries and the omentum, pelvic peritoneum, and a para-aortic lymph node. On immunohistochemistry, the tumor cells diffusely expressed p53, retained expression of PTEN, ARID1A, PMS2, and MSH6, and focally expressed estrogen receptors, androgen receptors, and NKX3.1. NKX3.1 was also expressed in glandular structures within the exocervical squamous epithelium. Prostate-specific antigen and prostatic acid phosphatase were focally positive. In conclusion, we describe a transgender man with NKX3.1-expressing endometrioid endometrial carcinoma who provides valuable suggestions regarding the effects of testosterone on endometrial cancer and appropriate gynecological care for transgender men.

Is it time to modify the Japanese Uterine Cervical Cancer Guidelines to recommend a higher dose for radio-resistant tumors?

Compared with the European or the United States' uterine cervical cancer management guidelines, which aim to deliver >85 Gy EQD2 (the equivalent effective dose in 2 Gy per fraction) to the high-risk clinical target volume (CTVHR) D90 (minimal dose of 90% of the CTVHR), the dose goal of the corresponding Japanese guidelines does not recommend delivering such a high dose to the CTVHR D90. Subsequently, while the rate of late radiation-induced toxicities is reported to be much lower in the Japanese schedule, the local control rate is relatively inferior to that of clinical results reported by the IntErnational study on MRI-guided BRAchytherapy in CErvical cancer study (EMBRACE-I) in which the dose goal for CTVHR D90 was >85 Gy and showed >90% local control regardless of tumor stage. In daily clinical practice, patients with residual disease supposedly due to insufficient total dose delivery are occasionally referred to our hospital for the possibility of re-irradiation, which is not usually recommended because the risk of late severe radiation-induced toxicity is high. In this report, the authors hope to raise a discussion in our community about modifying our treatment guidelines to recommend a higher dose at least for patients with poor response.

Genetic characteristics of platinum-sensitive ovarian clear cell carcinoma.

OBJECTIVE: Most ovarian clear cell carcinomas are resistant to platinum-based chemotherapy, while a small subset shows a positive response. The aim of this study was to clarify the clinical, pathological and genetic characteristics of platinum-sensitive ovarian clear cell carcinomas. METHODS: The study included 53 patients with stage III-IV ovarian clear cell carcinoma who had residual tumours after primary surgery and received platinum-based therapy between 2009 and 2018. A retrospective examination of platinum sensitivity was performed using the criterion of ≥6 months from the last day of first-line platinum therapy until recurrence/progression. Cases determined to be platinum-sensitive were subjected to immunohistochemical staining, genomic analyses using target sequencing (i.e. NCC Oncopanel) and homologous recombination deficiency (myChoice® HRD Plus) assays. RESULTS: Of the 53 stage III-IV ovarian clear cell carcinoma cases, 11 (21%) were platinum-sensitive. These cases showed better progression-free and overall survival than platinum-resistant cases (hazard ratio = 0.16, P < 0.001). Among the seven sensitive cases whose tumour tissues were available for molecular profiling, five were pure ovarian clear cell carcinoma based on pathological and genetic features, whereas the remaining two cases were re-diagnosed as high-grade serous ovarian carcinoma. The pure ovarian clear cell carcinomas lacked BRCA1 and BRCA2 mutations, consistent with the absence of the homologous recombination deficiency phenotype, whereas two cases (40%) had ATM mutations. By contrast, the two high-grade serous ovarian carcinoma cases had BRCA1 or BRCA2 mutations associated with the homologous recombination deficiency phenotype. CONCLUSION: The subset of platinum-sensitive ovarian clear cell carcinomas includes a majority with pure ovarian clear cell carcinoma features that lack the homologous recombination deficiency phenotype.

Neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian cancer: GOTIC-019 study.

INTRODUCTION: Three randomized controlled trials have resulted in extremely extensive application of the strategy of using neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for patients with advanced epithelial ovarian cancer in Japan. This study aimed to evaluate the status and effectiveness of treatment strategies using NAC followed by IDS in Japanese clinical practice. PATIENTS AND METHODS: We conducted a multi-institutional observational study of 940 women with Federation of Gynecology and Obstetrics (FIGO) stages III-IV epithelial ovarian cancer treated at one of nine centers between 2010 and 2015. Progression-free survival (PFS) and overall survival (OS) were compared between 486 propensity-score matched participants who underwent NAC followed by IDS and primary debulking surgery (PDS) followed by adjuvant chemotherapy. RESULTS: Patients with FIGO stage IIIC receiving NAC had a shorter OS (median OS: 48.1 vs. 68.2 months, hazard ratio [HR]: 1.34; 95% confidence interval [CI] 0.99-1.82, p = 0.06) but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80-1.31, p = 0.88). However, patients with FIGO stage IV receiving NAC and PDS had comparable PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74-1.53, p = 0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65-1.47, p = 0.93). CONCLUSIONS: NAC followed by IDS did not improve survival. In patients with FIGO stage IIIC, NAC may be associated with a shorter OS.

Discordances in expression of human epidermal growth factor receptor 2 between primary and metastatic uterine carcinosarcoma: A proposal for HER2-targeted therapy specimen selection.

Uterine carcinosarcoma (UCS) frequently expresses human epidermal growth factor receptor 2 (HER2) and metastasizes. However, little is known about changes in the HER2 expression status in metastatic lesions and its impact on clinical outcomes. In 41 patients with synchronous or metachronous metastases and matched primary UCSs, we assessed the HER-2 expression using immunohistochemistry and scored it per the 2016 American Society of Clinical Oncology/College of American Pathologists guidelines, modified for UCS. We compared HER2 scores between paired primary and metastatic lesions and reviewed the association between clinicopathological characteristics and impact on overall survival. HER2 scores of 3+, 2+, 1+, and 0 were observed in 12.2 %, 34.2 %, 26.8 %, and 26.8 % of primary tumors, respectively, and 9.8 %, 19.5 %, 43.9 %, and 26.8 % of metastatic tumors, respectively. HER2 intratumoral heterogeneity occurred in 46.3 % and 19.5 % of the primary and metastatic lesions, respectively. The agreement rate of the HER2 score was 34.2 % in the four-tiered scale, while it was 70.7 % in the two-tiered scale (score 0 vs. score ≥ 1+) with fair agreement (к = 0.26). Patients with HER2 discordance showed significantly shorter overall survival (hazard ratios = 2.38, 95 % confidence interval 1.01-5.5, p = 0.049). HER2 discordance was not associated with specific clinicopathological characteristics. Discordance in HER2 status between primary and metastatic tumors in UCS was frequently observed regardless of clinicopathological characteristics and was a poor prognostic factor. Even if one tumor (primary or metastatic) is HER2 negative, HER2 testing of other tumors may be beneficial in terms of patient treatment options.

Clinical impact of genetic alterations of CTNNB1 in patients with grade 3 endometrial endometrioid carcinoma.

To identify prognostic factors in patients with grade 3 (high-grade) endometrial endometrioid carcinoma, we evaluated the spectrum of genomic alterations and examined whether previously reported molecular subtypes of endometrial carcinoma were adapted to clinical outcome prediction. Seventy-five Japanese patients with grade 3 endometrial endometrioid carcinoma, who underwent a potentially curative resection procedure between 1997 and 2018 at the National Cancer Center Hospital, were included. We classified the patients into four risk groups of the disease based on the Proactive Molecular Risk Classifier for Endometrial Cancer. Genomic alterations in PTEN, ARID1A, TP53, and PIK3CA were detected in more than 30% of the patients. Overall survival and recurrence-free survival of patients with genomic alterations in CTNNB1 were poorer than those of patients with wild-type CTNNB1 (p = 0.006 and p = 0.004, respectively). Compared with that of alterations prevalent in Caucasians, the frequency of genomic alterations in POLE and TP53 was higher in our study than in The Cancer Genome Atlas dataset (p = 0.01 and p = 0.01, respectively). The tendency for recurrence-free survival in the POLE exonuclease domain mutation group was better than that in the TP53 mutation and mismatch repair-deficient groups (p = 0.08 and p = 0.07, respectively), consistent with the Proactive Molecular Risk Classifier for Endometrial Cancer risk classifier definition. The CTNNB1 mutation is a potential novel biomarker for the prognosis of patients with grade 3 endometrial endometrioid carcinoma, and prognosis classification using Proactive Molecular Risk Classifier for Endometrial Cancer may help screen Japanese patients with the disease.

High mesothelin expression is correlated with non-squamous cell histology and poor survival in cervical cancer: a retrospective study.

BACKGROUND: Mesothelin (MSLN) is a cell-surface glycoprotein found in various solid tumours. Cancer therapies targeting MSLN have been developed in recent years; however, the available information on MSLN expression in cervical cancer is limited. This study aimed to evaluate MSLN expression in various histological types of cervical cancer and examine its relationship with prognosis. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between January 2000 and December 2020 at our institution. MSLN expression was evaluated by immunohistochemistry using clone SP74 and defined as positive if MSLN was expressed at any intensity. High MSLN expression was defined as an intensity of ≥ 2 + in ≥ 30% of tumour cells. The association between MSLN expression and clinicopathological factors was evaluated. RESULTS: Overall, 123 patients were identified, and 140 tumour samples, including 17 paired primary and metastatic samples, were evaluated. Concerning histological type, 67 patients had squamous cell carcinoma (SCC), whereas 56 had non-SCC. MSLN expression was observed in 98.4% (121/123) of primary tumours. High MSLN expression was observed in 63.4% of samples (78/123), but it differed between the histological types (49.2% for SCC vs. 80.4% for non-SCC, p < 0.001). There was a significant correlation between MSLN expression in primary and metastatic lesions (Rs = 0.557, p = 0.015). In patients with common histological types, overall survival (OS) was shorter in the high MSLN expression group than in the low MSLN expression group (hazard ratio, 3.53; 95% confidence interval, 1.16-15.3, p = 0.03). CONCLUSIONS: MSLN was highly expressed in patients with cervical cancer, especially in those with non-SCC. High MSLN expression in the primary lesion was significantly associated with poor OS, and its expression was maintained in metastatic lesions. Our findings indicate that MSLN may be an attractive therapeutic target for cervical cancer. TRIAL REGISTRATION: Retrospectively registered. 2014-393. 1 June 2015.

DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer.

OBJECTIVE: To establish a quantitative method to evaluate the DNA methylation level of an immediate upstream region of major BRCA1 transcriptional start sites (TSSs), and to investigate whether methylation of the region is a prognostic factor in high-grade serous ovarian cancer patients after neoadjuvant chemotherapy. METHODS: Ninety-two FFPE samples of advanced high-grade serous ovarian cancers after neoadjuvant chemotherapy between 2011 and 2018 were used for mutation and methylation analysis. DNA methylation levels were assessed by pyrosequencing and DNA methylation microarray. An association between methylation level (or a mutation) and progression-free survival was assessed by Kaplan-Meier analysis. RESULT: Major BRCA1 transcripts and CpG sites immediately upstream of their TSSs were identified, and a pyrosequencing method was developed. BRCA1 methylation, BRCA1/2 mutations, and a RAD51C mutation were detected in 17/79 (21.5%), 17/92 (18.5%), and 1/92 (1.1%) high-grade serious ovarian cancer samples. In univariate analysis, BRCA1 methylation and no residual tumor were associated with progression-free survival (BRCA1 methylation: P = 0.025, no residual tumor: P = 0.0026). Multivariate analysis showed that both BRCA1 methylation (P = 0.038, HR = 0.47, 95% CI: 0.21-0.96) and no residual tumor (P = 0.012, HR = 0.49, 95% CI: 0.28-0.85) were significant favorable prognostic factors. CONCLUSION: A quantitative method to estimate the methylation level of the immediate upstream region of major BRCA1 TSSs was established. Methylation of the region of was an independent favorable prognostic factor in high-grade serous ovarian cancer patients.

Prevention of delirium with agitation by yokukansan in older adults after cancer surgery.

OBJECTIVE: Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection. METHODS: We performed a secondary per-protocol analysis of 149 patients' data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4-8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression. RESULTS: Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01-0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation. CONCLUSIONS: This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection.