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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. CTNNB1 genomic alterations were significantly associated with poor overall and recurrence‐free survival of G3EEC patients. Detected genomic alterations in PTEN (58.7%), ARID1A (52.0%), TP53 (48.0%), PIK3CA (44.0%), and POLE (33.3%) exceeded 30% in G3EEC. Frequency of TP53 and POLE genomic alterations was higher in our study than in TCGA dataset.

Germline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR‐related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR‐related PVs were examined. Kaplan–Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR‐related. HRR‐PV‐positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P < 0.0001) and advanced disease (18.5% vs. 5.9%, P < 0.0001). The HRR‐PV‐positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression‐free survival. HRR‐related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000–2019), the limited use of bevacizumab and poly (ADP‐ribose) polymerase inhibitors as maintenance therapy should be recognized. We revealed the prevalence and clinical features of homologous recombination repair‐related gene variants in ovarian cancer, containing non‐BRCA genes.

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.

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets ( P  = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P  = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P  = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P  = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy.

BackgroundDiagnosis of secondary ovarian tumors originating from colorectal cancer has previously been based upon history of malignancy and radiological findings of bilateral masses with a “stained glass appearance.” The purpose of this study was to perform a detailed investigation of the radiological and macroscopic features of ovarian metastases originating from colorectal cancer, which remain to be fully characterized.MethodsStudy participants were 48 consecutive patients with ovarian metastases from colorectal cancer who underwent resection of ovarian tumors at the National Cancer Center Hospital between August 1998 and January 2019. Ovarian tumors were classified into subgroups using computed tomography (CT), magnetic resonance imaging (MRI), and macroscopic appearance.ResultsCT/MRI findings and macroscopic appearance were classified into the following four types: type 1 (oval, homogeneous-solid) (n = 5); type 2 (heterogeneous-solid, small in size with multinodular surface) (n = 3); type 3 (solid-cystic, predominantly solid) (n = 18); and type 4 (cystic-solid, multilocular with solid components) (n = 22). Type 1 mimics Krukenberg tumors, type 2 mimics ovarian metastases from breast cancer, type 3 mimics primary ovarian endometrioid cancer, and type 4 mimics primary ovarian mucinous cancer, with a “stained glass appearance”. Twenty-eight (58%) patients had bilateral metastases. Eleven patients (23%) underwent hysterectomy and/or pelvic lymph node dissection in addition to ovarian resection.ConclusionWe introduced a novel classification system for ovarian metastases originating from colorectal cancer, which may be beneficial for assessing ovarian metastases from colorectal cancer and avoiding unnecessary surgery due to misdiagnosis of primary ovarian tumors.

PurposeThe purpose of this study was to evaluate the real world situation and clarify the problem in initial treatment for elderly patients with ovarian cancer in Japan.MethodsWe used the ovarian cancer database, containing all patients diagnosed and treated with International Federation of Gynecology and Obstetrics Stage I–IV ovarian cancer at the National Cancer Center Hospital in Japan from June 2008 to April 2013. Patients were stratified into two groups based on age: an elderly group, aged 70 years or older, and a younger group, aged below 70 years. We retrospectively assessed the rate of receiving standard therapy, and the feasibility and safety of chemotherapy compared with younger patients.ResultsIn total, 244 patients (elderly group, 36 patients; younger group, 208 patients) were analyzed. A significantly lower proportion of elderly patients than younger patients received standard therapy (15.7% vs. 32.5%, p = 0.026). Even for the elderly group, 95% patients underwent surgery in our institution. Conversely the rate of patients receiving nonstandard chemotherapy in the elderly group was significantly higher than in the younger group (30.5% vs. 9.6%, p = 0.01).ConclusionsThis study clarified the type of treatment being performed in the field, and the proportion of elderly ovarian cancer patients receiving standard therapy compared with younger patients in Japan. In addition, the actual situation of elderly patients in Japan might be different from that in Western countries. We need to evaluate the appropriate treatment for elderly patients in Japan.

Background/objectiveElderly patients with cancer are often at risk for undertreatment because of frailty, an aging-specific problem. However, current real-world conditions of recurrent ovarian cancer treatment in elderly patients remain unclear. This study aimed to clarify treatment patterns in elderly patients with recurrent ovarian cancer.Patients and methodsWe used an ovarian cancer database containing the diagnosis and initial therapy of all patients at the National Cancer Center Hospital in Japan from 2007 to 2014. Patients were stratified into the platinum-sensitive group and the platinum-resistant group. We retrospectively assessed chemotherapy use in patients aged ≤ 64, 65–69, 70–74, 75–79, and ≥ 80 years.ResultsAmong 253 patients (sensitive group: 135; resistant group: 118), by age group 91%, 95%, 100%, 100%, and 100% received chemotherapy in the sensitive group, and 79%, 67%, 50%, 29%, 0% received chemotherapy in the resistant group, respectively. In the resistant group, the percentage of patients aged 70–74 or 75–79 years who received chemotherapy was significantly lower than the percentage among patients aged ≤ 64 years, respectively (p = 0.01, p = 0.01). In multivariate analysis, age ≥ 70 years (odds ratio [OR], 4.412; 95% confidence interval (CI), 1.628–11.959; p = 0.004) and platinum-free interval < 3 months (OR, 3.434; 95% CI, 1.401–8.399; p = 0.007) were inversely associated with chemotherapy use.ConclusionsDoctors and patients did not consider chemotherapy in patients aged ≥ 70 years with platinum-resistant disease. Older age was independently and inversely associated with chemotherapy use in platinum-resistant ovarian cancer. Our results highlight the importance of demographic information in clinical decision-making for elderly patients.

PurposeWe evaluated magnetic resonance imaging (MRI) findings of dedifferentiated endometrial carcinoma (DEC), comprising undifferentiated carcinoma and low-grade endometrioid carcinoma.Materials and methodsWe recruited 11 patients with pathologically proven DEC treated at our institute. We evaluated primary lesion size, location and signal intensity on MRI, and prognosis. MRI and pathological findings were compared in eight resected patients.ResultsPrimary tumors ranged from 16 to 206 mm in diameter. DEC was located at the endometrium in 9 of the 11 patients; the remaining two patients showed diffuse involvement of the enlarged myometrium. These two patients with diffuse involvement type died within 4 months. Of the eight patients who underwent resection, seven had macroscopic intratumoral hemorrhage and six showed a high signal on T1-weighted images or low signal on T2-weighted images. Of the eight resected patients, four had tumor necrosis > 25% and tumor size > 5 cm. In these patients, necrosis appeared as nonenhanced areas on contrast-enhanced MRI.ConclusionMRI findings of DEC showed two patterns: mass-forming type and diffuse myometrial type with poor prognosis. Most patients with DEC had intratumoral hemorrhage, and large tumors (> 5 cm) had gross necrosis, which appeared as nonenhanced areas on contrast-enhanced MRI.

Lymph node metastasis (LNM) is a well-established prognostic factor in endometrial cancer (EC). We aimed to construct a model that predicts LNM and prognosis using preoperative factors such as myometrial invasion (MI), enlarged lymph nodes (LNs), histological grade determined by endometrial biopsy, and serum cancer antigen 125 (CA125) level using two independent cohorts consisting of 254 EC patients. The area under the receiver operating characteristic curve (AUC) of the constructed model was 0.80 regardless of the machine learning techniques. Enlarged LNs and higher serum CA125 levels were more significant in patients with low-grade EC (LGEC) and LNM than in patients without LNM, whereas deep MI and higher CA125 levels were more significant in patients with high-grade EC (HGEC) and LNM than in patients without LNM. The predictive performance of LNM in the HGEC group was higher than that in the LGEC group (AUC = 0.84 and 0.75, respectively). Patients in the group without postoperative pathological LNM and positive LNM prediction had significantly worse relapse-free and overall survival than patients with negative LNM prediction (log-rank test, P  < 0.01). This study showed that preoperative clinicopathological factors can predict LNM with high precision and detect patients with poor prognoses. Furthermore, clinicopathological factors associated with LNM were different between HGEC and LGEC patients.

Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of BMs from CC and uterine endometrial carcinoma EC. For patients with CC, early-stage disease and poorly differentiated carcinoma lead to BMs, and elderly age, poor performance status, and multiple BMs are listed as poor prognostic factors. Advanced-stage disease and high-grade carcinoma are high-risk factors for BMs from EC, and multiple metastases and extracranial metastases, or unimodal therapies, are possibly factors indicating poor prognosis. There is no “most effective” therapy that has gained consensus for the treatment of BMs. Treatment decisions are based on clinical status, number of the metastases, tumor size, and metastases at distant organs. Surgical resection followed by adjuvant radiotherapy appears to be the best treatment approach to date. Stereotactic ablative radiation therapy has been increasingly associated with good outcomes in preserving cognitive functions. Despite treatment, patients died within 1 year after the BM diagnosis. BMs from uterine cancer remain quite rare, and the current evidence is limited; thus, further studies are needed.