Evaluation of the role of intraoperative frozen section and magnetic resonance imaging in endometrial cancer.

OBJECTIVE: To evaluate the accuracy of preoperative endometrial biopsy and magnetic resonance imaging (MRI) of endometrial cancer compared with that of intraoperative frozen section. METHODS: This retrospective study included 264 patients who underwent surgery with intraoperative frozen section for endometrial cancer at our institution between 2014 and 2018. Diagnosis was determined by histologic type, grade, and myometrial invasion. Concordance rate, sensitivity, and specificity of preoperative diagnosis and intraoperative frozen diagnosis were calculated, in comparison to the final pathologic diagnosis. RESULTS: Preoperative and intraoperative diagnoses showed no statistically significant difference in determining histologic type and grade (P = 0.152). Intraoperative diagnosis showed higher sensitivity for endometrioid carcinoma grade 3 and other types, and higher specificity for grade 1. For myometrial invasion, intraoperative diagnosis showed significantly higher concordance rate than preoperative MRI findings (P < 0.01). Intraoperative diagnosis showed higher sensitivity and specificity in patients with and without myometrial invasion, respectively. CONCLUSION: Higher agreement between intraoperative and final diagnoses, especially in myometrial invasion, suggests that intraoperative frozen section is a good indicator for appropriate surgical procedure decision making.

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer.

In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson's correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.

Evaluation of preoperative prediction of intestinal invasion in patients with ovarian cancer.

OBJECTIVE: To optimize prediction for intestinal invasion of epithelial ovarian cancer. It is important to achieve debulking surgery to improve prognosis in ovarian cancer; intestinal resection is adopted if the cancer is invaded and resectable, but the preoperative evaluation method of intestinal invasion is still controversial. METHODS: Patients (n = 174) who underwent primary debulking surgery for epithelial ovarian cancer were recruited for retrospective study; 28 and 146 patients were classified into the invasion and non-invasion groups, whether they needed intestinal resection or not. We collected clinical data including evaluation of computed tomography (CT), magnetic resonance imaging (MRI), and barium contrast radiography, and analyzed their accuracy. RESULTS: The sensitivity and specificity for intestinal invasion were 33.3% and 98.6%, 42.9% and 98.6%, and 66.7% and 93.9% in CT, MRI, and barium contrast radiography, respectively. CT and MRI combined showed a sensitivity of 58.3% and specificity of 96.9%; all three methods combined was the most sensitive combination, showing a sensitivity of 79.2% and specificity of 90.8%. CONCLUSION: Combination of CT, MRI, and barium contrast radiography predicts intestinal invasion with the highest sensitivity. These three modalities, however, could not predict all intestinal invasion. Patients should be informed of the possibility of unexpected extensive resection.

Evaluation of safety and diagnostic performance for flexible hysteroscopy in 1591 outpatient cases.

BACKGROUND: To date, only few large studies are available concerning the safety and diagnostic concordance rates of outpatient flexible hysteroscopy. In our institution, outpatient hysteroscopy has been routinely and educationally applied Kosuke Tsuji to intrauterine lesions; thus, we retrospectively investigated the institution's outpatient flexible hysteroscopy cases. METHODS: A total of 1591 cases of outpatient flexible hysteroscopy conducted at our institution in 2012-2016 were retrospectively analyzed in terms of their clinical background, complications and diagnostic concordance rates. RESULTS: A total of 1591 cases included 546 cases of benign tumors (317 endometrial polyps, 168 myomas and 61 endometrial hyperplasia), 361 cases of atypical endometrial hyperplasia, 571 cases of endometrial cancers and 113 cases of other diagnoses. No major complications, including uterine perforation, occurred. However, one patient (0.06%) was diagnosed with septic shock caused by intrauterine infection that required prolonged immunosuppressive drug administration. Meanwhile, 335 patients diagnosed with benign tumors through outpatient flexible hysteroscopy underwent operation, and the diagnostic concordance rate was 74.6% (250 cases). However, this rate included 14 cases (4.2%) diagnosed with malignant tumors postoperatively. In preoperative endometrial cancer cases, the sensitivity and specificity for cervical invasion diagnosis were 39.4 and 90.8%, respectively. In addition, only one patient manifested positive ascites cytology intraoperatively, possibly caused by outpatient hysteroscopy. CONCLUSIONS: Outpatient flexible hysteroscopy is highly safe, with a slight negligible effect on ascites cytology. However, the diagnosis should be determined by multidisciplinary approaches, as hysteroscopy alone can miss malignancy.

Hysteroscopic Photodynamic Diagnosis Using 5-Aminolevulinic Acid: A High-Sensitivity Diagnostic Method for Uterine Endometrial Malignant Diseases.

STUDY OBJECTIVE: To examine the diagnostic accuracy of hysteroscopic photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5ALA) in patients with endometrial cancer and premalignant atypical endometrial hyperplasia. DESIGN: A single-center, open-label, exploratory intervention study. SETTING: University Hospital in Japan. PATIENTS: Thirty-four patients who underwent hysteroscopic resection in the Department of Obstetrics and Gynecology at Keio University Hospital. INTERVENTIONS: Patients were given 5ALA orally approximately 3 hours before surgery and underwent observation of the uterine cavity and endometrial biopsy using 5ALA-PDD during hysteroscopic resection. Specimens were diagnosed histopathologically and the diagnostic sensitivity and specificity of hysteroscopic 5ALA-PDD for malignancy in the uterine cavity was determined. Red (R), blue (B), and green (G) intensity values were determined from PDD images, and the relationships of histopathological diagnosis with these values were used to develop a model for objective diagnosis of uterine malignancy. MEASUREMENTS AND MAIN RESULTS: Three patients were excluded from the study because of failure of the endoscope system. A total of 113 specimens were collected endoscopically. The sensitivity and specificity of 5ALA-PDD for diagnosis of malignancy in the uterine cavity were 93.8% and 51.9%, respectively. The R/B ratio in imaging analysis was highest in malignant lesions, followed by benign lesions and normal uterine tissue, with significant differences among these groups (p <.05). The R/B and G/B ratios were used in a formula for prediction of malignancy based on logistic regression and the area under the receiver operating characteristic curve for this formula was 0.838. At a formula cutoff value of 0.220, the sensitivity and specificity for diagnosis of malignant disease were 90.6% and 65.4%, respectively. CONCLUSION: To our knowledge, this is the first study of the diagnostic accuracy of 5ALA-PDD for malignancies in the uterine cavity. Hysteroscopic 5ALA-PDD had higher sensitivity and identifiability of lesions. These findings suggest that hysteroscopic 5ALA-PDD may be useful for diagnosis of minute lesions.

Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach?

Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.