Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study.

OBJECTIVE: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. METHODS: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-µm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. RESULTS: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961-0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819-0.973) and 0.989 (95% CI: 0.973-0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. CONCLUSIONS: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

Prevalence of sarcopenia in patients with gynecological cancer.

BACKGROUND: The aim of the study was to investigate a prevalence of sarcopenia in patients with gynecological cancer in accordance with current diagnostic criteria of sarcopenia. METHODS: A series of 513 patients with gynecological cancer who were intended to newly receive initial or salvage treatment were recruited in a prospective study. Eligible patients were examined with dual energy X-ray absorptiometry and underwent handgrip strength test and the Short Physical Performance Battery before treatment. Sarcopenia was defined as both low skeletal muscle mass (skeletal muscle mass index) and low muscle strength (handgrip strength of <18.0 kg) or both low skeletal muscle mass index and low physical performance (Short Physical Performance Battery score of ≤9). RESULTS: A total of 475 patients (92.6%) were completely assessed in this study. Eligible patients' median age was 60 years (range: 29-89 years). Frequencies of patients with low skeletal muscle mass index, low hand grip strength and low Short Physical Performance Battery were 118 (24.8%), 70 (14.7%) and 80 (16.8%), respectively. Sarcopenia was finally identified in 45 patients (9.5%), which accounted for 38.1% of patients with low skeletal muscle mass index, 64.3% of the patients with low hand grip strength and 56.3% of the patients with low physical performance, respectively. CONCLUSIONS: The prevalence of sarcopenia of 9.5% in patients with gynecological malignancy who were scheduled to newly receive an initial or a salvage treatment. A large-scale, nation-wide study might be planned to elucidate an accurate prevalence of sarcopenia among gynecologic cancer patients.

Initial screening by immunohistochemistry is effective in universal screening for Lynch syndrome in endometrial cancer patients: a prospective observational study.

BACKGROUND: Few prospective reports of universal screening for Lynch syndrome exist for patients with endometrial cancer. In this study, we performed immunohistochemical staining for DNA mismatch repair-related genes (MLH1, MSH2, MSH6 and PMS2), to determine the extent to which Lynch syndrome can be diagnosed in endometrial cancer patients through universal screening. METHODS: We recruited 116 consecutive patients assumed to have uterine corpus malignancy from October 2019 to February 2021 in a prospective observational study. We performed immunohistochemical for mismatch repair-related proteins on samples from 100 patients who had surgicopathologically confirmed diagnoses of endometrial cancer. Samples with missing immunohistochemical results for any of the proteins had subsequent universal screening tests for microsatellite instability, DNA methylation of the MLH1 promoter region and mismatch repair genetics. RESULTS: We identified 19 (19.0%) patients with lost results for any of the proteins. All 19 patient samples had subsequent screening tests. We identified the microsatellite instability-high phenotype in 84.2% (16/19) of these patients and MLH1 methylation in 57.9% (11/19). Mismatch repair genetic testing detected two pathological variants, in MSH2 and MSH6, which indicated that the prevalence of Lynch syndrome was 2.0% in our cohort. Two cases of unclassified variant (MSH6) and one case of benign variant (PMS2) were also detected. CONCLUSIONS: Initial screening by immunohistochemical is an effective method in universal screening for Lynch syndrome in endometrial cancer patients.

Clinical relevance of addition of conventional treatment to concurrent chemoradiotherapy in patients with FIGO stage III-IV cervical cancer: a retrospective analysis of a Japanese cohort.

BACKGROUND: Concurrent chemoradiotherapy has limited therapeutic efficacy for stage III-IV cervical cancer. We aimed to identify a subgroup of patients with stage III-IV cervical cancer who benefit from concurrent chemoradiotherapy with additional treatment. METHODS: We retrospectively reviewed 120 patients with stage III-IV cervical cancer who were treated with concurrent chemoradiotherapy from 2002 to 2018. We compared overall survival between patients treated with concurrent chemoradiotherapy alone and those who received concurrent chemoradiotherapy with additional conventional treatments (systemic chemotherapy before and/or after concurrent chemoradiotherapy and/or extended-field radiation). Prognostic factors were statistically analysed. RESULTS: Overall, 44 (36.7%) and 21 (17.5%) patients were radiologically diagnosed with pelvic and para-aortic lymph node enlargement, respectively. The median tumour diameter was 5.7 cm. A total of 69 (57.5%) patients received no additional treatment, and 51 (42.5%) received additional treatment. Cox regression analysis identified the following prognostic factors: histological non-squamous cell carcinoma (hazard ratio, 3.9; 95% confidence interval, 1.8-8.2), tumour diameter of ≥6 cm (hazard ratio, 2.1; 95% confidence interval, 1.2-3.7), radiological pelvic lymph node enlargement (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0) and radiological para-aortic lymph node enlargement (hazard ratio, 2.1; 95% confidence interval, 1.1-4.1). Even in the lowest risk group (no risk factors), the 5-year overall survival rate was lower in the additional treatment group than in the concurrent chemoradiotherapy alone group (78.7% vs. 80.9%, respectively; log-rank test, P = 0.79). CONCLUSIONS: Addition of conventional treatments to concurrent chemoradiotherapy might not improve survival in patients with advanced cervical cancer. Novel treatment strategies including immune checkpoint inhibitors should be considered for such patients.

Validity of skeletal muscle mass index measurements for assessing sarcopenia in patients with gynecological cancer.

BACKGROUND: The current study investigated an optimal method for using CT scan in detection of low skeletal muscle mass quantity (SMQ). METHODS: In total, 82 consecutive patients with gynecological cancers were examined using computed tomography (CT) and dual-energy X-ray absorptiometry (DEXA) before treatment. Low SMQ was defined as a DEXA-based skeletal muscle mass index (SMI) of <5.40 kg/m2. Furthermore, CT-based SMI values were measured by six evaluators, and each evaluator measured SMI values two times for each subject. The first SMI value and the average SMI value were used for analyses. Receiver operating characteristic (ROC) analyses were performed to evaluate the performance of CT-based SMI measurements for detecting low SMQ. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: In total, 23 patients (28.0%) were diagnosed with low skeletal muscle mass. All areas under the curve (AUC) values from twelve (six evaluators × two measurements) ROC curves were within the range of 0.8-0.9. AUC values based on a single measurement and those based on two measurements were almost the same. The ICC was 0.828 (95% CI 0.777-0.874, P < 0.001) when using a single measurement value and increased to 0.959 (95% CI 0.944-0.971, P < 0.001) when using the average of the two measurements. CONCLUSIONS: A single measurement CT-based SMI efficiently identified patients with low SMQ in a daily clinical setting. The reliability of SMI measurements might be further improved by using a mean value of two measurements compared with the use of a single measurement value.

A BMI-category distribution pattern of intrinsic and treatment-related prognostic factors in endometrial cancer.

OBJECTIVE: In patients with endometrial cancer, obesity is associated with favorable prognostic characteristics but not with prolonged survival. The aim of this study was to elucidate the reason for this clinical paradox. METHODS: We retrospectively reviewed 1173 patients with endometrial cancer. Patients were divided into a non-obese group [body mass index (BMI) < 30 kg/m2], class I obesity group (BMI 30-35 kg/m2) and class II obesity group (BMI ≥ 35 kg/m2). The relationship between clinicopathological factors and disease-specific survival (DSS) was analyzed by Cox regression analysis. To correct for three-time significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0167. RESULTS: Three disease-intrinsic variables-older age, advanced stage and high-risk histology-and three treatment-related variables-no hysterectomy, no lymphadenectomy and no chemotherapy-were independently associated with poor DSS. DSS was similar among the three groups of patients even though the proportion of patients with plural pretreatment-related unfavorable risk factors significantly decreased with increment of BMI category (40.1 vs. 27.5 vs. 17.6%, P = 0.0003). The proportion of patients with plural treatment-related unfavorable prognostic factors significantly increased with increment of BMI category (21.3 vs. 26.7 vs. 39.3%, P = 0.0072). CONCLUSIONS: Poor-quality surgical staging in obese women may result in worse than expected survival outcomes.

Clinical implication of psoas muscle mass measurement for predicting death within 3 months in patients with incurable uterine cervical or corpus malignancy.

OBJECTIVE: The aim of this study was to find a clinical marker for identifying refractory cancer cachexia. METHODS: We analyzed computed tomography imaging data, which included the third lumbar vertebra, from 94 patients who died of uterine cervix or corpus malignancy. The time between the date of examination and date of death was the most important attribute for this study, and the computed tomography images were classified into >3 months before death and ≤ 3 months before death. Psoas muscle mass index was defined as the left-right sum of the psoas muscle areas (cm2) at the level of third lumbar vertebra, divided by height squared (m2). RESULTS: A data set of 94 computed tomography images was obtained at baseline hospital visit, and a data set of 603 images was obtained at other times. One hundred (16.6%) of the 603 non-baseline images were scanned ≤3 months before death. Mean psoas muscle mass index change rates at >3 months before death and ≤3 months before death were -1.3 and -20.1%, respectively (P < 0.001). Receiver operating characteristic curve analysis yielded a cutoff value of -13.0%. The area under the curve reached a moderate accuracy level (0.777, 95% confidence interval 0.715-0.838). When we used the cutoff value to predict death within 3 months, sensitivity and specificity were 74.0 and 82.1%, respectively. CONCLUSIONS: Measuring change in psoas muscle mass index might be useful for predicting cancer mortality within 3 months. It could become a potential tool for identifying refractory cancer cachexia.

Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Validity of measuring psoas muscle mass index for assessing sarcopenia in patients with gynecological cancer.

OBJECTIVE: The current study evaluated the performance of psoas muscle mass measurement for detecting low skeletal muscle mass quantity. METHODS: A sample of 82 consecutive patients with gynecological cancers was examined using computed tomography and dual energy X-ray absorptiometric scan before treatment. Skeletal muscle mass index was measured by dual energy X-ray absorptiometric scan and its cut-off value was set at 5.40 kg/m2 for detecting low skeletal muscle mass. Psoas muscle mass index was manually measured with cross-sectional computed tomography imaging at the level of L3 by six evaluators. RESULTS: Low skeletal muscle mass index was identified in 23 (28.0%) patients. Two-way analysis of variance confirmed a significant main effect of skeletal muscle mass index on mean psoas muscle mass index values (P < 0.0001). A receiver operating characteristic curve obtained from a total of 492 psoas muscle mass index data points gathered from six evaluators produced an area under the curve value of 0.697 (95% confidence interval 0.649-0.744) and a cut-off value of 3.52 cm2/m2, with sensitivity of 79.0% and specificity of 59.6%. Using the cut-off value, the kappa coefficient for evaluating diagnostic agreement between skeletal muscle mass index (low vs. normal) and psoas muscle mass index (low vs. normal) was 0.308 (95% confidence interval 0.225-0.392), suggesting poor agreement. Fleiss' kappa produced a coefficient of 0.418 (95% confidence interval 0.362-0.473), suggesting moderate agreement. CONCLUSIONS: Although relevance between skeletal muscle mass index and psoas muscle mass index was confirmed, intensity of relevance between them was weak. Psoas muscle mass index measurement should be subordinated to skeletal muscle mass index measurement for detection of low skeletal muscle mass.

Diagnostic criteria of sentinel lymph node micrometastasis or macrometastasis based on tissue rinse liquid-based cytology in gynecological cancer.

OBJECTIVE: This study aimed to establish intraoperative diagnostic criteria of sentinel lymph node (SLN) micro-/macrometastasis on the basis of tissue rinse liquid-based cytology (TRLBC) in gynecological cancer. METHODS: We enrolled 214 patients with gynecological cancer who underwent rapid diagnosis of SLN metastasis on the basis of TRLBC from a total of 490 SLNs. For slides that were classified as positive for atypical cells on cytological inspection, we counted the number of clusters (an atypical cell mass consisted of three or more cells) and the number of single cells (an atypical cell other than clusters). Receiver operating characteristic (ROC) analysis was applied to determine the efficiency of predicting SLN micro-/macrometastasis. RESULTS: On cytological inspection, 36 slides were classified as positive for atypical cells, while 21 slides (4.3%) were true positive, 15 (3.1%) were false positive, and 454 (92.6%) were true negative. There were no false negative results in this study. The area under the ROC curve for the number of cluster was superior to that for the number of single cells for distinguishing micro-/macrometastasis from negative/isolated tumor cells (0.86 vs. 0.67, P = 0.032). The optimum cut-off value of the number of clusters was 5 for distinguishing these two categories. CONCLUSIONS: TRLBC is a highly sensitive alternative for detecting SLN metastasis as a rapid intraoperative diagnosis. Counting the number of atypical cell clusters might be useful for distinguishing micro-/macrometastasis from isolated tumor cells.

Investigation of clinicopathological features of vulvar cancer in 1068 patients: A Japanese Gynecologic Oncology Group (JGOG) nationwide survey study.

OBJECTIVE: Vulvar cancer is a rare malignancy in the aging population, and optimizing treatment strategies requires large-scale investigation of the clinicopathological features of this disease. In Japan, no such surveys have been conducted in the past 30 years. This large-scale retrospective multi-center study aimed to examine the clinicopathological features of vulvar cancer in Japan. METHODS: Upon obtaining ethical approval by the participating institutions' review boards, the medical records of patients with vulvar cancer, who were treated between 2001 and 2010 were reviewed. The impact of clinicopathological factors on overall survival (OS) was investigated using a multivariate Cox regression model. RESULTS: After applying the inclusion and exclusion criteria, 1068 patients treated in 108 centers were included. The median age was 72 years. The disease was in stage I in 402 patients (37.6%), stage II in 249 patients (23.3%), stage III in 252 patients (23.6%), and stage IV in 165 patients (15.4%). Squamous cell carcinoma, Paget's disease, adenocarcinoma, and other diseases were diagnosed in 773 (72.4%), 154 (14.4%), 59 (5.5%), and 82 (7.7%) patients, respectively. Positive inguino-femoral lymph nodes were found in 265 (24.8%) patients. The 5-year OS rate for stage I, II, III, and IV vulvar cancer were 85.6%, 75.1%, 48.8%, and 40.0%, respectively. CONCLUSION: Our study shows that advanced age, disease stage, histological diagnosis, tumor diameter, and lymph node metastases significantly affect the OS of patients with vulvar cancer in Japan.

Tailored radical hysterectomy for locally advanced cervical cancer.

OBJECTIVE: The survival and prognostic factors for locally advanced cervical cancer treated with nerve-sparing Okabayashi-Kobayashi radical hysterectomy have not been elucidated. We aimed to evaluate the oncological outcomes of those patients after radical hysterectomy with adjuvant chemotherapy. METHODS: This retrospective cohort study was conducted from January 2002 to December 2011. Treatment was conducted at a single tertiary center in northern Japan. We used the Okabayashi-Kobayashi radical hysterectomy with lymphadenectomy. We applied unilateral nerve preservation for stage IIA/IIB cancer if there was a one-sided extension of the disease outside the cervix. Indication for adjuvant therapy was based on Sedlis criteria. High-risk was defined as evidence of lymph node metastasis, pathological parametrial invasion, and a positive/close surgical margin. The choice of adjuvant therapy was chemotherapy which consisted of paclitaxel and cisplatin. RESULTS: The study included 76 early-stage IB1 (≤4 cm) and IIA1 cervical cancer and 45 locally advanced stage IB2 (>4 cm), IIA2, and IIB disease treated consecutively. The median follow-up was 106 (range: 6-203) months. There were 18 (15%) patients with recurrence, with five of 76 in the early-stage (7%) and 13 of 45 in the locally advanced disease (29%) (P<0.001). For locally advanced cervical cancer, pT classification (P<0.001), lymph node metastasis (P=0.007), and histology (P=0.05) were associated with locoregional recurrence. The five-year locoregional recurrence rate in the locally advanced disease was 20% and 5% in the early-stage disease (P=0.01). The five-year disease-free survival in the locally advanced cervical cancer was 71% and 93% in the early-stage disease (P<0.001). The overall survival in locally advanced disease depended on the adeno-type histology and lymph node metastasis. CONCLUSION: The tailored use of nerve-sparing Okabayashi-Kobayashi radical hysterectomy with adjuvant chemotherapy based on tumor histology and lymph node metastasis may be a possible option as a treatment of locally advanced cervical cancer in selected patients.

Bevacizumab-related gastrointestinal perforation in patients with three or more prior chemotherapy regimens: A real-world experience.

OBJECTIVE: Associations between the number of prior chemotherapy (CT) regimens and gastrointestinal (GI) perforation in patients receiving bevacizumab treatment has not been fully investigated. The aim of the study was to investigate the impact of ≥3 prior CT regimens on GI perforation. MATERIALS AND METHODS: We retrospectively investigated the medical records of 133 patients with gynecological cancer who received bevacizumab-containing treatment. Bevacizumab was intravenously administered at a dose of 15 mg/kg every 4 weeks. Incidence of GI perforation was compared between ≤2 and ≥3 prior CT groups. RESULTS: Twenty-three (17.3%) patients had a history of ≥3 CT; these patients received bevacizumab at 4-week intervals. The percentage of patients with prior surgery was significantly higher in the ≥3 prior CT group (95.7% vs. 70.0%, P = 0.008), while those with prior bowel resection was significantly higher in the ≥3 prior CT group (30.4% vs. 12.7%, P = 0.034). There was no significant difference in the mean number of bevacizumab cycles between the two groups (10.7 vs. 8.9, P = 0.19). While GI perforation was observed in three (2.7%) patients in the ≤2 prior CT group, no GI perforation was found in the ≥3 prior CT group (P > 0.99). CONCLUSION: A history of ≥3 prior CT did not increase the risk for GI perforation when bevacizumab is administered at a dose of 15 mg/kg every 4 weeks in our cases.

Oncological Outcomes After Okabayashi-Kobayashi Radical Hysterectomy for Early and Locally Advanced Cervical Cancer.

Importance: The role of surgery in early-stage cervical cancer has been established, but it is controversial in locally advanced cervical cancer. Objective: To determine whether a radical hysterectomy method with extended removal of paracervical tissue for locally advanced cervical cancer is associated with satisfactory oncological outcomes. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2002, to December 31, 2011, and participants were patients with cervical cancer at a single tertiary center in Northern Japan. The median follow-up period was 106 months, and none of the patients were lost to follow-up at less than 60 months. Data analyses were performed from July 1, 2017, to December 31, 2018. Exposures: Patients underwent radical hysterectomy using the Okabayashi-Kobayashi method. Bilateral nerve preservation was used for stage IB1/IB2 disease and unilateral nerve preservation for stage IIA/IIB if disease extension outside the uterine cervix was 1-sided. Chemotherapy was used as the choice of adjuvant treatment for patients with an intermediate or high risk of recurrence, while some patients chose or were assigned to radiotherapy. Main Outcomes and Measures: Primary outcomes were the 5-year local control rate and 5-year overall survival rate along with risk factor analysis. Results: Of 121 consecutive patients, 76 (62.8%) had early-stage cervical cancer in 2008 International Federation of Gynecology and Obstetrics stages IB1 and IIA1 and 45 (37.2%) had locally advanced cervical cancer in stages IB2, IIA2, and IIB. The median (range) age was 42 (26-68) years. Adjuvant radiotherapy was used in 2 patients (3%) with early-stage cervical cancer and 3 (7%) of those with locally advanced cervical cancer. The 5-year local control rates for early-stage cervical cancer and locally advanced cervical cancer were 99% and 87%, respectively. The 5-year overall survival rates for early-stage cervical cancer and locally advanced cervical cancer were 95% and 82%, respectively. Cox regression analysis showed that lymph node metastasis and histology of adeno(squamous)carcinoma were independent risk factors for the overall survival of patients with cervical cancer treated with radical hysterectomy. Conclusions and Relevance: The nerve-sparing Okabayashi-Kobayashi radical hysterectomy for locally advanced cervical cancer may provide survival not inferior to radical hysterectomy or radiotherapy in published literature. The applicability of radical hysterectomy with adjuvant chemotherapy for locally advanced cervical cancer needs to be validated by prospective comparative trials.

MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1.

Epithelial-mesenchymal transition (EMT) is a key process contributing to cervical cancer (CC) metastasis, and microRNAs (miRNAs) modulate the expression of genes implicated in EMT. However, the accurate role of miR-361 in CC-associated EMT and the mechanisms underlying its function in CC remains largely unknown. The functional roles of miR-361 in CC cells were explored by a series of cell functional assays. Luciferase reporter assays were used to demonstrate the potential interaction between miR-361, HSP90, and long non-coding RNA (lncRNA) NEAT1. We detected a reduction of miR-361 expression in CC tissues compared with normal tissues, and miR-361 overexpression inhibited invasion and EMT phenotypes of CC cells by directly targeting a key EMT activator HSP90. Additionally, we detected significantly higher levels of HSP90 in CC tissues compared with normal tissues, and high expression of HSP90 predicted a poorer prognosis. We further identified NEAT1 as a significantly upregulated lncRNA in CC tissues and high expression of NEAT1 was associated with worse survival in CC patients. NEAT1 directly repressed miR-361 expression and played an oncogenic role in CC cell invasion and sphere formation. Conclusions: These results demonstrated that miR-361 directly targets HSP90 to inhibit the invasion and EMT features, and NEAT1 functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMT and sphere formation in CC cells, thus providing critical insights into the molecular pathways operating in this malignancy.

Imaging-based definition of lower uterine segment carcinoma to improve the detection sensitivity of probable Lynch syndrome.

OBJECTIVE: The aim of this study was to investigate a magnetic resonance imaging-based definition of lower uterine segment carcinoma. METHODS: We retrospectively reviewed 587 consecutive patients with endometrial cancer who underwent hysterectomy. Lower uterine segment carcinoma was determined through pathological examination and magnetic resonance imaging assessment. For imaging assessment, the location of the inner lining of the uterus was classified into four equal parts on a sagittal section image. A tumor was defined as lower uterine segment carcinoma when its thickest part was located in the second or the third part from the uterine fundus. Lower uterine segment carcinoma was further divided into lower uterine segment in a narrow sense, upon which diagnosis was exclusively based on pathological findings, and lower uterine segment in a broad sense that were the remaining lower uterine segment carcinomas except lower uterine segment carcinomas in a narrow sense. The relationship between lower uterine segment carcinoma and probable Lynch syndrome was investigated. Patients with loss of MSH2, MSH6, and PMS2 expression or those with tumors with loss of MLH1 and absence of MLH1 promoter methylation were diagnosed as probable Lynch syndrome. RESULTS: Lower uterine segment carcinoma was identified in 59 (10.2%) patients. Twenty-eight (47.5%) patients were categorized as lower uterine segment in a narrow sense and 31 (52.5%) as lower uterine segment in a broad sense. Among them, probable Lynch syndrome was identified in 12 (20.3%) cases. There was no difference in clinical profiles, including the prevalence of probable Lynch syndrome between the two categories. CONCLUSIONS: A magnetic resonance imaging-based expanded definition of lower uterine segment carcinoma is likely to secure characteristics equivalent to a conventional pathology-based definition of lower uterine segment carcinoma. The novel definition of lower uterine segment carcinoma might improve the detection of probable Lynch syndrome.

MicroRNA-361: A Multifaceted Player Regulating Tumor Aggressiveness and Tumor Microenvironment Formation.

MicroRNA-361-5p (miR-361) expression frequently decreases or is lost in different types of cancers, and contributes to tumor suppression by repressing the expression of its target genes implicated in tumor growth, epithelial-to-mesenchymal transition (EMT), metastasis, drug resistance, glycolysis, angiogenesis, and inflammation. Here, we review the expression pattern of miR-361 in human tumors, describe the mechanisms responsible for its dysregulation, and discuss how miR-361 modulates the aggressive properties of tumor cells and alter the tumor microenvironment by acting as a novel tumor suppressor. Furthermore, we describe its potentials as a promising diagnostic or prognostic biomarker for cancers and a promising target for therapeutic development.

Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes.

BACKGROUND: High-grade endometrioid and serous endometrial cancers (ECs) are an aggressive subtype of ECs without effective therapies. The reciprocal communication between tumor cells and their surrounding microenvironment drives tumor progression. Long noncoding RNAs (lncRNAs) are key mediators of tumorigenesis and metastasis. However, little is known about the role of lncRNAs in aggressive EC progression and tumor microenvironment remodeling. METHODS: We performed an array-based lncRNA analysis of a parental HEC-50 EC cell population and derivatives with highly invasive, sphere-forming, and paclitaxel (TX)-resistant characteristics. We characterized the roles of the lncRNA NEAT1 in mediating aggressive EC progression in vitro and in vivo and explored the molecular events downstream of NEAT1. RESULTS: We identified 10 lncRNAs with upregulated expression (NEAT1, H19, PVT1, UCA1, MIR7-3HG, SNHG16, HULC, RMST, BCAR4 and LINC00152) and 10 lncRNAs with downregulated expression (MEG3, GAS5, DIO3OS, MIR155HG, LINC00261, FENDRR, MIAT, TMEM161B-AS1, HAND2-AS1 and NBR2) in the highly invasive, sphere-forming and TX-resistant derivatives. NEAT1 expression was markedly upregulated in early-stage EC tissue samples, and high NEAT1 expression predicted a poor prognosis. Inhibiting NEAT1 expression with small hairpin RNAs (shRNAs) diminished cellular proliferation, invasion, sphere formation, and xenograft tumor growth and improved TX response in aggressive EC cells. We showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Furthermore, miR-361 also suppressed the expression of multiple prometastatic genes and tumor microenvironment-related genes, including MEF2D, ROCK1, WNT7A, VEGF-A, PDE4B, and KPNA4. CONCLUSIONS: NEAT1 initiates a miR-361-mediated network to drive aggressive EC progression. These data support a rationale for inhibiting NEAT1 signaling as a potential therapeutic strategy for overcoming aggressive EC progression and chemoresistance.

Cervical laser vaporization for women with cervical intraepithelial neoplasia-3.

OBJECTIVE: This study evaluated outcomes of laser vaporization of the cervix for women with cervical intraepithelial neoplasia (CIN)-3. METHODS: We retrospectively reviewed 161 consecutive patients with CIN3 who were treated with cervical laser vaporization between January 2008 and December 2012. At each follow-up visit, histologically confirmed CIN2, CIN3 and invasive carcinoma were defined as treatment failures, as were high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells that cannot exclude HSIL with subsequent treatment or lost to follow-up. Primary endpoints included long-term follow-up (at least 5 years of regular hospital visits) and treatment failure rate. Treatment failure rates were estimated by the Kaplan-Meier method. RESULTS: Patients' median age was 31 years old. Median follow-up period was 67 months (interquartile range: 52-74 months). Over 5 years, 70.8% continued their follow-up visits, but significantly more patients aged ≥35 years did so (86.4%) than did those aged ≤34 years (61.8%, P = 0.0009). Treatment failure was observed in 14 (8.7%) patients, 1 of whom progressed to invasive cancer (0.6%). Cumulative treatment failure rates were 1-year: 5.1%, 2-year: 6.4% and 5-year: 9.5%. Among patients who suffered treatment failures, 57.1% initial failures occurred within the first year and 71.4% within the first 2 years. CONCLUSIONS: Long-term oncologic outcomes of cervical vaporization in CIN3 remain at a suboptimal level. The importance of a minimum of 5 years of regular hospital visits should be emphasized to patients with CIN3 who are candidates for cervical laser vaporization, especially those aged ≤34 years.

Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges.

Recent studies have revealed both the promise and challenges of targeting long non-coding RNAs (lncRNAs) to diagnose and treat endometrial cancer (EC). LncRNAs are upregulated or downregulated in ECs compared to normal tissues and their dysregulation has been linked to tumor grade, FIGO stage, the depth of myometrial invasion, lymph node metastasis and patient survival. Tumor suppressive lncRNAs (GAS5, MEG3, FER1L4 and LINC00672) and oncogenic lncRNAs (CCAT2, BANCR, NEAT1, MALAT1, H19 and Linc-RoR) have been identified as upstream modulators or downstream effectors of major signaling pathways influencing EC metastasis, including the PTEN/PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, WNT/ß-catenin and p53 signaling pathways. TUG1 and TDRG1 stimulate the VEGF-A pathway. PCGEM1 is implicated in activating the JAK/STAT3 pathway. Here, we present an overview of the expression pattern, prognostic value, biological function of lncRNAs in EC cells and their roles within the tumor microenvironment, focusing on the influence of lncRNAs on established EC-relevant pathways. We also describe the emerging classification of EC subtypes based on their lncRNA signature and discuss the clinical implications of lncRNAs as valuable biomarkers for EC diagnosis and potential targets for EC treatment.