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Histopathologic diagnosis of a subset of uterine smooth muscle tumors is challenging. We report a critical review regarding the clinicopathological point of view of 62 cases of subsequently recurred or metastasized leiomyoma.Medical records and glass slides of 62 cases of uterine smooth muscle tumor diagnosed as leiomyoma, which subsequently recurred or metastasized, were critically reviewed by pathologists specializing in gynecologic pathology and oncology.In 47 (75.8%) of 62 cases, the diagnosis of leiomyoma was confirmed, including 11 intravascular leiomyomatosis (IVL) and benign metastasizing leiomyoma (BML). In 29 cases (46.8%) laparoscopic surgery was performed, of which morcellator without a bag was employed in 23 cases. Fifteen cases (24.2%) appeared to be underestimated and were re-classified as smooth muscle tumor of uncertain malignant potential (STUMP), leiomyosarcoma, or other malignant mesenchymal tumors. Recurrences in seven cases (11.3%) were interpreted to be a malignant transformation, and one STUMP recurred as STUMP.The recurrence or metastasis in cases of "leiomyoma" is attributed to iatrogenic or under-evaluation of primary tumors, although a subset of cases is a rare example of biological progression.

Background: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the benefits and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. Methods: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n=8) and central hypogonadism (CH) group (n=9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. Results: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.527) or uterine size (p = 0.07, R = -0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = -0.769) or bone density (p = 0.18, R = -0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. Conclusion: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCSs with hypogonadism, considering the type and timing of cancer treatment.

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

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Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients.Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups.Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10−20). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 × 10−5; Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients.Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374–85. ©2012 AACR.

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Purpose The aim of study was to evaluate the impact of adding an extensive pelvic peritoneal stripping procedure, termed “wide resection of the pelvic peritoneum,” (WRPP) to standard surgery for epithelial ovarian cancer on survival effectiveness and to investigate the role of ovarian cancer stem cells (CSCs) in the pelvic peritoneum. Methods A total of 166 patients with ovarian cancer undergoing surgical treatment at Kumamoto University Hospital between 2002 and 2018 were retrospectively analyzed. Eligible patients were divided into three groups based on the surgical approach: standard surgery (SS) group (n = 36), WRPP group (standard surgery plus WRPP, n = 100), and rectosigmoidectomy (RS) group (standard surgery plus RS, n = 30). Survival outcomes were compared between the three groups. CD44 variant 6 (CD44v6) and EpCAM expression, as markers of ovarian CSCs, in peritoneal disseminated tumors were evaluated using immunofluorescence staining. Results With respect to patients with stage III–IV ovarian cancer, there were significant differences in overall and progression-free survival between the WRPP and SS groups, as revealed by univariate (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17–0.69; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively) and multivariate Cox proportional hazards model (HR, 0.35; 95% CI, 0.17–0.70; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively). Further, no significant differences were observed in survival outcomes between the RS group and the SS or WRPP group. Regarding the safety of WRPP, no significant differences in major intraoperative and postoperative complications were found between the three groups. Immunofluorescence analysis revealed a high percentage of CD44v6/EpCAM double-positive ovarian cancer cells in peritoneal disseminated tumors. Conclusion The present study demonstrates that WRPP significantly contributes to improved survival in patients with stage III–IV advanced ovarian cancer. WRPP could result in eradicating ovarian CSCs and disrupting the CSC niche microenvironment in the pelvic peritoneum.

Background Despite being widely used, to date (June 2021), the regimen of bevacizumab 10 mg/kg every 2 weeks (Q2W) combined with chemotherapy is not approved in Japan for patients with platinum-resistant recurrent ovarian cancer. In this retrospective analysis, we evaluated the usage patterns of bevacizumab administered for platinum-resistant recurrent ovarian cancer. Methods We obtained clinical data from 155 Japanese medical facilities between November 2013 and December 2018 via a survey. Items included the number of cases of platinum-resistant recurrent ovarian cancer treated with bevacizumab according to dosage. For regimens including bevacizumab 10 mg/kg Q2W, additional information was requested relating to concomitantly administered agents, and the efficacy and safety of the regimen. Results Of 1739 bevacizumab-containing regimens reported in 1633 patients with recurrent ovarian cancer, 264 used 10 mg/kg Q2W. The overall response rate (ORR) with this regimen was 26.1%. Response rates varied according to regimen and were particularly favorable when bevacizumab 10 mg/kg Q2W was administered with paclitaxel (ORR, 53.0%) versus liposomal doxorubicin (15.0%; P P Conclusions Bevacizumab 10 mg/kg Q2W appears efficacious for patients with recurrent ovarian cancer, with a manageable toxicity profile. Approval of this regimen is clinically desirable for Japanese patients with ovarian cancer.

Peritoneal metastasis is a common mode of spread of ovarian cancer. Despite therapeutic advances, some patients have intractable peritoneal metastasis. Therefore, in-depth characterization of the molecular mechanism of peritoneal metastasis is a key imperative. Angiopoietin-like protein 2 (ANGPTL2) is an inflammatory factor which activates NF-κB signaling and plays an important role in the pathogenesis of various inflammatory diseases including cancers, such as lung and breast cancer. In this study, we examined the role of ANGPTL2 in ovarian cancer peritoneal metastasis. We observed no difference of cell proliferation between ANGPTL2-expressing and control cells. In the mouse intraperitoneal xenograft model, formation of peritoneal metastasis by ANGPTL2-expressing cells was significantly decreased compared to control. In the in vitro analysis, the expressions of integrin α5β1, α6, and β4, but not those of αvβ3, α3, α4, and β1, were significantly decreased in ANGPTL2-expressing cells compared to control cells. ANGPTL2-expressing cells showed significantly inhibited adherence to laminin compared to control. In addition, we observed upregulation of anoikis (a form of programmed cell death occurring under an anchorage-independent condition) and significant decrease in the expression of Bcl-2 in ANGPTL2-expressing cells as compared to control cells. These results suggest that ANGPTL2 expression in ovarian cancer cells represses peritoneal metastasis by suppressing anoikis resistance.

Sentinel lymph node (SN) biopsy is essential for evaluating survival and minimal treatment-related morbidity associated with cervical, endometrial, and vulvar cancer in Japan. As such, our aim in this study was to evaluate the current practice pattern of using SN biopsy for cervical, endometrial, and vulvar cancer in Japan. We deployed a 47-question survey on the use of SN biopsy for gynecological cancers to 216 gynecological oncology training facilities. The survey included information on the use of SN biopsy for uterine (cervical and endometrial) and vulvar cancers; details on the type, timing, and concentration of tracers used; surgical approach used for SN biopsy; method of biopsy and pathological examination; and facilities’ experience with clinical research on SN biopsy. The response rate was 84% (181/216), with 40 facilities (22%) having experience in SN biopsy for gynecological cancers, 34 (85%) for uterine cancers, and 15 (37%) for vulvar cancers. Radioisotope, indocyanine green (ICG), and blue dyes were available for the detection of uterine cancers in 21 (52%), 25 (62%), and 19 (48%) facilities and for vulvar cancers in 9 (22%), 3 (7%), and 11 (27%) facilities, respectively. Thirty-four facilities (85%) used intraoperative frozen section procedure for diagnosis when possible, with 24 (71%) of these facilities using 2-mm specimen cuts. Diagnosis included pathological examination (85%), immunostaining (57%), and one-step nucleic acid amplification (5%). Increasing research evidence, providing insurance coverage for radioisotope tracers, and increasing the availability of training are expected to increase the use of SN biopsy in Japan.

Aim This study aimed to evaluate the clinical features and pregnancy outcomes of placental mesenchymal dysplasia (PMD) in Japan. Methods We requested detailed clinical information and placental tissue of PMD cases in 2000-2018 from Japanese facilities with departments of obstetrics and gynecology and analyzed the pregnancy course and neonatal outcomes. Results We collected 49 cases of PMD. Of 18 patients with measured maternal serum alpha-fetoprotein (MSAFP) levels, 15 (83.3%) had elevated levels. Maternal serum human chorionic gonadotropin (MShCG) levels were transiently elevated in five (17.8%) of 28 patients. Forty-seven patients continued their pregnancies. All pregnancies were singleton and 40 (85.1%) were associated with adverse events including fetal growth restriction (FGR), threatened premature delivery, fetal demise, and hypertensive disorder of pregnancy in 34 (72.3%), 14 (29.8%), eight (17.0%), and six (12.8%) patients, respectively. Of 47 infants, there were eight stillbirths. There were 40 (85.1%) female infants, and eight (17.0%) had Beckwith-Wiedemann syndrome. Of 39 live births, 23 (59.0%) were associated with premature induction of labor or cesarean section for obstetric indications related to FGR. Eighteen (46.2%) neonates had complications. PMD-affected placentas were pathologically heterogeneous in both grossly PMD-affected and non-affected areas. Conclusions Our study included the largest number of PMD cases with detailed clinical information. PMD is a high-risk condition for both the mother and the child. Elevated MSAFP levels with normal MShCG levels indicate PMD. Conventional perinatal management of FGR in Japan might be effective in reducing the fetal mortality rate.

POLE-mutated endometrial cancer (EC) frequently shows high-grade endometrioid histology, which represents heterogeneity in the dualistic classification of EC. This study aimed to assess the clinicopathology and pathogenesis of POLE-mutated EC due to the scarcity of related information for Asian women. POLE variants were sequenced in tissues of Japanese women with EC. The tumor mutation burden (TMB) was assessed in tissues with a POLE variant of unknown significance. In the POLE-mutated EC tissues, the immunostaining expression of CD8, hormonal receptors, and p53 was evaluated, and the POLE variants in cancer and atypical endometrial hyperplasia (AEH) lesions were assessed by laser-capture microdissection. POLE variants were identified in five patients (3.9%) with high-grade endometrioid carcinoma among 127 patients with EC (S459F in two tissues and P441P in three tissues with a high TMB). The five cancer tissues coexisted with normal endometrium and/or AEH. Both AEH and cancer cells showed hormonal receptor positivity and harbored the same POLE mutation. Two patients showed a subclonal overexpression pattern of p53 in cancer and AEH lesions. In conclusion, POLE-mutated EC progresses through the type I pathway, even though it frequently shows high-grade endometrioid morphology. The common POLE mutation sites in EC might vary among races.

Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation of endometriotic cysts. In this study, we investigated the distribution of immune cells and CD163 (Hb receptor)-positive cells in the endometriotic cyst wall using immunohistochemistry. We also examined the role of macrophage activation by Hb on the pathogenesis of endometriotic cysts by measuring the cytokine concentration in the cystic fluids and macrophage-culture supernatant using ELISA. Macrophages were the most prominent immune cells observed in the endometriotic cysts and were differentially distributed in the different histological areas of the cyst wall. The localization of CD163-positive macrophages was restricted to the hemorrhagic and outer areas in the cyst wall. High concentrations of IL-6 and CCL2 were found in the cystic fluids, and inflammatory cytokines (IL-6, TNF-α, and CCL2) were secreted from macrophages on stimulation by Hb. IL-6 is a promotional factor for endometriotic stromal cells and ovarian clear cell carcinoma, the most common histological subtype of endometriosis-related ovarian cancer, hence, the continuous activation of macrophages by Hb could be a potential mechanism underlying endometriosis development and carcinogenesis.

Background Epithelial ovarian cancer has a clear predilection for the omentum as the site of metastasis; however, its contribution to clinical outcomes remains unresolved. This study aimed to evaluate the prognostic significance and efficacy of chemotherapy in the presence of omental metastasis. Methods A retrospective cohort study was performed in 56 patients with stage III–IV ovarian cancer who underwent primary debulking surgery between 2004 and 2018 at Kumamoto University Hospital. Results Thirty-six (64.3%) patients were categorized into the omental metastasis-positive group, whereas 20 (35.7%) patients were in the omental metastasis-negative group. The 5-year overall survival rates were 43.4% in the omental metastasis-positive group and 93.8% in the omental metastasis-negative group. Statistically significant differences were observed in overall survival (p = 0.002) and progression-free survival (p = 0.036) between the omental metastasis-positive and metastasis-negative groups. Notably, multivariate analysis demonstrated that the existence of omental metastasis is an independent risk factor for overall survival in patients with stage III–IV ovarian cancer (hazard ratio 8.90, 95% confidence interval 1.16–69.77; p = 0.038). Furthermore, the omental metastasis-positive group had significantly lower overall response rates to chemotherapy for recurrent disease, compared to the omental metastasis-negative group (31.6% vs. 85.7%, p = 0.026). Conclusion Our present data demonstrated that omental metastasis is closely associated with an unfavorable prognosis due to increased chemoresistance in patients with stage III–IV ovarian cancer. Elucidating the biological mechanism of omental metastasis will shed light on novel therapeutic approaches for the management of advanced ovarian cancer patients.

To evaluate the oncologic and obstetric outcomes of cervical conization followed by pelvic lymphadenectomy, which is used as a fertility-sparing procedure, in reproductive-aged patients with early-stage cervical cancer.We performed a retrospective study of patients with stage IA1-IB1 cervical cancer who underwent cervical conization followed by pelvic lymphadenectomy from 2011 to 2020 at Kumamoto University Hospital.In total, eight patients underwent conization followed by pelvic lymphadenectomy. The median age of the patients was 33 (range: 28-36) years. Four (50.0%) patients were nulliparous. Seven (87.5%) patients were diagnosed with squamous cell carcinoma (87.5%) and one (12.5%) with adenocarcinoma. Five (62.5%), two (25.0%), and one (12.5%) presented with stage IA1, IA2, and IB1 disease, respectively. Five (62.5%) patients had lymphovascular space invasion (LVSI) based on the assessment of specimens obtained via conization. However, none had lymph node metastasis based on pelvic lymphadenectomy. Regarding long-term oncologic outcomes, recurrence was not observed at a median follow-up of 60 (range: 8-107) months. In addition, obstetric outcomes were consistently favorable in terms of achieving pregnancy, preterm delivery, and live birth. During the study period, two patients who actively attempted to conceive had four pregnancies, resulting in full-term deliveries, and one was on her first trimester of pregnancy.Cervical conization combined with pelvic lymphadenectomy represents a feasible conservative management for histologically well-selected patients with early-stage cervical cancer. Furthermore, an optimal histopathological evaluation of conization specimens will contribute to decision-making regarding the use of this fertility-sparing procedure.

Cervical cancer (CC) is usually initiated by infection with high‐risk types of human papillomavirus (HPV). The HPV E6 and E7 proteins target p53 and RB, respectively, but other cellular targets likely exist. We generated uterus‐specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Mutant cervical epithelial cells showed YAP1‐dependent hyperproliferation, altered self‐renewal, impaired contact inhibition, and chromosomal instability. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion. In human CC, strong YAP1 activation was observed from the precancerous stage. Human cells overexpressing HPV16 E6/E7 showed inactivation of not only p53 and RB but also PTPN14, boosting YAP1 activation. Estrogen, cigarette smoke condensate, and PI3K hyperactivation all increased YAP1 activity in human cervical epithelial cells, and PTPN14 depletion along with PI3K activation or estrogen treatment further enhanced YAP1. Thus, immediate CC onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo‐YAP1 signaling a major CC driver., We generated uterus‐specific MOB1A/B double KO (uMob1DKO) mice, which immediately developed cervical squamous cell carcinoma in situ. Cervical cancer (CC) onset may initiate when YAP1 activity exceeds an oncogenic threshold, making Hippo‐YAP1 signaling a major CC driver. p53 activation was increased in uMob1DKO cells, and additional p53 loss in uMob1DKO mice accelerated tumor invasion.

Objective The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology. Methods Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model. Results 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases. Conclusions This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline.

Study Objective To identify the clinical presentation, diagnostic evaluation, operative or medical management, and postoperative recurrence of umbilical endometriosis. Design A retrospective national survey. Setting Obstetrics and Gynecology and Plastic Surgery Departments at a teaching hospital in Japan. Patients Patients with umbilical endometriosis or malignant transformation. Interventions A national survey was conducted to identify and evaluate cases of umbilical endometriosis or malignant transformation documented between 2006 and 2016. Measurements and Main Results The following were evaluated for each patient: age at diagnosis, body mass index, medical history, presence of extragenital endometriosis, surgical history, symptoms, imaging modalities, surgical therapy, hormonal therapy, follow-up period, postoperative recurrence, and time to recurrence. Ninety-six patients were identified with pathologically diagnosed benign umbilical endometriosis. The patients frequently had swelling (86.5%), pain (81.3%), or bleeding (44.8%) in the umbilicus. Sensitivity was 87.1% for physical examination, 76.5% for transabdominal ultrasonography, 75.6% for computed tomography, and 81.8% for magnetic resonance imaging. The cumulative recurrence rate was 1.34% at 6 months, 6.35% at 12 months, and 6.35% at 60 months after surgery. Importantly, there was no recurrence after wide resection including of the peritoneum (0 of 37 cases). The efficacy of dienogest (an oral progestin), gonadotropin-releasing hormone agonists, and oral contraceptives was 91.7%, 81.8%, and 57.1%, respectively. Finally, 2 cases of malignant transformation were identified. Conclusion There was a low recurrence rate following surgery, and hormonal treatment is an option, although the current findings suggest surgical therapy as the first choice of treatment for umbilical endometriosis.

The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management.A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC.A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities.Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12‐16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population‐level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1‐3 (CIN1‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012‐2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6‐year period were observed in CIN1 (50.0% to 0.0%, P trend

Background Placental mesenchymal dysplasia (PMD) is a morphological abnormality resembling partial hydatidiform moles. It is often associated with androgenetic/biparental mosaicism (ABM) and complicated by Beckwith–Wiedemann syndrome (BWS), an imprinting disorder. These phenomena suggest an association between PMD and aberrant genomic imprinting, particularly of CDKN1C and IGF2. The existence of another type of PMD containing the biparental genome has been reported. However, the frequency and etiology of biparental PMD are not yet fully understood. Results We examined 44 placental specimens from 26 patients with PMD: 19 of these were macroscopically normal and 25 exhibited macroscopic PMD. Genotyping by DNA microarray or short tandem repeat analysis revealed that approximately 35% of the macroscopic PMD specimens could be classified as biparental, while the remainder were ABM. We performed a DNA methylation analysis using bisulfite pyrosequencing of 15 placenta-specific imprinted differentially methylated regions (DMRs) and 36 ubiquitous imprinted DMRs. As expected, most DMRs in the macroscopic PMD specimens with ABM exhibited the paternal epigenotype. Importantly, the biparental macroscopic PMD specimens exhibited frequent aberrant hypomethylation at seven of the placenta-specific DMRs. Allelic expression analysis using single-nucleotide polymorphisms revealed that five imprinted genes associated with these aberrantly hypomethylated DMRs were biallelically expressed. Frequent aberrant hypomethylation was observed at five ubiquitous DMRs, including GRB10 but not ICR2 or ICR1, which regulate the expression of CDKN1C and IGF2, respectively. Whole-exome sequencing performed on four biparental macroscopic PMD specimens did not reveal any pathological genetic abnormalities. Clinical and molecular analyses of babies born from pregnancies with PMD revealed four cases with BWS, each exhibiting different molecular characteristics, and those between BWS and PMD specimens were not always the same. Conclusion These data clarify the prevalence of biparental PMD and ABM-PMD and strongly implicate hypomethylation of DMRs in the pathogenesis of biparental PMD, particularly placenta-specific DMRs and the ubiquitous GRB10, but not ICR2 or ICR1. Aberrant hypomethylation of DMRs was partial, indicating that it occurs after fertilization. PMD is an imprinting disorder, and it may be a missing link between imprinting disorders and placental disorders incompatible with life, such as complete hydatidiform moles and partial hydatidiform moles.

Objective Associations between hospital treatment volume and survival outcomes for women with 3 types of gynecologic malignancies, and the trends and contributing factors for high-volume centers were examined. Methods The Japan Society of Obstetrics and Gynecology tumor registry databased retrospective study examined 206,845 women with 80,741, 73,647, and 52,457 of endometrial, cervical, and ovarian tumor, respectively, who underwent primary treatment in Japan between 2004 and 2015. Associations between the annual treatment volume and overall survival (OS) for each tumor type were examined using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups (low-, moderate-, and high-volume centers) based on hazard risks. Results Hazard ratio (HR) for OS each the 3 tumors decreased with hospital treatment volume. The cut-off points of treatment volume were defined for high- (≥50, ≥51, and ≥27), moderate- (20–49, 20–50, and 17–26), and low-volume centers (≤19, ≤19, and ≤16) by cases/year for endometrial, cervical, and ovarian tumors, respectively. Multivariate analysis revealed younger age, rare tumor histology, and initial surgical management as contributing factors for women at high-volume centers (all, p, Synopsis For women with gynecologic malignancy, hospital treatment volume had an impact on survival outcome. The practice pattern shifted with scattering of patients and treatments at high-volume centers were decreasing. High-volume centers in Japan were associated with improved overall survival of gynecologic malignancies.

To assess the impact of COVID-19 on cervical cancer screening.The Japanese Society of Gynecologic Oncology launched COVID-19 Task Force surveyed the municipalities in urban areas of Japan. Questionnaires were sent to 20 ordinance-designated cities and 23 wards of Tokyo metropolitan area in Japan via telephone and mail in January 2021. An additional survey was conducted in March and April 2021, counted the monthly checkups in 2020 and, as a control data, the number of monthly checkups in 2019. "The State of Emergency" between April 7 and May 25, 2020, included 13 prefectures. The data collected in this research involved the number of screenings only. The chi-square test was performed for statistical analysis.The number of cancer screenings from March to August, with May being the month with the lowest number of screenings, was less than 50% of that in the previous year. In particular, the drop in the number of cancer screenings in the "Prefectures operating under special safety precautions" was remarkable and significantly lower than that in other Prefectures. However, after August, the number recovered to the usual level, despite the second wave of the pandemic occurring nationwide. The initial "the State of Emergency" caused a significant decrease in the number of people receiving population-based screenings, but the recovery has been remarkable, and the total number is expected to be the same as in previous years.The initial "the State of Emergency" caused a significant decrease in the number of people receiving population-based screenings.