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Abstract Background Interval debulking surgery (IDS) following neoadjuvant chemotherapy is a treatment option for advanced ovarian cancer. Optimal surgery is required for better survival; however, while peritoneal washing cytology (PWC) has been identified as a prognostic factor, its comprehensive assessment during IDS remains unexplored. Therefore, we aimed to evaluate PWC efficacy during IDS, alongside other factors including residual disease and the modeled cancer antigen 125 (CA-125) ELIMination rate constant K (KELIM), by retrospectively reviewing the medical records of 25 patients with advanced ovarian cancer underwent neoadjuvant chemotherapy and IDS between January 2017 to June 2023. Results Twelve (48.0%) patients were PWC-positive, and the remainder were PWC-negative. PWC was performed at laparotomy during IDS, after which five (41.7%) PWC-positive and four (30.8%) PWC-negative patients received bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, for maintenance treatment. Four (33.3%) PWC-positive and 10 (76.9%) PWC-negative patients received poly adenosine diphosphate (ADP)-ribose polymerase inhibitors. In patients who received bevacizumab and poly ADP-ribose polymerase inhibitors, overall survival and progression-free survival did not significantly differ between those who were PWC-positive and PWC-negative (p = 0.27 and 0.20, respectively). Progression-free survival significantly differed between those with favorable and unfavorable CA-125 KELIM (p = 0.02). Multivariate analysis indicated that optimal surgery and favorable CA-125 KELIM were associated with better progression-free survival (p

The incidence and mortality rates of cervical cancer are increasing among young Japanese women. In November 2021, the Japanese Ministry of Health, Labour, and Welfare reinstated the active recommendation of the human papillomavirus (HPV) vaccine, after it had been suspended in June 2013 due to reports of adverse reactions. However, vaccine hesitancy is prevalent in the younger generation in Japan. To identify obstacles to vaccine uptake, we conducted a randomized study using different methods to provide educational content to improve health literacy regarding cervical cancer and HPV vaccination among Japanese female students. We surveyed 188 Japanese female students, divided into three groups according to the intervention: no intervention, print-based intervention, and social networking service-based intervention. Twenty questionnaires and the Communicative and Critical Health Literacy scales were used as health literacy scales. Participants' knowledge and health literacy improved regardless of the method of education. In fact, participants acquired proper knowledge when given the opportunity to learn about the importance of the disease and its prevention. Therefore, medical professionals in Japan must provide accurate scientific knowledge regarding routine HPV vaccination and the risk of cervical cancer in young women to improve their health literacy and subsequently increase HPV vaccination rates in Japan, which may lead to cervical cancer elimination. Trial registration number: UMIN000036636.

Background: Lobular endocervical glandular hyperplasia (LEGH) is a benign cervical condition that has been proposed as a precursor lesion to minimal deviation adenocarcinoma (MDA), a rare but highly aggressive subtype of well-differentiated gastric-type endocervical adenocarcinoma (GAS). MDA is more frequently observed in patients with Peutz–Jeghers syndrome (PJS) and is strongly associated with mutations in the STK11 gene. While LEGH is not inherently linked to PJS, its potential progression to MDA warrants vigilance, particularly in patients with PJS due to their heightened risk of gynecologic malignancies. Here, we report a case of LEGH diagnosed during surveillance for PJS, analyzed via whole genome sequencing. LEGH is a benign cervical condition, considered a precursor lesion to minimal deviation adenocarcinoma, often observed in patients with Peutz–Jeghers syndrome (PJS) and potentially linked to mutations in the STK11 gene. Case: A 23-year-old woman, diagnosed with PJS at age 11, was referred to a gynecologist after a cystic lesion was detected in the cervix during a follow-up computed tomography scan. Initial examinations, including imaging and colposcopy, did not indicate LEGH or a malignant tumor. Imaging alone is insufficient to exclude premalignant or malignant conditions, as abnormal cervical lesions often require biopsy for a definitive diagnosis. However, cervical cytology showed nuclear atypia was minimal, but some clusters exhibited disordered alignment, and the cytoplasm contained yellowish mucus suggestive of LEGH. Based on these findings, cytology follow-up was planned. However, the patient did not return for further follow-up. After one year and five months, the patient presented with increased mucous vaginal discharge. Cervical cytology indicated atypical glandular cells, and magnetic resonance imaging with contrast enhancement revealed an enlarged cervical lesion, suggesting minimal deviation adenocarcinoma. We performed cervical conization, and a histopathological examination helped confirm LEGH. High-throughput next-generation sequencing of the excised cervical tissue revealed a missense mutation in the serine/threonine kinase 11 (STK11) gene on chromosome 19 (c.1062C > G) and three missense mutations in STK11 interacting protein (STK11IP) on chromosome 2 (c.2G > T, c.1687G > A, c.2255C > T). Mutations in STK11, particularly those affecting its regulatory domains, may significantly increase cancer risk in patients with PJS, and that STK11IP plays a crucial role in modulating STK11 activity. The patient, seeking to preserve fertility, has been monitored for five years post-surgery without evidence of malignant transformation. Continuous monitoring with periodic imaging and cytological assessments has shown no evidence of malignant transformation. The absence of elevated tumor markers further supports the conservative approach. While there are no tumor markers specific to cervical cancer, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), and carbohydrate antigen 19–9 (CA19-9) were measured as part of the screening process in this case. Conclusion: We conclude that whole genome sequencing in patients with PJS and LEGH could be pivotal in predicting cervical malignancy. This case emphasizes the utility of whole genome sequencing in predicting the risk of cervical malignancy in patients with PJS and LEGH and highlighting the critical role of genetic factors in the management and surveillance of these patients. Continuous monitoring post-surgery showed no evidence of malignant transformation, supporting a conservative approach in fertility-preserving treatment scenarios.

Abstract More specific screening systems for cervical cancer may become necessary as the human papillomavirus (HPV) vaccine becomes more widespread. Although p16/Ki-67 dual-staining cytology has several advantages, it requires advanced diagnostic skills. Here, we developed an automated on-chip immunostaining method using a microfluidic device. An electroactive microwell array (EMA) microfluidic device with patterned thin-film electrodes at the bottom of each microwell was used for single-cell capture by dielectrophoresis. Immunostaining and dual staining for p16/Ki-67 were performed on diagnosed liquid cytology samples using the EMA device. The numbers of p16/Ki-67 dual-stained cells captured by the EMA device were determined and compared among the cervical intraepithelial neoplasia (CIN) lesion samples. Seven normal, fifteen CIN grade 3, and seven CIN grade 2 samples were examined. The percentage of dual-positive cells was 18.6% in the CIN grade 2 samples and 23.6% in the CIN grade 3 samples. The percentages of dual-positive staining increased significantly as the severity of the cervical lesions increased. p16/Ki67 dual immunostaining using the EMA device is as sensitive as the conventional method of confirming the histopathological diagnosis of cervical samples. This system enables a quantified parallel analysis at the individual cell level.

Abstract Background Granulosa cell tumors (GCTs) account for approximately 2% of ovarian malignancies and are considered a rare type of ovarian cancer. GCTs are characterized by irregular genital bleeding after menopause due to female hormone production as well as late recurrence around 5–10 years after initial treatment. In this study, we investigated two cases of GCTs to find a biomarker that can be used to evaluate the treatment and predict recurrence. Case presentation Case 1 was a 56-year-old woman who presented to our hospital with abdominal pain and distention. An abdominal tumor was found, and GCTs were diagnosed. Serum vascular endothelial growth factor (VEGF) levels decreased after surgery. Case 2 involved a 51-year-old woman with refractory GCTs. Carboplatin–paclitaxel combination therapy and bevacizumab were administered after the tumor resection. After chemotherapy, a decline in VEGF levels was observed, but serum VEGF levels increased again with disease progression. Conclusions VEGF expression may be of clinical importance in GCTs as a clinical biomarker for disease progression, which may be used to determine the efficacy of bevacizumab against GCTs.

BackgroundLenvatinib-pembrolizumab combination (LEAP) is an approved therapy in Japan for advanced endometrial cancer, based on the data from the KEYNOTE-775 clinical trial. We report a case of posterior reversible encephalopathy syndrome (PRES) in a patient who received LEAP therapy for advanced endometrial cancer.Case presentationA 53-year-old patient with stage IVB endometrial cancer having rectal metastases, after four cycles of paclitaxel-carboplatin therapy, was found to have increased rectal invasion, peritoneal dissemination, and multiple paraaortic lymph node metastases. She was treated with LEAP therapy and discharged on day 12 without adverse events, except for mild anemia on day 11 of treatment. She was carefully managed in the outpatient department, but on day 18, she was admitted to the emergency department with severely impaired consciousness and generalized seizures. Computed tomography of the head and lumbar tap showed no abnormal findings, and the seizures resolved with anticonvulsant medication alone. Based on a thorough physical examination and findings on magnetic resonance imaging (MRI), which showed high signal intensity in the left occipital lobe, encephalopathy, rather than encephalitis, was the likely diagnosis. Symptomatic improvement was observed, and pembrolizumab monotherapy was resumed.ConclusionsIf consciousness is impaired during LEAP treatment, it is necessary to differentiate between immunogenic encephalitis caused by pembrolizumab or encephalopathy caused by lenvatinib. MRI and lumbar tap can help in distinguishing between the two and diagnosing the responsible drug.

Abstract Background Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists. Case presentation A 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired. Conclusions To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Abstract Background Physician-scientists are a vital segment of the healthcare workforce, but they may face significant challenges balancing and integrating clinical responsibilities, scientific research, and domestic responsibilities. This study investigates factors associated with burnout among highly successful early career physician-researchers in Japan. Method Among 1790 physician awardees of Grant-in-Aid for Young Scientists by the Japanese Ministry in 2014–2015, 490 participated in this cross-sectional survey in 2016 (usable response rate 23.8%). The primary outcome was psychological burnout, measured by the Copenhagen Burnout Inventory (i.e., personal burnout, work-related burnout, and patient-related burnout). “Workplace resources” in our study refers to the presence of career education in the workplace, promotion of gender equity, well-being consultation services on “career and work,” “research,” “harassment,” and/or “mental health,” as well as the presence of a role model in the workplace who has perceived good work-life balance. Results Among 408 physician-researchers (75% male, mean age 37 yrs), personal burnout scores were slightly higher in women than in men (mean score, 41.9 points vs. 36.7 points, difference, 5.2, 95% confidence interval, 0.5–9.9, p = 0.029), but work-related and patient-related burnout scores did not differ significantly between genders. Over half of women (64%) and men (58%) had a mentor (p = 0.374). In multivariable general linear regression models, personal burnout scores were higher for women (β = 4.98, p = 0.045), and lower among those who had a mentor (β = − 5.82, p = 0.010) and whose workplaces had well-being consultation services (β = − 0.79, p = 0.022). Work-related burnout scores were lower among those with larger amounts of grant funding (β = − 4.70, p = 0.013), a mentor (β = − 6.12, p = 0.002), well-being consultation services (β = − 0.78, p = 0.008) and a role model with a perceived good work-life balance (β = − 4.00, p = 0.038). Patient-related burnout scores were higher among physician-scientists aged older than 37 years (β = 6.25, p = 0.002) and those who had board certification (β = 9.01, p = 0.017), while these scores were lower among those had larger amounts of funding (β = − 5.01, p = 0.006) or a mentor (β = − 5.35, p = 0.006). Conclusions Workplace resources and mentorship appear to be associated with lower levels of psychological burnout for both men and women early career physician-scientists.

Ulipristal acetate (UPA), a selective progesterone receptor modulator, is used for the treatment of uterine fibroids and selectively inhibits the proliferation and inflammation of leiomyoma cells. As few studies have focused on the molecular biological mechanism of UPA in Ishikawa endometrial cancer cells, we aimed to identify the effects of UPA on these cells. Ishikawa cells were treated with different concentrations of UPA. Cell viability and colony formation assays were performed to assess the growth of cancer cells, whereas invasion and migration assays were used to measure cell motility and invasiveness. Western blotting, caspase 3/7 assay, TUNEL assay, and flow cytometry were performed to analyze apoptosis. Moreover, expression levels of the proinflammatory cytokines oncostatin M, its receptor, interleukin 6, and interleukin 8 were examined using quantitative real-time PCR. UPA decreased cell viability and growth, thereby inhibiting cell migration and invasion via induction of apoptosis. Contrary to expectation, stand-alone application of UPA increased the expression of the proinflammatory cytokines but concomitant use of UPA and the estrogen receptor antagonist ICI 182,720 decreased it. These data revealed a novel dual role of UPA: It could attenuate cell growth via activation of apoptosis while simultaneously provoking the activation of proinflammatory cytokines in endometrial cancer cells. These indicate that the combination of UPA and an estrogen receptor antagonist may be useful in suppressing the secretion of proinflammatory cytokines by UPA alone.

Chlamydia trachomatis infections may occur in multiple organs, including the lungs, lymph nodes, peritoneal cavity, and genitourinary systems. This disease results in significant ascites, the swelling of lymph nodes, and elevated tumor markers (CA125), sometimes mimicking an ovarian malignancy. At our hospital, we often perform examination laparoscopic surgery in cases of suspected gynecologic cancers before initial treatment. In this paper, we report the case of a 19-year-old woman who came to our hospital because of an ovarian tumor and ascites. There was no history of sexual intercourse (self-reported). We suspected ovarian cancer from image inspections, so we performed laparoscopic surgery for diagnosis. The final pathological diagnosis was acute-to-chronic inflammation of the bilateral fallopian tubes, and a cytologic examination of the ascites was negative for malignant cells. The C. trachomatis antigen was positive on vaginal examination after the operation. Based on this result, we diagnosed this patient with C. trachomatis infection. Chlamydia peritonitis should be a differential diagnosis for cancer peritonitis in juvenile patients with abnormal ascites. Exploratory laparoscopy should help confirm the pathological diagnosis.

Abstract Background Stratified mucin-producing intraepithelial lesion (SMILE) is a rare precursor lesion in the uterine cervix that is considered a variant of adenocarcinoma in situ (AIS). Although human papillomavirus (HPV) is thought to be related to the development of SMILE, there is little information available on the detection of HPV integrated into the lesion. Case presentation A 30-year-old female underwent a routine uterine cervical cancer screening, and her Pap smear indicated the possible existence of atypical glandular cells. A cervical biopsy with endocervical curettage was performed. The histopathological analysis showed that she had SMILE and high-grade squamous intraepithelial lesion (HSIL) on her cervix. The lesion was found to be positive for HPV genotypes 52 and 68 by multiplex PCR. In situ hybridization with HPV RNA probes revealed that these HPV types were involved in the onset of HSIL and SMILE, respectively. Conclusions Rare, high-risk HPV genotypes may contribute to the development of SMILE, and their detection can be useful for preventing the progression to carcinoma and ensuring adequate patient management.

Abstract Background Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. Methods Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. Results The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). Conclusions As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.

Abstract Background A previous report showed that a glucagon-like peptide-1 receptor (GLP-1R) agonist (exenatide) induced apoptosis in endometrial cancer cells. However, the pathophysiological role of GLP-1R in endometrial cancer has not been fully elucidated. Here, we investigated the effects of the GLP-1R agonist liraglutide in endometrial cancer cells and examined the association between GLP-1R expression and clinicopathological characteristics in endometrial cancer patients. Methods Human Ishikawa endometrial cancer cells were treated with different concentrations of liraglutide. To assess the effects of liraglutide, cell viability, colony formation, flow cytometry, Western blotting, and immunofluorescence assays were performed. Autophagy induction was examined by analyzing LC3 and p62 expression and autophagosome accumulation. Moreover, using a tissue microarray, we analyzed GLP-1R expression in 154 endometrial cancer tissue samples by immunohistochemistry. Results In accordance with the previous report, liraglutide inhibited Ishikawa cell growth in a dose-dependent manner. Liraglutide significantly induced autophagy, and phosphorylated AMPK expression was elevated. Immunohistochemical analysis revealed that GLP-1R expression was associated with positive estrogen receptor and progesterone receptor status, and higher GLP-1R expression was significantly correlated with better progression-free survival. Conclusions The use of liraglutide to target autophagy in endometrial cancer cells may be a novel potential treatment for endometrial cancer. Furthermore, higher GLP-1R expression may be associated with better prognosis in endometrial cancer patients.

Abstract Background Accumulating evidence from medical workforce research indicates that poor work/life balance and increased work/home conflict induce psychological distress. In this study we aim to examine the existence of a priority gap between ideal and real lives, and its association with psychological burnout among academic professionals. Methods This cross-sectional survey, conducted in 2014, included faculty members (228 men, 102 women) at a single medical university in Tokyo, Japan. The outcome of interest was psychological burnout, measured with a validated inventory. Discordance between ideal- and real-life priorities, based on participants’ responses (work, family, individual life, combinations thereof), was defined as a priority gap. Results The majority (64%) of participants chose “work” as the greatest priority in real life, but only 28% chose “work” as the greatest priority in their conception of an ideal life. Priority gaps were identified in 59.5% of respondents. A stepwise multivariable general linear model demonstrated that burnout scores were associated positively with respondents’ current position (P

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.

We investigated relationships between the perception of organizational climate with gender equity and psychological health among 94 women and 211 men in a Japanese private university in 2015 using the Copenhagen Burnout Inventory (i.e., personal, work-related and student-related burnout). Perceptions of organizational climate with respect to gender equity were measured with two scales including organizational engagement with a gender equal society in the workplace (consisting of three domains of 'Women utilization', 'Organizational promotion of gender equal society' and 'Consultation service'); and a gender inequality in academia scale that had been previously developed. Multivariable linear models demonstrated significant statistical interactions between gender and perceptions of organizational climate; 'Women utilization' or lack of 'Inequality in academia' alleviated burnout only in women. In consequence of this gender difference, when 'Women utilization' was at a lower level, both personal (p=.038) and work-related (p=.010) burnout scores were higher in women, and the student-related burnout score was lower in women when they perceived less inequality in academia than in men (p=.030). As such, it is suggested organizational fairness for gender equity may be a useful tool to help mitigate psychological burnout among women in academia. [ABSTRACT FROM AUTHOR]