Utility of vaginal vault cytology in the local recurrence of cervical cancer.

BACKGROUND: In Japan, 8000 women were newly diagnosed with cervical cancer in 2018. The healthcare insurance policy in Japan allows physicians to utilize vaginal volt cytology tests and serum biomarker measurement at every visit and imaging analysis at an adequate interval with screening for recurrence after initial treatment. However, the major surveillance guidelines published in the United States and European countries recommend focusing on pelvic examinations and symptom reviews to avoid unnecessary tests. This study aimed to reassess the benefits of standard surveillance methods adopted in this study by retrospective analysis. METHODS: From January 2009 to December 2015, the medical records of patients with recurrence who were initially diagnosed with International Federation of Gynecology and Obstetrics stage I-III cervical cancer were collected for this study. Clinicopathological data were statistically analyzed to identify significant factors. In the first 2 years, the patients underwent regular surveillance, including pelvic examination, serum tumor marker tests, vaginal vault cytology every 1-3 months, and imaging analysis at 6- to 12-month intervals. In the following 2 years, the patients received a regular check with the same methods every 4 months and an annual imaging analysis. Afterward, the patients had regular screening every 6 to 12 months. RESULTS: In the study period, 84 of the 981 patients experienced recurrence, and 88.1% had an asymptomatic recurrence. The disease-free interval was not related to the recurrence site. In univariate analysis, primary treatment, recurrence site, and diagnostic method were significant factors for survival outcomes. In contrast, multivariate analysis indicated that only primary treatment was a significant factor. In patients with local recurrence, multivariate analysis demonstrated that radiation as salvage therapy was an independent predictive factor for overall survival after recurrence. CONCLUSIONS: In this retrospective study, routine imaging analysis and serum biomarker measurement did not contribute to patient prognosis after recurrence. In contrast, vaginal vault cytology can improve survival after recurrence in some patients. Tailored surveillance methods based on individual disease conditions and treatment modalities can improve post-recurrent survival outcomes.

Association between financial toxicity and health-related quality of life of patients with gynecologic cancer.

OBJECTIVES: Patients often struggle with their financial situation during cancer treatment due to treatment-related costs or loss of income. This resulting negative effect is called financial toxicity, which is a known as a side effect of cancer care. This study aimed to evaluate the association between financial toxicity and health-related quality of life among patients with gynecologic cancer using validated questionnaires. METHODS: In this multicenter study, patients with gynecologic cancer receiving anti-cancer drug treatment for > 2 months were recruited. Patients answered the COmprehensive Score for Financial Toxicity (COST) tool, EORTC-QLQ-C30, disease-specific tools (EORTC-QLQ-OV28/CX24/EN24), and EQ-5D-5L. Spearman's rank correlation coefficient was used to determine associations. RESULTS: Between April 2019 and July 2021, 109 cancer patients completed the COST questionnaire. The mean COST score was 19.82. Strong associations were observed between financial difficulty (r = - 0.616) in the EORTC-QLQ-C30 and body image (r = 0.738) in the EORTC-QLQ-CX24, while weak associations were noted between the global health status/quality of life (r = 0.207), EQ-5D-5L index score (r = 0.252), and several function and symptom scale scores with the COST score. CONCLUSIONS: Greater financial toxicity was associated with worse health-related quality of life scores, such as financial difficulty in gynecologic cancer patients and body image in cervical cancer patients as strong associations, and weakly associated with general health-related quality of life scores and several function/symptom scales.

Validity of the COmprehensive Score for financial Toxicity (COST) in patients with gynecologic cancer.

OBJECTIVE: Financial toxicity is a financial burden of cancer care itself, which leads to worse quality of life and higher mortality and is considered an adverse effect. The COmprehensive Score for financial Toxicity (COST) tool is a patient-reported outcome measurement used to evaluate financial toxicity. We aimed to validate the internal consistency and reproducibility of the COST tool in patients with gynecologic cancer. METHODS: In this multicenter study covering the period April 2019 to July 2021, using the COST tool in Japan, patients diagnosed with ovarian, cervical, or endometrial cancer receiving systemic anti-cancer drug therapy for more than 2 months were eligible. Patients with no out-of-pocket costs for direct medical costs were excluded. The patients answered the initial test and a retest, which was completed from 2 to 14 days after the initial test. Internal consistency and reproducibility were assessed using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Cronbach's alpha ≥0.8 indicates good internal consistency, and ICC ≥0.8 is highly reliable. RESULTS: A total of 112 patients (ovarian: 50, cervical: 26, endometrial: 36) responded to the initial test, and 89 patients answered the retest from 2 to 14 days after the initial test. The median patient age was 58 (range, 28-78) years. The median COST score was 19. Cronbach's alpha showed good internal consistency at 0.83 (95% CI 0.78 to 0.87). The ICC at 0.850 (95% CI 0.777 to 0.900) showed high reliability. CONCLUSIONS: The COST tool has good internal consistency and reliable reproducibility in patients with gynecologic cancer in Japan. The COST tool quantifies financial toxicity in the insurance system, where patients have limited out-of-pocket direct medical costs. The results support the use of the COST tool in patients with gynecologic cancer.

Periaortic Abdominal Fat Area as a Predictor of Surgical Difficulties during Extraperitoneal Laparoscopic Para-aortic Lymphadenectomy.

STUDY OBJECTIVE: To evaluate whether obesity is a marker of surgical difficulty during extraperitoneal para-aortic lymphadenectomy. DESIGN: Retrospective observational cohort study. SETTING: Tertiary medical center in the Kanazawa area of Japan. PATIENTS: Eighty-four patients with primary endometrial cancer who underwent extraperitoneal laparoscopic para-aortic lymphadenectomy (LPAND) between January 2005 and December 2017 were included. INTERVENTIONS: We investigated the correlation between operative times and body mass indexes, visceral fat areas, and periabdominal artery fat areas (PAFAs). The number of lymph nodes harvested was used as an indicator of the degree of surgical completion. MEASUREMENTS AND MAIN RESULTS: There was no correlation between the operative time and body mass index. Significant correlations were observed between operative time and visceral fat area (p = .026; r = 0.243) and between operative time and PAFA (p = .007; r = 0.293). A multivariate analysis showed that PAFA was a significant independent marker that could be used to predict prolonged operative times for extraperitoneal LPAND (p = .045; odds ratio, 3.05). The number of para-aortic lymph nodes harvested was not significant in the high- and low-PAFA groups (22 and 25, respectively; p = .525). CONCLUSION: PAFA is an adequate marker of prolonged operative time for extraperitoneal LPAND among patients with endometrial cancer.

An electrical scalpel conization versus Shimodaira-Taniguchi conization procedure for cervical intraepithelial neoplasia.

The incidence of cervical intraepithelial neoplasia(CIN) among reproductive-aged women has increased in Japan. Cervical conization is commonly applied for local cervical treatment to preserve fertility. The Shimodaira-Taniguchi (S-T) conization procedure is widely used in Japan. S-T conization uses a high-frequency current and a triangular probe with a linear excision electrode to remove cervical tissue as a single informative specimen. However, alternative of an electrosurgical scalpel (ES) has the advantage of adjusting the surgical margin to the transformation zone in order to preserve the maximum amount of healthy cervical tissue with good hemostasis. The aim of this study is to retrospectively analyze data regarding surgical margin status, perioperative adverse events, cervical stenosis, and preterm birth between S-T and ES.Between January 2009 and December 2014, the medical records of 1166 patients who were diagnosed as CIN II, III, or stage 1a1 cervical cancer and who were treated with conization in 7 hospitals in Gunma Prefecture, Japan were enrolled for this retrospective study. The clinicopathological data was analyzed to statistically compare outcome between S-T and ES conization.There was no difference for age or post-operative follow-up period between ES and S-T treatments. However, positive surgical margins were significantly less frequent in patients who were treated with S-T than in those treated with ES, resulting in a reduced incidence of re-treatment for S-T in comparison with ES patients. In perioperative adverse events, S-T had more patients who were administered antibiotics. The incidence of preterm delivery and cervical stenosis did not differ significantly between the groups.We demonstrate here that S-T is an alternative procedure for cervical conization with a low risk of recurrence and acceptably low rate of adverse events such as cervical stenosis and preterm delivery. The results of this study can provide useful information for future management of patient with cervical intraepithelial neoplasia.

Simultaneous resection of endometrial cancer and high-level paraaortic paraganglioma using retroperitoneoscopic surgery.

•Paraganglioma is sometimes suspected as lymph node metastasis or lymph node recurrence of various malignant tumors.•Retroperitoneoscopic surgery is a valid approach to treat the tumor, located above the renal vein.•Resection using retroperitoneoscopic surgery without catecholamine-related complications is possible.

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients.

OBJECTIVE: The ubiquitin C-terminal hydrolase L1 (UCHL1) plays a key role in tumor invasion and metastasis. Ubiquitin C-terminal hydrolase L1 is overexpressed in various cancers and reported to be correlated with a poor prognosis. The objective of this study was to determine the prognostic significance of UCHL1 in endometrial cancer. METHODS: The expression of UCHL1 in endometrial cancer was assessed using quantitative reverse transcription polymerase chain reaction and immunohistochemistry in 56 and 215 resected tumor specimens, respectively. RESULTS: The 4-year survival rates of the high UCHL1 messenger RNA expression group and high UCHL1 protein expression group were 78% and 71%, respectively, compared with 96% and 95% for the low UCHL1 messenger RNA expression group and low UCHL1 protein expression group, respectively. Kaplan-Meier and log-rank tests indicated a significant correlation between expression of UCHL1 and disease-free survival and overall survival. Moreover, multivariate stepwise Cox proportional hazard regression model analysis showed that UCHL1 was a significant independent marker for predicting a poor disease-free survival and overall survival. In 43 patients with metastatic lesions, immunohistochemical analysis of metastatic lesions revealed that the recurrence rate and mortality rate were 62% and 41%, respectively, in 29 UCHL1-positive patients and 36% and 29%, respectively, in 14 UCHL1-negative patients. CONCLUSIONS: The results of this study suggest that high UCHL1 expression is a strong marker of poor prognosis of endometrial cancer. Furthermore, we suggest that UCHL1 may be involved in the development of distant metastasis in endometrial cancer.

Expression of the gonadotropin receptors during follicular development.

Background: Gonadotropins induce follicular development that leads to ovulation and luteinization. In women, the level of gonadotropins, along with the expression of their receptors, changes dynamically throughout the menstrual cycle. This study aimed to clarify the mechanisms underlying these phenomena. Methods: The literature was reviewed, including that published by the authors. Main findings Results: Follicle-stimulating hormone receptor expression in the granulosa cells was induced by androgens that were derived from growth differentiation factor-9-stimulated theca cells. In the theca cells, luteinizing hormone receptor (LHR) expression was noted from their appearance. In the granulosa cells, follicle-stimulating hormone (FSH) stimulation was essential for LHR expression. However, FSH alone was not sufficient to respond to the luteinizing hormone (LH) surge for oocyte maturation, ovulation, and subsequent luteinization. To achieve these stages, various local factors that were derived from the granulosa and theca cells in response to FSH and LH stimulation had to work synergistically in an autocrine/paracrine manner to strongly induce LHR expression. Following the LH surge, the LHR expression decreased markedly; miRNAs were involved in this transient LHR downregulation. Following ovulation, LHR expression drastically increased again toward luteinization. Conclusion: The expression of gonadotropin receptors is controlled by sophisticated and complicated systems; a breakdown of this system could lead to ovulation disorders.

Retinoic acid enhances progesterone production via the cAMP/PKA signaling pathway in immature rat granulosa cells.

Retinoic acid (RA) is a metabolite of vitamin A and has important roles in development, differentiation, and reproduction. Activin has been shown to regulate the RA pathway and affect granulosa cell (GC) proliferation, suggesting that RA is important for early follicle development. However, little is known about the effects of RA on GC functions, particularly steroidogenesis, during the early follicle stage. The aim of this study was to investigate the effects of all-trans-RA (atRA) on progesterone production in immature rat GCs cultured without gonadotropin. Our results demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein (StAR) and cytochrome P450scc (Cyp11a1) mRNAs, but not 3ß-hydroxysteroid dehydrogenase mRNA in immature rat GCs. Additionally, analysis of the mechanisms through which atRA upregulated StAR and Cyp11a1 mRNAs revealed that atRA enhanced intracellular cAMP accumulation and phosphorylation of cAMP response-element binding protein (CREB). In addition, H-89, an inhibitor of protein kinase A (PKA), abolished the stimulatory effects of atRA, indicating that atRA enhanced progesterone synthesis through cAMP/PKA signaling. In conclusion, our data demonstrated that atRA has a crucial role in progesterone synthesis in rat GCs during the early follicle stage.

TNF-α Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells.

Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by an NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.

IL-6 up-regulates the expression of rat LH receptors during granulosa cell differentiation.

IL-6 is produced in granulosa cells under normal physiological conditions, including during ovulation. However, the roles of IL-6 in ovarian function, including regulation of LH receptor (LHR) expression in granulosa cells, have not been explored in detail. The aim of this study was to identify the mechanism underlying the effect of IL-6 on LHR expression in the granulosa cells of female Wistar rats. Our results indicated that IL-6 clearly enhanced the FSH-induced LHR mRNA expression in a dose-dependent manner and did not stimulate cAMP accumulation by itself. The membrane protein level of LHR, assessed by a binding assay, was increased by FSH and was further enhanced by association with IL-6. Results of the luciferase assay, using promoter constructs of LHR 281 bp upstream of the translational start site, revealed that IL-6 increased the promoter activity induced by FSH, but this effect was not observed with treatment by IL-6 alone. This ability of IL-6 to enhance FSH-induced LHR mRNA expression was blocked by the Janus tyrosine kinase (JAK) pathway inhibitor, but not by the ERK1/2 inhibitor. Thus, we speculated that this IL-6 activity might be mediated by the JAK/signal transducer and activator of transcription pathway. In addition, IL-6 augmented FSH-induced IL-6 receptor α mRNA expression and FSH elevated IL-6 production in granulosa cells, which indicates that IL-6 may positively regulate paracrine and autocrine actions in granulosa cells. These results suggest that IL-6 up-regulates FSH-induced LHR production by increasing mRNA transcription, and JAK/signal transducer and activator of transcription 3 signaling is required for up-regulation by IL-6 in granulosa cells.