Latrophilin-3 as a downstream effector of the androgen receptor induces urothelial tumorigenesis.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.

Ten-year questionnaire study on human papillomavirus vaccination targeting new female medical school students: Follow-up to the 2015 report.

AIM: We aimed to conduct a fixed-point observation questionnaire survey of changes in young women's human papillomavirus (HPV) vaccination status over the course of 10 years. We also investigated the influence of suspension of governmental recommendation for HPV vaccination since June 2013. METHODS: During 2011-2020, we conducted a self-completed questionnaire survey among newly enrolled female medical school students in Yokohama, Japan. The questionnaire featured items regarding HPV vaccination status, age, previous sex education, and knowledge about cervical cancer and HPV vaccination. RESULTS: HPV vaccine uptake rates in 2011 (5.4%) and 2012 (13.5%), when vaccination was self-funded, increased after 2013 (48.7%), when vaccination fees were subsidized. The rate dropped drastically in 2019 (14.3%) and 2020 (5.1%), after suspension of recommendation by the government. Comparisons between new students in 2015/2016, who had high vaccination rates (65.2%), and new students in 2019/2020, who had low vaccination rates (9.8%), showed decreased levels of HPV vaccination awareness, with fewer students having covered cervical cancer prevention in sex education and with respondents having less knowledge about the details of HPV vaccination. CONCLUSIONS: After the suspension of proactive HPV vaccine recommendation, markedly fewer students have been vaccinated against HPV, even those at the vaccination target age. This situation has substantially influenced the lower awareness about cervical cancer prevention, even among medical school students. To protect young women from cervical cancer in Japan, it is crucial for the government to resume proactive recommendation of HPV vaccines as soon as possible.

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer.

The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.

FOXO1 inactivation induces cisplatin resistance in bladder cancer.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

Role of glucocorticoid signaling in urothelial tumorigenesis: Inhibition by prednisone presumably through inducing glucocorticoid receptor transrepression.

Glucocorticoids, including dexamethasone (DEX) and prednisone (PRED), have been prescribed in patients with neoplastic disease as cytotoxic agents or comedications. Nonetheless, it remains uncertain whether they have an impact on the development of bladder cancer. We, therefore, assessed the functional role of the glucocorticoid-mediated glucocorticoid receptor (GR) signaling in urothelial tumorigenesis. Tumor formation was significantly delayed in xenograft-bearing mice with implantation of control bladder cancer UMUC3 cells or nonneoplastic urothelial SVHUC cells undergoing malignant transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA), compared with respective GR knockdown xenografts. Using the in vitro system with MCA-SVHUC cells, we screened 11 GR ligands, including DEX, and found significant inhibitory effects of PRED on their neoplastic transformation. The effects of PRED were restored by a GR antagonist RU486 in GR-positive MCA-SVHUC cells, while PRED failed to inhibit the neoplastic transformation of GR knockdown cells. Significant decreases in the expression levels of oncogenes (c-Fos/c-Jun) and significant increases in those of a tumor suppressor UGT1A were seen in MCA-SVHUC-control cells (vs GR-short hairpin RNA) or PRED-treated MCA-SVHUC-control cells (vs mock). In addition, N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder cancer in all of eight mock-treated mice vs seven (87.5%) of DEX-treated (P = .302) or four (50%) of PRED-treated (P = .021) animals. Finally, DEX was found to considerably induce both transactivation (activation of glucocorticoid-response element mediated transcription and expression of its targets) and transrepression (suppression of nuclear factor-kappa B transactivation and expression of its regulated genes) of GR in SVHUC cells, while PRED more selectively induced GR transrepression. These findings suggest that PRED could prevent urothelial tumorigenesis presumably via inducing GR transrepression.

Aberrant Nuclear Localization of aPKCλ/ι is Associated With Poorer Prognosis in Uterine Cervical Cancer.

We previously reported that aberrant expression of atypical protein kinase C λ/ι (aPKCλ/ι) in low-grade squamous intraepithelial uterine cervix lesions was associated with an increased risk of progression to higher grade. This study aimed to investigate aPKCλ/ι expression patterns in cervical squamous cell carcinoma (SCC) and its association with disease progression. We immunohistochemically assessed aPKCλ/ι expression in 168 SCC samples and 13 normal uterine cervix samples. In 69.0% of SCC cases, aPKCλ/ι was expressed more abundantly than in normal epithelium, but there was no significant association between aPKCλ/ι intensity and disease progression (P=0.087, Cochran-Mantel-Haenszel test). aPKCλ/ι in normal cervical epithelium was confined to the cytoplasm or intercellular junctions. In contrast, aPKCλ/ι was predominantly localized within the nucleus in 36.9% of SCC samples (P<0.001, χ test), and the prevalence was significantly increased relative to advanced tumor stage (P<0.001, Cochran-Mantel-Haenszel test). Moreover, patients with SCC with aPKCλ/ι nuclear localization had worse prognoses than those with cytoplasmic localization (P<0.001, log-rank test). aPKCλ/ι localization differed between the intraepithelial lesion and adjacent invasive cancer in 40% of cases, while the expression pattern was similar between primary and matched metastatic tumors. In conclusion, aPKCλ/ι nuclear localization in cervical cancer is associated with tumor progression and worse prognosis. This is the first report to show aberrant nuclear aPKCλ/ι localization in a subgroup of cervical cancer patients and its association with worse prognosis.

The interaction between androgen receptor and semenogelin I: a synthetic LxxLL peptide antagonist inhibits the growth of prostate cancer cells.

BACKGROUND: We previously demonstrated that a seminal plasma protein, semenogelin I (SgI), functioned as an androgen receptor (AR) coactivator. Meanwhile, several short sequence motifs in AR coregulators, such as LxxLL (L=leucine), have been shown to mediate specific interactions with AR. METHODS: We investigated the role of the LxxLL motif within SgI in the interactions with AR and cell growth in prostate cancer lines in vitro. RESULTS: A full-length SgI with mutations in the motif (i.e., LxxAA; A=alanine) failed to significantly increase cell proliferation/migration as well as androgen-mediated AR transcription. Co-immunoprecipitation showed no physical interactions between AR and the mutant SgI. In addition, transfection of an 18-amino acid peptide of SgI containing LxxLL, but not LxxAA, resulted in considerable reduction in cell growth and prostate-specific antigen expression in LNCaP and C4-2 lines. CONCLUSIONS: The LxxLL motif of SgI could be a novel therapeutic target for both androgen-sensitive and castration-resistant prostate cancers.

Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression.

BACKGROUND: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and cancer progression. METHODS: We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines. RESULTS: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. CONCLUSIONS: EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression.

Normalization of abnormal plasma amino acid profile-based indexes in patients with gynecological malignant tumors after curative treatment.

BACKGROUND: We developed a novel plasma amino acid profile-based index (API) to detect ovarian, uterine, cervical, and endometrial cancers. In this study, we aimed to evaluate whether abnormal API values could be normalized after curative treatment in patients with gynecological malignant tumors. METHODS: Patients with gynecological cancer with abnormal API values were included in this study. Pre-operative absolute API values were compared with those after curative treatment. The normalization rates of API values in patients negative for the expression of three well-known tumor markers (SCC, CA125, and CA19-9) were also evaluated. In addition, related amino acid profiles in healthy controls and patients under pre- and post-treatment conditions were analyzed. RESULTS: Among 94 patients with abnormal pre-operative API values, the median API value was decreased from 9.52 to 2.17 after treatment (normalization rate: 88.3%). The decreased ranges were similar in patients with adenocarcinoma (6.28; 95% confidence interval [CI]: 5.43-6.95) and squamous carcinoma (7.44; 95% CI: 3.04-8.46). In 93.5% (43/46) of patients negative for tumor markers prior to operation, API values were normalized after the successful treatment. In addition, some pre-operative abnormal amino acid profiles, including Ile, Trp, and His, were reversibly normalized after treatment. CONCLUSION: The API is a promising tumor marker in gynecological malignancies for the diagnosis of remission, particularly in patients negative for general tumor markers. Further studies are needed to explore the mechanisms related to the normalization of abnormal amino acid profiles.

Uridine 5'diphospho-glucuronosyltransferase 1A expression as an independent prognosticator in urothelial carcinoma of the upper urinary tract.

OBJECTIVE: To determine the expression status of uridine 5'diphospho-glucuronosyltransferase 1A, a major phase II drug metabolism enzyme, in upper urinary tract urothelial carcinoma, as well as to assess its prognostic significance. METHODS: We immunohistochemically stained for uridine 5'diphospho-glucuronosyltransferase 1A in tissue microarray consisting of 99 upper urinary tract urothelial carcinoma samples and paired non-neoplastic urothelial tissues. We also assessed the effect of uridine 5'diphospho-glucuronosyltransferase 1A knockdown on urothelial cancer cell growth. RESULTS: Uridine 5'diphospho-glucuronosyltransferase 1A was positive in 92.9% (27.3% weak [1+], 37.4% moderate [2+], 28.3% strong [3+]) of tumors, which was significantly (P < 0.001) lower than in benign urothelial tissues (98.8%; 3.5% 1+, 18.8% 2+, 76.4% 3+). All 37 (100%) non-muscle-invasive versus 55 (88.7%) of 62 muscle-invasive tumors (P = 0.043) were immunoreactive for uridine 5'diphospho-glucuronosyltransferase 1A. The rates of moderate-to-strong uridine 5'diphospho-glucuronosyltransferase 1A expression and its positivity were also strongly associated with the absence of concomitant carcinoma in situ (P = 0.034) and lymphovascular invasion (P = 0.016), respectively. However, there were no statistically significant associations between uridine 5'diphospho-glucuronosyltransferase 1A expression and tumor grade or pN/M status. Uridine 5'diphospho-glucuronosyltransferase 1A loss in M0 tumors was strongly associated with lower progression-free survival (P < 0.001) and cancer-specific survival (P < 0.001) rates. Multivariate analysis further identified a strong correlation of uridine 5'diphospho-glucuronosyltransferase 1A positivity with reduced cancer-specific mortality (hazard ratio 0.28, P = 0.018). Meanwhile, uridine 5'diphospho-glucuronosyltransferase 1A knockdown in urothelial cancer cells resulted in significant increases in their viability and migration. CONCLUSIONS: These results suggest a preventive role of uridine 5'diphospho-glucuronosyltransferase 1A signals in the development and progression of upper urinary tract urothelial carcinoma. Loss of uridine 5'diphospho-glucuronosyltransferase 1A expression might serve as an independent predictor of poor prognosis in patients with upper urinary tract urothelial carcinoma.

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract.

Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma (UUTUC). Overall, phospho-ELK1 was positive in 47 (47.5%; 37 weak (1+) and 10 moderate (2+)) of 99 UUTUCs, which was significantly (P = 0.002) higher than in benign urothelium (21 (25.3%) of 83; 17 1+ and 4 2+) and was also associated with androgen receptor expression (P = 0.001). Thirteen (35.1%) of 37 non-muscle-invasive versus 34 (54.8%) of 62 muscle-invasive UUTUCs (P = 0.065) were immunoreactive for phospho-ELK1. Lymphovascular invasion was significantly (P = 0.014) more often seen in phospho-ELK1(2+) tumors (80.0%) than in phospho-ELK1(0/1+) tumors (36.0%). There were no statistically significant associations between phospho-ELK1 expression and tumor grade, presence of concurrent carcinoma in situ or hydronephrosis, or pN status. Kaplan-Meier and log-rank tests revealed that patients with phospho-ELK1(2+) tumor had marginally and significantly higher risks of disease progression (P = 0.055) and cancer-specific mortality (P = 0.008), respectively, compared to those with phospho-ELK1(0/1+) tumor. The current results thus support our previous observations in bladder cancer and further suggest that phospho-ELK1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.

Aberrant Expression of the Cell Polarity Regulator aPKCλ/ι is Associated With Disease Progression in Cervical Intraepithelial Neoplasia (CIN): A Possible Marker for Predicting CIN Prognosis.

Atypical protein kinase C λ/ι (aPKCλ/ι) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKCλ/ι may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKCλ/ι expression and CIN. aPKCλ/ι expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKCλ/ι overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKCλ/ι nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P<0.05), suggesting that CIN grade is related to aPKCλ/ι overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKCλ/ι overexpression or aPKCλ/ι nuclear localization had a higher progression rate than CIN1 cases with normal aPKCλ/ι expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P<0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKCλ/ι overexpression (hazard ratio=4.26; 95% confidence interval, 1.50-12.1; P=0.007), and aPKCλ/ι nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24-10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKCλ/ι could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types.

Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

OBJECTIVE: Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. STUDY DESIGN: Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. RESULTS: EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). CONCLUSION: This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.

Is there a need for screening of cervical HPV infections and carcinoma?

Antenatal cervical screening aims to detect cervical intraepithelial neoplasms as precancerous lesions and invasive cervical cancer. Whether this screening is performed routinely during pregnancy varies depending on each country's screening participation rates, guidelines, and the risks to the pregnant woman. In some countries with the high rate of routinely implemented cervical screening among the target women, women are recommended to defer cervical screening intentionally to post-delivery, though having screening in consultation with physicians may be possible if routine screening overlaps. However, when cervical screening rate in fertile women is low and the incidence of cervical cancer is high, cervical screening during pregnancy may play an important role in the early detection of cervical cancer. Cervical screening using high-risk human papillomavirus (HPV) testing is accepted worldwide as a highly sensitive and objective test method, and it should replace traditional primary cervical cytology in the future. However, the benefits and disadvantages of using HPV testing in pregnant women is unclear because a false positive rate may be increased due to pregnant women being generally under an immunosuppressed condition.

High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis.

Overexpression of atypical protein kinase Cλ/ι (aPKCλ/ι), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA, an upstream regulator of tumor suppressor Hippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA-aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA/aPKCλ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and Kaplan-Meier log-rank test. We found an intimate correlation between the expression level of KIBRA and aPKCλ/ι (P = 0.012). Furthermore, high expression of KIBRA is correlated with lymphatic (P = 0.046) and venous invasion (P = 0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKCλ/ι-expressing gastric cancer correlated with disease-specific (P = 0.037) and relapse-free survival (P = 0.041) by Kaplan-Meier with log-rank test and higher lymphatic invasion cases by Fisher's exact test (P = 0.042). Furthermore, overexpression of the aPKC-binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC-expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.

Evaluating the risk factors for developing resistance to parenteral therapy for tubo-ovarian abscess: a case-control study.

AIM: The aim of this study was to identify factors that can predict the resistance to parenteral therapy in patients with tubo-ovarian abscesses (TOA). MATERIAL AND METHODS: We conducted a case-control study involving 55 admitted patients with TOA. The subjects eligible for this study included 28 patients who failed antibiotic therapy and required surgery (surgical cases) and 27 patients who were conservatively cured (control cases). The clinical characteristics of the patients on admission were reviewed. Logistic regression analysis was performed after univariate analysis to identify potentially important variables and to calculate odds ratios with 95% confidence intervals. RESULTS: As per the univariate analysis, compared to the control cases, the surgical cases were older (40.4 vs 31.5 years), had higher white blood cell counts (14000 vs 11828 cells/mm³), higher C-reactive protein levels (16.1 vs 7.6 mg/dL), and a larger abscess diameter (6.6 vs 3.9 cm). There were no significant differences in gravidity, parity, body temperature, rate of endometrial cyst formation, and Chlamydia trachomatis infection rates between the groups. Multiple logistic regression analysis indicated that the only statistically significant risk factor predicting parenteral antibiotic therapy failure was the abscess diameter >5 cm (odds ratio = 69.6; 95% confidence interval = 9.3-527, P < 0.0001). CONCLUSION: An abscess diameter >5 cm is an important factor for predicting the failure of antibiotic therapy in patients with TOA. Moreover, it is useful for determining whether patients with TOA should be surgically treated.

Low skeletal muscle mass predicts poor prognosis for patients with stage III cervical cancer on concurrent chemoradiotherapy.

OBJECTIVES: The aim of this study was to evaluate whether low skeletal muscle mass before initial treatment is an independent prognostic factor defining overall survival (OS) and progression-free survival (PFS) in patients diagnosed with stage III cervical cancer. METHODS: Body composition and clinicopathologic data were collected retrospectively. Information was extracted and analyzed from the medical records of 92 patients with stage III cervical cancer and undergoing concurrent chemoradiotherapy. Skeletal muscle mass in the L3 region was measured using cross-sectional computed tomography images and corrected for body surface area to calculate the skeletal muscle index (SMI). The primary outcome was OS, and the secondary outcome was PFS. Statistical analyses were performed using the Mann-Whitney U test. The Kaplan-Meier method was used to determine OS and PFS. Univariate and multivariate analyses were performed with Cox proportional hazard ratios. RESULTS: The optimal cutoff value for predicting 5-y survival was 35.6 cm2/m2, defined based on data derived from 24 patients with a low SMI and 68 patients without a low SMI. A low SMI was significantly associated with shorter OS (hazard ratio [HR], 2.470; 95% confidence interval [CI], 1.208-5.053; P = 0.013), with no significant difference in PFS (HR, 1.651; 95% CI, 0.876-3.110; P = 0.121). Multivariate analysis also identified a low SMI as an independent OS-defining prognostic factor (HR, 2.473; 95% CI, 1.151-5.314; P = 0.020). CONCLUSION: A low pretreatment SMI is an independent prognostic factor for OS in patients diagnosed with stage III cervical cancer and treated with concurrent chemoradiotherapy.

Role of cervical cancer screening during prenatal checkups for infectious diseases: A retrospective, descriptive study.

OBJECTIVE: This study was conducted to evaluate the status and role of cervical cytology affected by human papillomavirus infection and other infectious diseases screened during routine prenatal checkups. METHODS: We retrospectively examined medical records containing the screening results for infectious diseases and cervical cancer in women who delivered neonates in our hospital from 2014 to 2017. RESULTS: Among 3393 deliveries, 18.8% of women underwent a regular cervical cancer screening within 1 year of becoming pregnant, and 2641 women underwent a cervical cytology screening during this pregnancy. The cytological diagnostic results showed that 2562 women (97.0%) were negative for intraepithelial lesions or malignancy, whereas 79 (3.0%) had abnormal results. Of those with abnormal cytology results, 70 had abnormal cytology that was newly detected in this pregnancy, and 42 had grade ≥1 cervical intraepithelial neoplasia lesions. Spatulas were the most frequently used cytological sampling instruments, followed by cotton swabs. Cervical cytology revealed no major adverse reactions during these pregnancies. CONCLUSIONS: Our results confirm the importance of screening for infectious diseases during pregnancy. Only 20% of the women underwent a regular pre-pregnancy cervical cytology screening. Cervical cytology screening during pregnancy may currently be playing a crucial role in preventing cervical cancer in Japan.

Can Catch-Up Vaccinations Fill the Void Left by Suspension of the Governmental Recommendation of HPV Vaccine in Japan?

In 2013, the Ministry of Health, Labor, and Welfare (MHLW) in Japan announced a suspension of the governmental recommendation for routine HPV vaccinations. In 2020, MHLW started individual notifications of HPV vaccine to the targeted girls. In April 2022, the governmental recommendation was restarted, and catch-up vaccinations started. We evaluated the benefits and limitations of the MHLW's new vaccination strategies by estimating the lifetime risk for cervical cancer for each birth FY under different scenarios to suggest a measure for the vaccine suspension generation. It was revealed that catch-up immunization coverage among the unvaccinated must reach as high as 90% in FY2022, when the program begins, in order to reduce the risk of the females already over the targeted ages to the same level or lower than that of women born in FY1994-1999 who had high HPV vaccination rates. For women whose vaccination coverage waned because of their birth FYs, strong recommendations for cervical cancer screening should be implemented.

Outcome of Radiation Therapy for Stage IVB Uterine Cervical Cancer With Distant Lymph Nodes Metastases; Sequential Irradiation for Distant Lymph Nodes Metastases.

BACKGROUND/AIM: This study aimed to evaluate the outcome of radiation therapy for patients with distant lymph node (LN) metastases, without organ metastases from uterine cervical cancer (UCC). PATIENTS AND METHODS: Twenty-six patients with UCC with distant LN metastases received radiotherapy and were retrospectively analyzed. The sites of distant LN metastasis were as follows; Supraclavicular in 19, inguinal in nine, axillary in four, and others in three. The mean dose prescribed for these was 50 (range=40-60) Gy. RESULTS: The 2-year overall, cause-specific, and progression-free survival, and local control of primary tumor rates were 51.3%, 51.3%, 46.9%, and 67.9%. In multivariate analysis, performance status ≥1 (p=0.007), para-aortic LN metastases (p=0.001), and lack of high-dose-rate intracavitary brachytherapy (p=0.033) were significantly associated with poor overall survival. Performance status ≥1 (p=0.004), and para-aortic LN metastases (p=0.014) were significantly associated with poor cause-specific survival. CONCLUSION: This study demonstrated favorable local control in patients with UCC with distant LN metastases.