Human papillomavirus self-sampling and urine-sampling tests and the management and short-term outcomes of cervical intraepithelial neoplasia: A prospective observational study.

AIM: The importance of human papillomavirus (HPV) co-testing using physician-, self-, and urine-collected samples to predict cervical intraepithelial neoplasia (CIN) grade 1-2 prognoses has not been previously reported. Therefore, this study aimed to investigate outcomes of patients with CIN 1-2 who simultaneously underwent physician-, self-, and urine-collection sampling tests. METHODS: This study was conducted in Japan between October 2019 and November 2022 and examined the proportion of cases with CIN 1-2 progressions, the percentage of cases with persistent CIN 1-2, and the outcome differences according to the results of physician-, self-, and urine-sampling tests. RESULTS: There were 105 and 59 CIN 1 and 2 cases, respectively, with progression or persistence in 27 (29.3%) and 21 (50.0%) cases, respectively. The median follow-up was 20 and 12 months, respectively. Progression and persistence of CIN 1 were significantly associated with HPV-positive physician- and self-collected samples. No significant difference was observed between cases with CIN 2 who had HPV-positive and HPV-negative results using any sampling method. CONCLUSIONS: Physician- and self-testing for HPV are crucial for predicting disease progression risk in CIN 1 cases. Future research with an extended observation period and consideration of the progression risks is warranted.

Human papillomavirus testing and cytology using physician-collected uterine cervical samples vs. self-collected vaginal samples and urine samples.

BACKGROUND: Human papillomavirus (HPV) testing using self-collected vaginal samples and urine samples is convenient and effective for improving the screening rate. But, to serve as an alternative cervical cancer screening technique, such tests must offer sensitivity equivalent to the HPV testing of physician-collected cervical samples. To examine the effectiveness of HPV testing using self-collected samples and urine samples, we compared the results of HPV testing using these samples with those of HPV testing using physician-collected samples and cytological examinations. METHODS: The study population included 300 women (age: 20-50 years) with abnormal cervical cytology. The results of HPV testing using self-collected samples and urine samples and physician-collected samples and cervical cytology were compared. RESULTS: For all HPV types, the κ-value was 0.773 for physician- and self-collected samples and 0.575 for physician-collected and urine samples. The κ-value for HPV type 16-positive samples was 0.988 for physician- and self-collected samples and 0.896 for physician-collected and urine samples. The κ-value for HPV type 18-positive samples was 0.856 for physician- and self-collected samples and 0.831 for physician-collected and urine samples. For other HPV types, the value was 0.809 for physician- and self-collected samples and 0.617 for physician-collected and urine samples. CONCLUSIONS: The obtained results were consistent between physician- and self-collected samples as well as between physician-collected and urine samples. Considering that the agreement rate was particularly high for the high-risk HPV types 16 and 18, HPV testing using physician-collected samples, self-collected samples, and urine samples was equally effective for the types with high carcinogenicity.

Efficacy of liquid-based genetic diagnosis of endometrial cancer.

Although liquid-based cytology (LBC) has increased the sensitivity of cytological diagnosis of endometrial cancer (EC) compared with conventional smear cytology, the sensitivity of LBC for the detection of EC is between 70% and 96% and remains unsatisfactory. In the present study, we compared the efficacy of LBC with liquid-based genetic diagnosis (LBGDx) by amplicon sequencing of five genes including PTEN, PIK3CA, CTNNB1, KRAS, and TP53 in 48 LBC subjects who underwent endometrial screening. Consequently, LBC classified 15 samples as "positive or suspicious for malignancy" and the 15 were later confirmed as EC. However, LBC failed to identify five cases who were diagnosed as EC by additional transvaginal ultrasound and endometrial curettage, indicating that the sensitivity of cytology alone was 75% (15/20). LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three. Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma. However, LBGDx did not identify any pathogenic mutations in three of the 20 EC, indicating that the sensitivity of LBGDx alone was 85% (17/20). Although five EC were negative for malignancy by LBC and three were negative for pathogenic mutations by LBGDx, the combination of LBC and LBGDx would successfully diagnose all 20 EC. These data suggested that LBGDx is a useful strategy to improve the sensitivity of screening of EC by LBC.

Rare case of occult testosterone-producing ovarian tumor that was diagnosed by selective venous hormone sampling.

CASE: A 32 year old woman was referred because of secondary amenorrhea, hirsutism, and voice deepening. OUTCOME: The blood testosterone level was markedly high. A transvaginal ultrasound revealed a small region in the left ovary, but whether or not it was a tumor was unclear. Therefore, selective ovarian venous sampling was performed. Consequently, the testosterone level was selectively increased in a blood sample that was taken from the left ovarian vein, the tumor was successfully localized, and a laparoscopic left oophorectomy was performed. Although the left ovary appeared to be normal at laparoscopy, the androgen-secreting tumor was located within it. The tumor was diagnosed as a Leydig cell tumor by histopathological analyses. CONCLUSION: This report demonstrates that selective blood sampling from ovarian veins before an operation is effective in localizing an androgen-producing ovarian tumor that is difficult to diagnose by imaging studies.

Influence of Ku86 and XRCC4 expression in uterine cervical cancer on the response to preoperative radiotherapy.

DNA double-strand breaks (DSB) are severe damages induced by ionizing radiation. Non-homologous end joining (NHEJ) is a major mechanism for repairing DSB. Immunohistochemical analysis of proteins involved in NHEJ, such as Ku86 and XRCC4 (X-ray repair cross-complementing protein 4) may be useful for predicting tumor radiosensitivity. We examined the relationship between expression of DSB-related proteins in biopsy specimens of uterine cervical cancer and the pathological effect of 40 Gy of preoperative radiotherapy. 119 patients with uterine cervical cancer were treated between 2000 and 2011. Pathological effects of preoperative radiotherapy were classified by examining hysterectomy specimens. Patients with complete response (pCR) had a significantly better overall 5-year survival rate than those without pCR (96.3 vs. 76.9 %, P = 0.02). The pCR rate was significantly higher in patients with low Ku86 and XRCC4 expression than in other patients (47.4 vs. 21.3 %, P = 0.04). Logistic regression analysis also demonstrated that low Ku86 and XRCC4 expression was a significant predictor of pCR (P = 0.03). Patients with high Ku86 and XRCC4 expression had a significantly lower 5-year metastasis-free rate than others (79.3 vs. 93.5 %, P = 0.02). Proteins involved with NHEJ might have an influence on results of radiotherapy for uterine cervical cancer.

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following paclitaxel and carboplatin in patients with gynecologic cancers: A randomized, multicenter, phase-II trial.

AIM: Chemotherapy-induced nausea and vomiting (CINV) can affect a patient's quality of life, leading to poor compliance with further treatments. Previous studies have provided minimal data about carboplatin-based regimens. Female sex is a known risk factor for CINV. The purpose of this study was to evaluate palonosetron plus single-dose dexamethasone (DEX) for preventing CINV caused by carboplatin plus paclitaxel combination therapy (TC regimen) in patients with gynecologic cancers. MATERIAL AND METHODS: Patients were recruited for this phase-II, multicenter, randomized trial from 12 hospitals in Hokkaido, Japan. Eligible patients were women with uterine cervical, endometrial or ovarian cancer scheduled to receive conventional TC regimen or dose-dense TC regimen; 116 patients were randomly assigned to receive palonosetron in combination with 1-day DEX or 3-day DEX. RESULTS: During the overall period, complete response (CR) was observed in 67.9% (95% confidence interval, 53.7-80.1) of patients in the 3-day DEX arm, and 60.7% (95% confidence interval, 46.8-73.5) of patients in the 1-day DEX arm; CR was significantly lower in the 1-day DEX arm if motion sickness was already present (P = 0.0370). In the severe hyperemesis gravidarum cohort, CR in the 1-day DEX arm tended to be lower than in the 3-day DEX arm. CONCLUSION: Combination therapy of palonosetron and 1-day DEX was effective for subjects undergoing a TC regimen for gynecologic cancers. However, the possibility of reduced efficacy of 1-day only DEX therapy in women undergoing a TC regimen could not be refuted and requires further investigation.

Low-dose SN-38 with paclitaxel induces lethality in human uterine cervical adenocarcinoma cells by increasing caspase activity.

Combination of anticancer drugs may provide a rational molecular basis for novel chemotherapeutic strategies. Paclitaxel and SN-38 (an active metabolite of CPT-11) are effective for many kinds of cancer. Therefore, we investigated the possibility that combination of these drugs could be effective against cervical adenocarcinoma cells. In this study, we examined cell growth inhibition after 96 h using the MTT assay and examined the release of fragmented DNA into the cytoplasm during apoptotic cell death by PI staining. Single and combined use of paclitaxel and SN-38 produced significant cytolethality against the cervical adenocarcinoma cell line CAC-1. Addition of a low concentration of SN-38 reduced the IC50 value of paclitaxel compared to that without SN-38, although the low concentration of paclitaxel did not enhance the cytotoxicity of SN-38. FACS scan analysis suggested that these drugs induced apoptosis and cell cycle arrest, and that caspase-3 and -7 were activated in the process. MTT assay and the IC50 demonstrated that paclitaxel had strong cytotoxicity against CAC-1 as well as other cancer cells. In this study, though only a single cell line was used for the experiment and the data are limited, our results suggest that paclitaxel together with low-dose CPT-11 is a promising basis for a new combination cancer chemotherapy.

Comparative Evaluation of Preoperative Imaging and Postoperative Histopathology in 108 Patients Who Underwent Laparoscopic- or Robot-Assisted Surgery for Endometrial Cancer.

Objectives: The aim of this study was to compare preoperative imaging evaluation results and postoperative histopathology examinations of patients who underwent laparoscopic- or robot-assisted surgery for suspected Stage IA endometrial carcinoma. Materials and Methods: There were 298 patients diagnosed with endometrial cancer at our institution between April 2014 and March 2019. Preoperative imaging evaluation based on magnetic resonance imaging (MRI) and computed tomography (CT) revealed 180 patients suspected of having Stage IA disease. Of these, 72 underwent open surgery, 12 underwent robot-assisted surgery, and 96 underwent laparoscopic surgery. In this study, preoperative imaging evaluation results and postoperative histopathology examinations of 108 patients who underwent laparoscopic- or robot-assisted surgery were retrospectively compared. Results: Of the 108 patients, who underwent laparoscopic- or robot-assisted surgery for suspected Stage IA disease, 98 had Stage IA, two had Stage IB, and four had Stages II and III disease. The sensitivity of imaging evaluations based on preoperative MRI and CT was 90.7%. Conclusion: Utilizing preoperative MRI and CT imaging resulted in a high rate of successful diagnosis of Stage IA endometrial carcinoma.

Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands.

Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.

A case of ovarian actinomycosis.

BACKGROUND: Pelvic actinomycosis is uncommon and often presents as a complication of an intrauterine device (IUD). A diagnosis of actinomycosis can be made from the finding of sulfur granules within inflammatory exudate on histologic examination after surgery. However, it may be possible to diagnose actinomycosis before surgery by finding Actinomyces-like organisms on Papanicolaou smears. CASE: A 41-year-old woman had been diagnosed as having a pelvic abscess, and bilateral salpingo-oophorectomy was performed. She had been an IUD user for 6 years. Actinomyces-like organisms were detected in her previous Papanicolaou cervical smears. If the patient had been treated when the Actinomyces-like organisms were detected by Papanicolaou smears, the serious ovarian actinomycosis might have been avoided. CONCLUSION: We suggest that routine cervical examinations are important for women who are IUD users.

Gene expression profiling in two morphologically different uterine cervical carcinoma cell lines derived from a single donor using a human cancer cDNA array.

PURPOSE: To examine the differentially expressed cancer-related genes in two morphologically different uterine cervical carcinoma cell lines derived from the same patient by an Affymetrix Human Cancer G110 Array carrying 1700 cancer-associated genes. In addition, to investigate specific gene expression depending on histological type, we examined expression of the selected genes in a panel of established cervical carcinoma cell lines derived from cervical adenocarcinoma and squamous cell carcinoma (SCC). EXPERIMENTAL DESIGN: Two distinct human uterine cervical carcinoma cell lines SKG-IIIa and SKG-IIIb derived from a single donor were screened using a cDNA microarray. The array results were additionally validated using semiquantitative RT-PCR. Expressions of the 10 selected genes were analyzed in the nine established cervical carcinoma cell lines using RT-PCR. RESULTS: The cDNA microarray analysis showed that 16 genes in SKG-IIIa were upregulated more than 10-fold compared to SKG-IIIb, and seven genes in SKG-IIIb were upregulated. Semiquantitative RT-PCR analysis of a subset of these differentially expressed genes gave results consistent with microarray findings. Among the 10 selected genes, insulin-like growth factor-binding protein-3, inhibitor of apoptosis protein 1, and cadherin-13 were more frequently expressed in SCC cell lines. 1-8D gene of interferon-inducible genes, Sno oncogenes, and transforming growth factor-beta II receptor were expressed in both SCC and adenocarcinoma cell lines. CONCLUSIONS: Our experimental data demonstrated that multiple genes are differentially expressed in uterine cervical carcinoma cell lines. It is suggested that these genes are involved with the differences in morphological characteristics and carcinogenesis of cervical carcinoma.

Expression of vascular endothelial growth factor and E-cadherin in human ovarian cancer: association with ascites fluid accumulation and peritoneal dissemination in mouse ascites model.

Ascites formation and peritoneal dissemination are critical problems in patients with advanced ovarian cancer. Vascular endothelial growth factor (VEGF), also known as angiogenic growth factor, is a potent mediator of peritoneal fluid accumulation and angiogenesis of tumors. E-Cadherin is an adhesion molecule that is important for cell-to-cell interaction. To elucidate the molecular mechanism of ascites formation and peritoneal dissemination of ovarian cancer, we examined the expression of VEGF and E-cadherin in different ovarian cancer cell lines and utilized nude mice to compare the biological characteristics of ovarian cancer cells. Three human ovarian cancer cell lines (AMOC-2, HNOA and HTBOA) were used in this study. Expression of genes was analyzed by northern blotting and RT-PCR methods. AMOC-2 expressed E-cadherin, but not VEGF. HNOA expressed VEGF without E-cadherin expression. HTBOA expressed both VEGF and E-cadherin. Each human ovarian cancer model revealed a specific feature. The AMOC-2 mouse had a single large peritoneal tumor without ascites or remarkable peritoneal dissemination. HTBOA and HNOA mice had bloody ascites and marked peritoneal dissemination. Introduction of VEGF antisense into HTBOA cells could inhibit the ascites formation. It is suggested that VEGF is important for the ascites formation via the increased vascular permeability effect. The deregulation of E-cadherin expression might be involved in the peritoneal dissemination. These molecules are important for the formation of specific features of advanced ovarian cancer. Ovarian cancer cell lines that had different gene expression patterns produced nude mouse human ovarian cancer models with different characteristics.

E1AF/PEA3 reduces the invasiveness of SiHa cervical cancer cells by activating serine proteinase inhibitor squamous cell carcinoma antigen.

E1AF/PEA3, a member of the Ets family of transcription factors, is associated with the malignant characteristics of cancer cells. The initial aim of our study was to test whether the invasiveness of SiHa cervical cancer cells could be diminished by transfection with antisense E1AF. Using an in vitro invasion assay in which cells penetrate a layer of Matrigel, we found that this was not the case; indeed, the invasiveness of the transfectants was enhanced. To better understand the mechanism of this enhancement, we used the cDNA microarray technique to search for genes whose expression was altered in the antisense E1AF-transfected SiHa cells. Among several genes affected, we found that expression of squamous cell carcinoma antigen (SCCA), a member of the ovalbumin serine proteinase inhibitor family, was significantly reduced. Forced expression of E1AF enabled activation of SCCA expression, and Luciferase reporter assays revealed that E1AF activates the SCCA promoter. Introduction of antisense SCCA into SiHa cells inhibited production of SCCA protein and markedly increased the invasiveness of the cells. Taken together, these results suggest that E1AF suppresses the invasiveness of SiHa cervical cancer cells through transcriptional activation of the SCCA serine proteinase inhibitor gene.