The difference in the effectiveness of human papillomavirus vaccine based on smoking status.

AIM: This study aimed to clarify (1) the effectiveness of human papillomavirus (HPV) vaccine against precancerous lesions of uterine cervical cancer and (2) the difference in these effectiveness based on smoking status. METHODS: This retrospective cross-sectional study considered women aged 20-24 who underwent cervical cancer screening in Saga City from April 2014 to March 2020. Cervical cytology and histological diagnosis were compared with or without HPV vaccination and smoking. RESULTS: The study included 7253 women (2467 vaccinated and 4786 unvaccinated). Among the vaccinated women, 462 were smokers, 2003 were nonsmokers: among the nonvaccinated women, the numbers were 1217 and 3554, respectively. 0.28% (7/2467) of participants with vaccination had HSIL+ compared to 0.77% (37/4786) without vaccination (odds ratio [OR] 0.36, 95% confidence interval [CI], 0.16-0.81). About 0.32% (8/2467) with vaccination had cervical intraepithelial neoplasia (CIN) 2+ compared to 0.69% (33/4786) without vaccination (OR 0.46, 95% CI, 0.21-1.00). Four women without vaccination had CIN3+. In nonsmokers, HPV vaccination significantly suppressed the incidence of HSIL+ from 0.42% (15/3554) to 0.1% (2/2003) (OR 0.21, 95% CI, 0.05-0.95), but the suppressive effect was not significant in smokers (OR 0.59, 95% CI, 0.22-1.56). In vaccinated women, the incidence of CIN2+ was 0.20% (4/2003) in nonsmokers and 0.87% (4/462) in smokers (OR 0.22, 95% CI, 0.05-0.89, p = 0.02). CONCLUSIONS: HPV bivalent/quadrivalent vaccination is effective in protecting against CIN but insufficient in smokers. The nine-valent vaccine should be introduced into routine vaccination as soon as possible to prevent high-risk HPV infection other than 6/11/16/18.

Tissue-specific Physical and Biological Microenvironments Modulate the Behavior of Cervical Squamous Cell Carcinoma.

The mechanisms controlling the aggressiveness and survival of cervical SCC cells remain unclear. We investigated how the physical and biological microenvironments regulate the growth, apoptosis and invasiveness of cervical cancer cells. Dynamic flow and air exposure were evaluated as physical microenvironmental factors, and stromal fibroblasts were evaluated as a biological microenvironmental factor. To investigate any regulatory effects of these microenvironmental factors, we established a new culture model which concurrently replicates fluid streaming, air exposure and cancer-stromal interactions. Three cervical cancer cell lines were cultured with or without NIH 3T3 fibroblasts. Air exposure was realized using a double-dish culture system. Dynamic flow was created using a rotary shaker. Dynamic flow and air exposure promoted the proliferative activity and decreased the apoptosis of cervical cancer cells. Fibroblasts regulated the invasive ability, growth and apoptosis of cervical cancer cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by dynamic flow, air exposure and cellular interactions, depending on the cervical cancer cell type. This study demonstrates that the physical and biological microenvironments interact to regulate the aggressiveness and survival of cervical cancer cells. Our simple culture system is a promising model for developing further treatment strategies for various types of cancer.

Cytological Appearances of Ovarian Seromucinous Borderline Tumor in Ascites: Presentation of 2 Cases.

BACKGROUND: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites. CASE PRESENTATION: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT. CONCLUSION: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.

Long term outcomes from lymphatic venous anastomosis after total hysterectomy to prevent postoperative lymphedema in lower limb.

BACKGROUND: Lymphedema in lower limb is one of major postoperative complications followed by a total hysterectomy with lymph node dissection. The objective of this report is to examine a long-term result of lymphaticovenous anastomosis procedure as a preventive surgery. METHODS: Sixteen patients with endometrial cancer underwent an abdominal hysterectomy with a bilateral salpingo-oophorectomy. Just after pelvic lymph node dissection, either end-to-end or sleeve anastomosis utilizing venules and suprainguinal lymph vessels was performed. During the observation period from 4 to 13 years, the symptom of lymphedema in lower extremities has been assessed. RESULTS: Among 16 patients, 1 presented postoperative lymphedema grade 3 (CTCAE (Common Terminology Criteria for Adverse Events) Ver. 4.0, 10025233) in lower limb, and a second surgery at 7 years after the first one was required. Other 6 patients showed non-severe symptoms of lymphedema, diagnosed as grade 1. The rest 9 patients did not show any symptoms of postoperative lymphedema in a long term (up to 13 years). CONCLUSION: From the long term outcomes of our 16 cases, we propose that a direct lymphaticovenous microsurgery immediately after a hysterectomy with lymphadenectomy of external inguinal lymph node is one of the appropriate therapeutic choices to prevent severe lymphedema in lower limb.

Decreased cytokeratin 7 expression correlates with the progression of cervical squamous cell carcinoma and poor patient outcomes.

AIM: To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma. METHODS: We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76). RESULTS: The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients. CONCLUSION: This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.

What Has Changed Since the Introduction of Human Papillomavirus Testing with the Cytology-Based Cervical Cancer Screening System in Japan A Social Experiment.

BACKGROUND: Uterine cervical cancer is the fourth most common female cancer in the world. In Japan, we have an apparently low rate of joining cervical cancer screening programs compared with Western countries. Furthermore, the incidence and mortality rate of cervical cancer among the younger generation has been increasing. OBJECT: The aim of this study was to assess the effectiveness of cervical cancer screening with human papillomavirus (HPV) testing and cytology in Japan. METHODS: Collaborating with Saga City government, we initiated a cervical cancer screening system consisting of HPV testing and baseline cervical cytology from April 2011 as a social experiment. A total of 17,284 participants have been screened with this new combination system. RESULTS: After HPV testing with cytology-based cervical cancer screening, the number of screenings done in women aged under 40 years has significantly increased. In addition, the number of women diagnosed with cervical intraepithelial neoplasia grade 3 has increased (25 of 14,025 vs. 146 of 23,049 under 50 years: p < 0.001). CONCLUSION: These data suggested that the introduction of HPV testing with cytology-based cervical cancer screening as an adjunct to conventional cytology resulted in better efficiency and more accurate screening among the Japanese population.

Clear Cell Carcinoma of the Uterine Cervix Presented as a Submucosal Tumor Arising in a Background of Cervical Endometriosis.

Clear cell carcinoma (CCC) of the uterine cervix without prenatal diethylstilbestrol exposure is rare, and its etiology is unclear. We present a case of cervical CCC presenting as a submucosal tumor, which strongly suggests an association between cervical endometriosis and cervical CCC. A 56-year-old postmenopausal Japanese woman visited a gynecologic clinic with a complaint of watery vaginal discharge. A few atypical cells suggesting adenocarcinoma were detected in a cervical cytologic specimen. Magnetic resonance imaging revealed a cystic lesion with a solid component at the uterine cervix. Under a tentative diagnosis of cervical cancer, surgery was performed. Although a freshly resected specimen initially showed no tumorous lesion in the cervical mucosa, cutting of the mucosa revealed a solid tumor with a final diagnosis of CCC. The findings of aggregation of hemosiderin-laden macrophages and ectopic endometrium adjacent to the tumor strongly suggest that this tumor arose from cervical endometriosis.

Preoperative Chemoradiotherapy in Locally Advanced Bulky Squamous Cell Carcinoma of the Uterine Cervix.

OBJECTIVES: The aim of this study was to evaluate long-term survival and feasibility in patients with bulky squamous cell carcinoma of the uterine cervix who underwent surgery after concurrent chemoradiotherapy. METHODS: A review of patients with locally advanced bulky squamous cell cervical cancer who underwent chemoradiation followed by surgery with pelvic lymphadenectomy was performed. Chemoradiotherapy included 2 monthly doses of intra-arterial chemotherapy with cisplatin (50 mg/m) and mitomycin C (10 mg/body) and external irradiation to the whole pelvis and high-dose-rate brachytherapy. From 2000 to 2006, 23 patients were enrolled in a single institution. Patient distribution according to the International Federation of Gynecology and Obstetrics stage was as follows: 9 stage IB2, 10 stage IIB, and 4 stage IIIB. Radiological lymph node involvement was present in 69.6% (16/23), including 2 cases of para-aortic lymph node swelling. The radiological response, pathological response, overall and disease-free survival, and late complications were assessed. RESULTS: Among the patients, 12 (52.2%) showed pathological complete response, and 11 (47.8%) showed a pathological partial response for cervical lesions. Among the cases of radiological pelvic lymph node swelling, the response rate was 93.3% (14/15). Only 1 case showed viable cancer cells in the resected pelvic lymph nodes among radiological complete response cases. In the median follow-up duration (121 months; range, 17-180 months), the 5-year overall survival and disease-free survival were 95.7% and 86.7%, respectively. Seven events in 4 patients led to the development of postoperative fistula formation requiring a rescue surgery. CONCLUSIONS: Chemoradiotherapy followed by surgery was effective for patients with bulky squamous cell carcinoma of the uterine cervix. Further investigation to select suitable patients for this multimodal treatment will be required.

A lower serum level of middle-molecular-weight adiponectin is a risk factor for endometrial cancer.

BACKGROUND: The present study was undertaken to examine the correlation between serum levels of adiponectin isoforms and the risk for endometrial cancer. METHODS: This retrospective case-control study included 43 Japanese women with endometrial cancer and 62 Japanese women with no history of cancer. Serum levels of total adiponectin and the respective isoforms were determined by enzyme-linked immunosorbent assay. Multivariate logistic regression analysis was performed on the serum levels of total adiponectin and its isoforms, high molecular weight, middle molecular weight, and low molecular weight adiponectins, after adjustment for confounders (age, body mass index, hypertension, and diabetes mellitus). RESULTS: The distribution of body mass index revealed a statistically significant difference between patients and controls (P = 0.001). A statistically significant difference (P < 0.01) was also found in the incidence of diabetes mellitus between the two groups, although there was no significant difference in the incidence of hypertension. In controls, an inverse correlation was observed between body mass index and serum adiponectin levels. However, in patients, an inverse correlation was found only between body mass index and serum middle molecular weight adiponectin level. After adjustment for confounding variables, the factor found to be most closely associated with endometrial cancer was a lower serum level of middle molecular weight adiponectin (adjusted odds ratio 4.89, 95 % confidence interval value 1.25-19.11, P = 0.022). CONCLUSION: Low serum level of middle molecular weight adiponectin was the only independent risk factor for endometrial cancer suggesting that the application of adiponectin might prevent or decrease the risk for endometrial cancer.

Pyomyositis associated with chemotherapy for endometrial cancer: a case report.

Pyomyositis is a rare complication of chemotherapy for non-hematological malignancies. A 58-year-old woman with endometrial carcinoma, in whom pyomyositis developed during adjuvant chemotherapy, was presented in this report. After initiating empiric antibiotic therapy for febrile neutrocytopenia, screening CT showed multiple abscesses in the lower limbs. Operative drainage of the abscess was effective.

The usefulness of combined measurements of squamous cell carcinoma antigens 1 and 2 in diagnosing atopic dermatitis.

BACKGROUND: The squamous cell carcinoma antigen (SCCA) is widely used as a serological biomarker for various cancers. There are two known SCCA molecules, SCCA1 and SCCA2. We previously found that interleukin-4 or interleukin-13, two related Th2-type cytokines that play an important role in allergic diseases, induce expression of SCCA1 and SCCA2. In this study, we examined whether combined measurements of SCCA1 and SCCA2 are useful for diagnosing atopic dermatitis (AD). METHODS: We established new enzyme-linked immunosorbent assays (ELISAs) to specifically detect SCCA1 or SCCA2. We applied serum samples from AD patients with food allergies and from cervical cancer patients to these ELISAs. We performed receiver operating characteristic analyses to diagnose AD and to distinguish AD from cervical cancer. RESULTS: Serum concentrations of both SCCA1 and SCCA2 were elevated in AD patients. The serum concentrations of SCCA1 and SCCA2 positively correlated with the clinical severity of AD, showing high specificity (0.86-0.88) and sensitivity (0.86) against control donors. The serum concentrations of SCCA1 and SCCA2 were elevated in cervical cancer patients; however, the SCCA2/SCCA1 ratios clearly distinguished AD patients from cervical cancer patients with high specificity (0.87) and sensitivity (0.87). Expression of SCCA2 was predominant in AD patients, whereas cervical cancer patients showed a predominance of SCCA1. CONCLUSIONS: Combined measurements of SCCA1 and SCCA2 are very useful in estimating the severity of allergic diseases, making it possible to distinguish allergic diseases from cancers.

Gene expression profiles and microsatellite instability in uterine corpus endometrioid adenocarcinoma.

AIM: We examined corpus cancer to identify whether there are distinctive patterns of global gene expression and microsatellite instability, and to gain molecular understanding of its carcinogenesis and progression. METHODS: Thirty endometrioid corpus cancer tissue samples (21 of G1 and nine of G2/3) were analyzed by cDNA microarray based on 637 cancer-associated genes and by a polymerase chain reaction method for microsatellite instability. RESULT: Of the 30 cases, 10 (33%) were recognized as having microsatellite instability. In all cases, four genes were overexpressed and five genes were underexpressed. There were six microsatellite instability-specific overexpressed or high-frequency genes and 15 underexpressed or low-frequency genes. Furthermore, we identified several genes by grade analysis. CONCLUSIONS: These results may be useful resources for the development of diagnostic assays, prognostic factors, or therapeutic targets for corpus endometrioid cancer.

Uterine artery embolization followed by dilation and curettage for cervical pregnancy.

BACKGROUND: Cervical pregnancy can be a life-threatening condition due to the risk of severe hemorrhage. Progression of ultrasonographic diagnostic technology has allowed the early detection of cervical pregnancy. However, a standard treatment protocol for fertility preservation has not yet been established. CASE: Two women with cervical pregnancy presented with cardiac activity at 6 and 7 weeks of gestation. They were treated with transfemoral uterine artery embolization followed by dilation and curettage with minimal bleeding. One patient gave birth to a healthy neonate 20 months after the procedure. CONCLUSION: Early cervical pregnancies were treated with dilation and curettage after uterine artery embolization. This treatment can be considered as conservative management for patients who desire to preserve their fertility.

Antiproliferative effects of the major tea polyphenol, (-)-epigallocatechin gallate and retinoic acid in cervical adenocarcinoma.

OBJECTIVE: To investigate the combined effect of the major tea polyphenol, (-)-epigallocatechin gallate (EGCG) and retinoic acid (RA) on cervical adenocarcinoma. METHODS: Cell growth rate was examined after treatment for 4, 7 and 10 days with 0-100 microM EGCG and/or 1 microM RA in two cervical adenocarcinoma cell lines, HeLa and TMCC-1. The effect of EGCG treatment was examined for the induction of apoptosis by DNA ladder assay and caspase-3-related protease activity in cell lysate. Telomerase activity was detected by stretch PCR telomere extension assay. hTERT expression levels were quantified by a real-time PCR system. RESULTS: Combining EGCG and RA increased the antiproliferative effect in adenocarcinoma cell lines, whereas EGCG or RA treatment alone caused a less sensitive response in these cells. Neither EGCG nor RA treatment alone affected apoptosis and telomerase activity. The combination treatment of EGCG and RA induced apoptosis and inhibited telomerase activity in adenocarcinoma cell lines. These results were consistent with those of an antiproliferative effect of EGCG and/or RA in cervical adenocarcinoma cells. CONCLUSION: Our data suggest that EGCG and RA combined to prevent the carcinogenesis of cervical adenocarcinoma, induce apoptosis and inhibit telomerase activity. The treatments of combining EGCG and RA may be effective in preventing or treating cervical adenocarcinoma.

MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion.

OBJECTIVE: To evaluate whether magnetic resonance imaging (MRI) is a reliable modality for verifying preoperative diagnosis of stage IA endometrial carcinoma. METHODS: One hundred sixteen patients with endometrial carcinoma underwent preoperative pelvic non-contrast T2-weighted or dynamic MRI. We compared the interpretations of the MRI results with the histological findings of the resected uterus. RESULTS: In assessing the depth of myometrial invasion, the accuracy of MRI was 62.1%. As to the presence of cancerous myometrial invasion, the positive predictive value was 94.4% as high as previously reported by other institutions. However, the negative predictive value, the probability of the absence of myometrial invasion, was only 42.2%. Even when dynamic study was applied to the patient, the value only improved up to 60.0%. CONCLUSION: MRI has a definite advantage in evaluating deep myometrial invasion, but not the absence of invasion. We should take precautions against the risk of under-diagnosis when selecting stage IA endometrial carcinoma with use of MRI to preserve fertility or to eliminate lymphadenectomy.

Inhibitory effect of the tea polyphenol, (-)-epigallocatechin gallate, on growth of cervical adenocarcinoma cell lines.

To investigate the effect of (-)-epigallocatechin gallate (EGCG) on cervical adenocarcinoma, we performed a cell proliferation assay. TRAP assay is used for telomerase activity, flow cytometry analysis and pKi-67 immunofluoroscein staining in cervical adenocarcinoma cell lines (OMC-4, TMCC-1). Our results showed that EGCG inhibited the proliferation assay, TRAP assay for telomerase activity of both cell lines. Although cell apoptosis was induced, we observed that the expression of pKi-67 was suppressed. Our data suggest that EGCG may be effective for the treatment of cervical adenocarcinoma. The mechanisms of the anti-tumor effects were revealed to be the inhibition of telomerase activity, the induction of apoptosis and cell cycle dysregulation.

[Prognostic factors of vulvar cancer].

While vulvar cancer is rare in Japan, the management of this disease has changed dramatically over the past 20 years. The radical vulvectomy that was previously believed to be the only effective treatment for vulvar cancer has now been replaced by more individualized treatments, from the standpoint of QOL. Because the lesion diameter and groin node status (laterality and number positive) are the most important prognostic factors of vulvar cancer, numerous refinements have been made in the management. The refinements include conservative surgery for patients with isolated lesions, omission of groin lymph node dissection in T 1 A tumors with stromal invasion <1 mm, and omission of contralateral groin lymph node dissection in T 1 tumor with negative ipsilateral node metastasis. In addition to these changes, elimination of groin dissection using sentinel lymph node procedure and preoperative chemoradiation for patients with advanced disease are currently under investigation. In this review, we discuss these issues along with the evidence upon which these therapies are based.

Successful pregnancies in 2 infertile patients with endometrial adenocarcinoma.

Two infertile patients with well-differentiated endometrial adenocarcinoma succeeded in having their own babies with assisted reproductive technology following treatment with a high dose of medroxyprogesterone acetate and repeated endometrial curettages. Their follow-up pathological examinations revealed no evidence of recurrent disease. Consequently, conservative treatment may be indicated in patients with well-differentiated endometrial adenocarcinoma at an early stage who desire to preserve their fertility.