Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Long-term outcomes of high-risk human papillomavirus infection support a long interval of cervical cancer screening.

Knowing that infection of high-risk human papillomavirus (HPV) causes virtually all cervical cancer (CC), the long-term outcomes of HPV infection, especially the absolute risk and time lapse of developing CC, are beyond the scope of ordinary follow-up study owing to ethical concerns. The present study followed the natural history and long-term outcomes of HPV infection in a cohort of women by national health insurance care and data linkage without additional disturbance. The status of cervical HPV infection was determined in 1708 healthy women, aged 20-90 (median 43), enrolled from 10 hospitals in seven cities around the island country of Taiwan. Records of consecutive Pap smear results and cancer reports of 108 cytology-negative, HPV-positive and 1202 cytology- and HPV-negative women with no prior record of CC or abnormal cervical cytology were retrospectively analysed for a duration of up to 75 months (median 61 months). The cumulative incidences of high-grade squamous intraepithelial lesion (HSIL) and in situ/invasive cancer in HPV-positive women were 5.6 and 3.7%, respectively, and those in HPV-negative women were 0.3 and 0%. After adjusting for other risk factors, HPV-positive subjects had 24.9 (95% CI: 7.0-108.3; P<0.0001) folds of risk of developing HSIL or above cervical neoplasia as compared to HPV-negative subjects, whereas risk for low-grade intraepithelial lesion and atypical squamous cytology was not increased. The study showed that women with a prevalent infection of high-risk HPV had a 4% cumulative risk for CC in 6 years, whereas those tested negative had little risk. The result supports an HPV test-orientated CC screening programme with intervals of at least 5 years.

Adenomyosis and risk of preterm delivery.

OBJECTIVE: To evaluate the risk of preterm delivery in patients with adenomyosis. DESIGN: A 1:2 nested case-control study. SETTING: Tertiary-care institution. POPULATION: A base cohort population of 2138 pregnant women who attended routine prenatal check-up between July 1999 and June 2005. METHODS: From this base cohort population, gravid women with singleton pregnancy who delivered prior to the completion of 37 weeks of gestation were identified and formed the study group. Singleton gravid women who had term delivery and who matched with age, body mass index, smoking, and status of previous preterm delivery were recruited concurrently and served as control group. Preterm delivery cases were further divided into spontaneous preterm delivery and preterm premature rupture of membranes (PPROM) cases. MAIN OUTCOME MEASURES: Risk analysis of preterm delivery between gravid women with and without adenomyosis. RESULTS: One-hundred and four preterm delivery case subjects and 208 control subjects were assessed. Overall, gravid women with adenomyosis were associated with significantly increased risk of preterm delivery (adjusted odds ratio 1.96, 95% CI 1.23-4.47, P=0.022). For subgroup analysis, gravid women with adenomyosis had an adjusted 1.84-fold risk of spontaneous preterm delivery (95% CI 1.32-4.31, P=0.012) and an adjusted 1.98-fold risk of PPROM (95% CI 1.39-3.15, P=0.017). CONCLUSIONS: Gravid women with adenomyosis were associated with increased risk of both spontaneous preterm delivery and PPROM. A common pathophysiological pathway may exist in these two disorders. Further in-depth biochemical and molecular studies are necessary to explore this phenomenon.

Potential role of preoperative serum CA125 for the differential diagnosis between uterine leiomyoma and uterine leiomyosarcoma.

PURPOSE: Most comparisons between uterine leiomyoma and uterine leiomyosarcoma have been based on postoperative pathological or molecular analyses. Very few reports have investigated preoperative differentiation between uterine leiomyoma and uterine leiomyosarcoma. METHODS: Between January 1990 and December 2003, 42 consecutive patients with uterine leiomyosarcoma treated at index hospitals were analyzed. Meanwhile, 84 patients with uterine leiomyomas were used as controls. The diagnostic performance of preoperative serum CA125 for the differential diagnosis between uterine leiomyoma and uterine leiomyosarcoma using receiver operating characteristic (ROC) curves was evaluated. Data presentations were categorized into premenopausal and postmenopausal groups. Diagnostic efficiency was calculated as the sensitivity multiplied by the specificity. RESULTS: Values of preoperative serum CA125 were significantly higher in the uterine leiomyosarcoma group than those in the uterine leiomyoma group. There was significant overlapping of preoperative serum CA125 between the uterine leiomyoma group and early-stage uterine leiomyosarcoma. For both the premenopausal and postmenopausal group, there was a significant difference in the distribution of preoperative serum CA125 in early-stage and advanced-stage uterine leiomyosarcoma. The optimal cutoff values of serum CA125 for the premenopausal group and postmenopausal group was 162 U/mL and 75 U/mL, respectively. CONCLUSION: These findings demonstrated that preoperative serum CA125 had a potential role in the differential diagnosis between early-stage and advanced-stage uterine leiomyosarcoma. Further investigation with a larger sample size at adequate power is necessary to verify the current study.

The distribution and differential risks of human papillomavirus genotypes in cervical preinvasive lesions: A Taiwan Cooperative Oncologic Group Study.

To clarify the distribution and relative risk of different human papillomavirus (HPV) genotypes in cervical preinvasive lesions, 1246 women with abnormal Papanicolaou smear including atypical squamous cell of unknown significance (ASCUS), atypical glandular cell of unknown significance (AGUS), low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) were enrolled in a multicenter, cross-sectional study. Colposcopy and HPV tests with hybrid capture 2 and polymerase chain reaction-reverse line blot were performed. The prevalences of HPV in ASCUS/AGUS-negative histology, ASCUS/AGUS, LSIL, HSIL, and invasive cancer were 33.8%, 38.3%, 74.9%, 84.3% and 100%, respectively, with an overall positive rate of 68.8%. The most common HPV types were HPV 16 (18.5%), 52 (16.5%), 58 (13.2%), 33, 51, 53, 18, 39, 59, 66, MM8, and 31. In comparing the relative risk of HPV infection in different disease status, LSIL and HSIL/carcinoma had a 4.64 (95% CI: 2.98-7.24) and 10.53 (95% CI: 6.69-16.58) folds of risk of high-risk HPV infection than the negative group. The same was true in mixed HPV infection, but not in low-risk type infection. Looking into each high-risk HPV type, the relative infection risks for LSIL and HSIL/carcinoma, in comparison with the negative group, were 1.67 (0.63-4.43) and 8.67 (3.46-21.70), 2017 (1.01-4.68) and 3.04 (1.42-6.47), and 1.40 (0.52-3.77) and 5.22 (2.07-13.19) for HPV type 16, 52 and 58, respectively. The study confirmed the high prevalence and risky nature of HPV 52 and 58 in Taiwanese population and conveyed the need to include these HPV types in vaccine development.

Improved early detection of cervical intraepithelial lesions by combination of conventional Pap smear and speculoscopy.

PURPOSE: To evaluate the efficacy of the addition of speculoscopy to a Pap smear in cervical cancer screening. METHODS: All women were screened using the Pap smear plus speculoscopy (PapSure) and colposcopy in the multicenter trial. The final diagnosis of each patient was based on a histological evaluation of the colposcopic target biopsy. Results were analyzed using a proportional compare test, sensitivity, specificity and predictive value with significant value determined at less than 0.05. RESULTS: Of 1,717 eligible cases, 26 cases had LGSIL and 16 cases had HGSIL. Of the Pap smears, five cases had LSIL and 14 cases had HGSIL. Of the combination of the PapSure, 23 cases had LGSIL and 16 cases had HGSIL. The sensitivity of the Pap smear to that of PapSure was calculated at 45.2% and 92.9%, respectively (p < 0.001). The estimated cost to detect a cervical lesion using PapSure is less than that of the Pap smear. CONCLUSION: The addition of speculoscopy along with a Pap smear screening results in early detection of cervical lesions in comparison to the Pap smear alone. This screening combination is also more cost-effective and requires fewer visits to the clinic in comparison to a Pap smear screening alone.

Parametrial tumor spreading patterns in cervix cancer patients treated by radical hysterectomy.

OBJECTIVES: To evaluate tumor-spreading patterns in the parametrium. METHODS: We conducted a prospective clinical trial between January 1998 and December 2000 to define a new method for parametrium evaluation. The parametrium was divided into three areas, paracorpus, paracervix, and paravagina. A total of 284 consecutive patients with FIGO stage IB to IIA cervical cancer who had undergone radical hysterectomy were considered for the study. RESULTS: Of the 262 patients who were found eligible for evaluation, 135 had histopathologic analysis performed according to the new method and 127 with the traditional method. The detection of rate of parametrial invasion was 36 (26.7%) with the new and 13 (10.2%) with the traditional method (P=0.0014). The frequency of pelvic lymph node metastasis was 66.7% in patients who had tested positive for invasion of the paracorpus, 57.7% in those who had tested positive for invasion of the paracervix, and 71.4% in those who had tested positive for invasion of the paravagina. The frequency of pelvic lymph node metastasis in patients who had tested negative for invasion of the paracorpus, paracervix, or paravagina was 4.0%. Tumor cells tend to spread laterally and inferiorly in the parametrium. CONCLUSIONS: Using our classification of three parametrium areas for histologic examination can increase the detection rates of parametrial tumor invasion and help prevent failure of local treatment by allowing to implement appropriate adjuvant therapy.

Hyperamylasemia associated with endometroid carcinoma of the ovary.

Hyperamylasemia and alternations of serum isoamylases have been recorded in lung tumors, tubal disorders such as acute salpingitis and ruptured ectopic pregnancies and a variety of ovarian tumors, and they have been suggested as potential tumor markers. Hyperamylasemia was noted in a patient with a stage IIIC endometroid adenocarcinoma of the ovary. Serum levels of amylase decreased rapidly after removal of the ovarian tumor. In patients presenting with acute abdominal pain and elevated amylase levels, ovarian cancer should be considered in addition to acute pancreatitis.

Five-year follow-up of patients with recurrent postmenopausal bleeding.

BACKGROUND: The most common symptom of endometrial cancer is postmenopausal bleeding. For women who present with postmenopausal bleeding and a benign tissue diagnosis, recurrent bleeding is a worrisome problem. We evaluated such patients to search for a model of good management. METHODS: We studied women aged 50 years or over who presented with postmenopausal bleeding and underwent either dilatation and curettage (D & C) or endometrial biopsy from 1990 to 1991 at Long Island Jewish Medical Center, New Hyde Park, NY, USA. The selected patients were monitored for 5 years, until 1996. For those who had an initial benign tissue diagnosis and presented with recurrent postmenopausal bleeding in the following 5 years, we studied the differences in histologic diagnoses. RESULTS: Seventy-seven patients had an initial benign tissue diagnosis of postmenopausal bleeding followed by recurrent bleeding. After repeat D & C or endometrial biopsy (2-6 times), 16 patients (20.8%) had endometrial cancer or endometrial complex hyperplasia. Of the 12 patients who had two or more benign tissue diagnoses, seven (58.3%) had tumors found in subsequent surgery. The diagnoses included endometrial cancer, ovarian cancer, cervical cancer and benign tumor. Postmenopausal women aged 65 years or over had a much greater chance (13/29, 44.8%) of having endometrial cancer or complex hyperplasia than women aged below 65 years (6/48, 12.5%) who presented with recurrent postmenopausal bleeding and had an initial benign tissue diagnosis (c2 = 7.893, p = 0.0050). CONCLUSIONS: Although the initial tissue diagnosis might be benign, the possibility of endometrial cancer or complex hyperplasia cannot be ruled out for women with recurrent postmenopausal bleeding. Diagnostic D & C or endometrial biopsy combined with other tools (vaginal ultrasound, hysteroscopy, transvaginal sonohysterography) are more reliable for evaluating women with recurrent postmenopausal bleeding than D & C or endometrial biopsy only. If these diagnostic results are negative, a total hysterectomy with bilateral salpingo-oophorectomy should be considered to reduce the risk of endometrial cancer in women who present with recurrent bleeding.

Treatment of primary pure angiosarcoma of ovary with multiple lung metastases: a case report.

Angiosarcomas rarely involve the female genital tract. There have only been sporadic case reports of angiosarcomas of the cervix, uterus, vagina, parametrium, broad ligament and pelvis, and only 11 well-documented case reports of primary ovarian angiosarcoma in the English language literature to date. We present a case of primary pure ovarian angiosarcoma with lung metastasis that had partial response after chemotherapy with adriamycin and ifosfamide. But pulmonary hemorrhage and respiratory failure resulted in her death 7 months after initial diagnosis.

Down-regulation of BRCA1 and BRCA2 in human ovarian cancer cells exposed to adriamycin and ultraviolet radiation.

Germ-line mutations of the BRCA1 and BRCA2 genes predispose women to develop cancers of the breast and ovary, but the biologic functions of these genes remains unclear. We have investigated the responses of the BRCA1 and BRCA2 gene products to cytotoxic agents in 3 human ovarian cancer cell lines: SK-OV-3 (which contains a p53 deletion mutation), CAOV-3 (which over-expresses a mutant p53) and PA-1 (which expresses wild-type p53). In screening studies, we determined the effects of 7 different agents on BRCA1 and BRCA2 expression. We found that Adriamycin (ADR) and ultraviolet (UV)radiation significantly down-regulated BRCA1 and BRCA2 mRNA expression in SK-OV-3 cells. On the other hand, camptothecin, nitrogen mustard, taxol, vincristine and etoposide had no effect on BRCA1 or BRCA2 mRNA levels at doses that yielded degrees of cytotoxicity similar to or greater than ADR. The down-regulation of BRCA1 and BRCA2 mRNAs was dose and time dependent; significant down-regulation was first observed at 8-16 hr after exposure to ADR. BRCA1 protein levels were also down-regulated following treatment of SK-OV-3 cells with ADR. Similar results were observed in CAOV-3 and PA-1 cells treated with ADR, and this finding could not be directly attributed to ADR-induced changes in the cell cycle distribution. The ADR doses required for significant decreases of BRCA1 and BRCA2 were about 10-15, 5-10 and 2 microM, respectively, for SK-OV-3, CAOV-3 and PA-1; the IC50 doses for loss of cell viability (determined by Trypan blue dye exclusion) were 23, 14 and 0.4 microM, respectively. Thus, at equitoxic doses of ADR, PA-1 cells were more resistant to down-regulation of BRCA1 and BRCA2 than SK-OV-3 or CAOV-3. Our findings suggest that 1) BRCA1 and BRCA2 expression in human ovarian cancer cell lines is selectively down-regulated by 2 DNA-damaging agents (ADR and UV radiation); 2) these responses are not due to non-specific cytotoxicity; and 3) the BRCA1 and BRCA2 responses may be dependent, in part, on the p53 functional status of the cells. We speculate that the down-regulation of BRCA1 and BRCA2 may be part of a cellular survival response activated by certain forms of DNA damage.

Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents.

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.