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.

High prevalence of human herpesvirus type 8 infection in patients with pulmonary tuberculosis in Taiwan.

Blood samples were collected from 101 untreated pulmonary tuberculosis (TB) patients and 101 age- and sex-matched healthy control subjects. TB patients had lower lymphocyte and a higher monocyte counts than control subjects (p <0.0001 for both). The seropositive rate of human herpesvirus (HHV) type 8 antibody was higher in patients (30/101) than in control subjects (15/101) (p = 0.01). Antibody titres in patients also exceeded those in control subjects (p 0.006). Lymphocyte and monocyte counts between seronegative and seropositive subjects were not different. Four patients were positive for HHV-8 DNA. The study revealed a significantly higher HHV-8 seroprevalence in untreated pulmonary TB patients than in general population.

High seroprevalence of human herpesvirus type 8 in patients with hepatocellular carcinoma.

Cirrhosis patients have immunologic insufficiency and a high seroprevalence of human herpesvirus type 8 (HHV-8). Nearly all hepatocellular carcinoma (HCC) patients are cirrhotic and have immunoabnormalities. This study aimed to assess the HHV-8 seroprevalence and hemograms in HCC patients. Blood samples from 95 HCC patients, 95 age-, sex-, and Child-Pugh class-matched cirrhotics, and 95 age- and sex-matched healthy controls were analyzed for anti-HHV-8 antibodies, HHV-8 DNA, and lymphocyte, monocyte, and platelet counts. HCC patients had lower lymphocyte and platelet counts and a higher monocyte count than the healthy controls (each p < 0.0001). HCC patients, and particularly those with a severe Child-Pugh class, had higher platelet counts than the corresponding cirrhosis patients (p = 0.003 and 0.002, respectively). HHV-8 seropositivity and antibody titers in HCC patients were comparable with values in cirrhosis patients and were much higher than in controls (both p < 0.0001). HCC patients, but not cirrhosis patients, had a higher prevalence of high anti-HHV-8 antibody titers (≥ 1:160) than healthy controls (p = 0.003). HCC patients with lymphopenia or thrombocytopenia had lower HHV-8 seropositivity than those without lymphopenia and thrombocytopenia (p = 0.04 and 0.01, respectively). One each of HCC and cirrhosis patients were positive for HHV-8 DNA. HCC patients seemed to suffer from less severe or shorter duration of portal hypertension compared with Child-Pugh class-matched cirrhosis patients. HCC patients had a high HHV-8 seroprevalence, which seemed to be inversely associated with lymphopenia and thrombocytopenia.

Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer.

miR-126 is an endothelial-specific microRNA essential for maintaining vessel integrity during development. Its role of tumor angiogenesis in cancer stroma is unclear. This study investigated the temporal and spatial expression and the role of miR-126 in the course of cervical carcinogenesis. miR-126 was found to be mainly expressed in the stromal endothelium of the uterine cervix. This downregulation was recapitulated in a cell coculture model, wherein cross talk of cervical cancer cells and fibroblasts induced a downregulation of miR-126 in human umbilical vein endothelial cells, with consequent increase of tube formation. Coinjection of cancer-associated fibroblasts of human cervix enhanced tumorigenesis of cervical cancer cells, with an increase of microvessel density and dye retention in the tumor vasculature. In association with angiogenesis, host-originated miR-126 in these xenograft tumors was progressively downregulated, whereas supplement of the miR-126 precursor in the coinjection suppressed angiogenesis and tumor growth. A proangiogenic gene adrenomedullin (ADM), which was found to be upregulated in the stroma of cervical cancer and which localized mainly in the blood and lymphatic vessels, was identified as a target of inhibition by miR-126 at the carcinoma in situ-to-invasion stage. The study suggests a cancer stroma cross talk induced repression of miR-126 and upregulation of ADM, and probably other proangiogenic factors, to facilitate angiogenesis and invasion growth of cervical cancer.

Human placental multipotent mesenchymal stromal cells modulate trophoblast migration via Rap1 activation.

INTRODUCTION: Little is known about the interaction between human placental multipotent mesenchymal stromal cell (hPMSC) and trophoblast. We hypothesize that hPMSCs produce hepatocyte growth factor (HGF) which may interact with trophoblasts and regulate their migration during placentation. METHODS: hPMSCs were isolated from term placentas and conditioned medium was collected after 2 days of culture in hypoxic (<1% O2) or control (20% O2) conditions. Selective agonist and inhibitor or siRNA for protein kinase A (PKA) or Rap1 were combined with Rap1-GTP pull down assays, flow cytometry, integrin ß1 activation assays and adhesion and migration studies to investigate HGF signaling effects in trophoblasts. The hPMSC abundance and HGF level in preeclamptic placentas were compared with gestational age-matched controls. RESULTS: HGF was expressed by hPMSCs and was decreased in hypoxia. HGF induced cAMP production and Rap1 activation in trophoblasts, which in turn activated integrin ß1. The HGF and PKA activator 6-Bnz-cAMP induced Rap1 activation with increased trophoblast adhesion and migration. The alterations were inhibited by PKA inhibitor H89 or Rap1 siRNA. HGF and cAMP expression were reduced in preeclamptic placentas. hPMSC number was decreased in preeclamptic placenta compared to controls (0.68 ± 0.1% vs. 1.32 ± 0.5%; P = 0.026). hPMSC conditioned medium enhanced trophoblast migration which was inhibited by c-Met blocking antibody, but migration was reduced by conditioned medium from hPMSC cultured in hypoxia. CONCLUSIONS: hPMSCs secrete HGF and increase trophoblast cAMP production. The cAMP effector PKA modulates adhesion and migration of trophoblast via signaling to Rap1 and integrin ß1.

Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer.

Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.

Cost-effectiveness analysis of human papillomavirus DNA testing and Pap smear for cervical cancer screening in a publicly financed health-care system.

OBJECTIVE: to evaluate the long-term cost-effectiveness of different strategies for human papillomavirus (HPV) DNA testing combined with Pap smear for cervical cancer screening in Taiwan. METHODS: this study adopts a perspective of Department of Health in cost-effectiveness analysis to compare a no-screening strategy with nine different screening strategies. These strategies comprise three screening tools (Pap smear alone, HPV DNA testing followed by Pap smear triage, and HPV DNA testing combined with Pap smear), and three screening intervals (annually, every 3 years, and every 5 years). Outcomes are life expectancy, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Probabilistic sensitivity analyses (PSAs) were conducted to assess parameter uncertainty. RESULTS: when three times gross domestic product per capita is used as the decision threshold, all nine screening strategies were cost-effective compared with the no-screening strategy. Compared with the current screening strategy (an annual Pap smear), HPV DNA testing followed by Pap smear triage every 5 years and every 3 years were cost-effective. Results of PSA also indicated that a HPV DNA testing followed by Pap smear triage every 5 or every 3 years achieved the highest expected net benefits. CONCLUSIONS: possible economic advantages are associated with extending the cervical cancer screening interval from one Pap smear annually to HPV DNA testing followed by Pap smear triage every 5 years with an ICER $1 247 000 per QALY gained, especially in a country with a publicly financed health-care system.

Retroperitoneal schwannoma: a common tumour in an uncommon site.

We describe a female adult patient who presented with acute retention of urine and vague abdominal discomfort. A provisional diagnosis of ovarian tumour was made after cross-sectional imaging. At laparotomy a very large retroperitoneal mass was biopsied and found to be a schwannoma after pathological examination. The clinical, radiological, and pathological features of this disease are discussed in this report.

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.

'Street ketamine'-associated bladder dysfunction: a report of ten cases.

Ten young ketamine abusers presented with lower urinary tract symptoms to two regional hospitals in Hong Kong. Investigations demonstrated contracted bladders and other urinary tract abnormalities. These types of findings have never been reported before in ketamine abusers. The possible aetiology is also discussed.

Human papillomaviral load changes in low-grade squamous intraepithelial lesions of the uterine cervix.

To better predict risk of progression of low-grade squamous intraepithelial lesions (LSILs) of the uterine cervix in women with human papillomavirus (HPV) infections, 294 baseline cervical specimens from women with LSILs were evaluated. Specimens were tested for HPV DNA using hybrid capture 2 (HC2) and PCR-reverse line blotting. 65 LSILs with HPV DNA types 16, 18, 52, or 58 were examined for physical status, E2/E6 ratio and viral load at two time points, along with patient age. Women with LSILs whose viral loads increased between baseline and 6 month follow-up had a 45% risk of developing HSIL (OR=7.6, 95% CI=1.9-29.4, P<0.01), as evaluated by real-time PCR and a 44% risk (OR=6.1, 95% CI=1.6-22.7, P<0.01), as evaluated by HC2. The two viral load measures correlated well (Person's coefficient, r=0.687, P<0.001). Such evaluations of viral load changes (increased or not increased) through repeat HPV DNA testing could predict progression of disease in LSIL cases of HPV types 16, 18, 52, and 58, which correlates to clinical implications.

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.

Emergency peripartum hysterectomy in a teaching hospital in Eastern Taiwan.

This study aims to review the incidence, indications, risk factors and complications associated with emergency peripartum hysterectomy in a teaching hospital. We reviewed records of patients undertaking emergency peripartum hysterectomy performed at our institution from 1998 to 2004. Emergency peripartum hysterectomy was defined as one performed for haemorrhage unresponsive to other treatments <24 h after delivery. Eight cases of emergency peripartum hysterectomy were performed. The rate of peripartum hysterectomy was 0.25%. The main indications for hysterectomy were uterine atony and abnormal placentation. No maternal death occurred. Use of peripartum hysterectomy may become necessary in managing obstetrical haemorrhage refractory to other measures.

Plasma proteomic profiling for detecting and differentiating in situ and invasive carcinomas of the uterine cervix.

The objective of this study was to identify multiple plasma protein markers that might be characteristic of in situ and invasive cervical cancers. Plasma samples obtained from patients with in situ cervical cancer (carcinoma in situ [CIS], n= 32), from patients with early invasive cervical cancer without lymph node metastasis (squamous cell carcinoma [SCC], n= 60), and from age-matched disease-free controls (n= 37) were analyzed by cation-exchange protein chips and surface-enhanced laser desorption and ionization time-of-flight mass spectrometry. A classification tree defined by six protein peaks could discriminate 84 of the 92 cancers (CIS and SCC) and 36 of the 37 controls, with 91% sensitivity and 97% specificity. In comparing the CIS and SCC samples, two protein peaks with Mr values of 6586.41 and 3805.68 were able to classify 55 of the 60 SCC and 31 of the 32 CIS samples, with 92% sensitivity and 97% specificity. This study demonstrates for the first time the feasibility of differentiating in situ and invasive cervical cancers through plasma protein profiling. Identification of the proteins different in invasive and in situ cancer may be of great value in the understanding of cervical cancer invasion and in the development of novel therapeutic intervention.

Differential viral loads of human papillomavirus 16 and 58 infections in the spectrum of cervical carcinogenesis.

Human papillomavirus (HPV) load was reported to be related to the severity of cervical neoplasia but with controversy. The viral load-disease severity relationship was showed in HPV 16, but no study was made in HPV 58, the second most prevalent HPV in cervical cancer in East Asia. We studied cervical HPV loads in HPV 16- and HPV 58-infected cases of normal, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (CC) by using quantitative polymerase chain reaction (Q-PCR) with type-specific primers in defined cell number. With the exception of HPV 16 infection in normal, viral loads varied greatly in each disease regardless of genotypes. The load of HPV 16 differed significantly among disease severities, with a dramatic increase from normal (1.14 +/- 2.25 copies/cell) to LSIL, HSIL, and CC (1599 +/- 2301, 7489 +/- 24,087 and 1878 +/- 2979 copies/cell, respectively) (P < 0.01). No significant difference was noted among different HPV 58 infections, with loads in normal, LSIL, HSIL, and CC of 503 +/- 641, 7951 +/- 27,557, 353 +/- 744, and 1139 +/- 2895 copies/cell, respectively. In comparison with HPV 16, HPV 58 subclinical infection confers a significant higher load (P < 0.01). Different HPV types behave differentially in the spectrum of cervical carcinogenesis. Unlike HPV 16, the infection load of HPV 58 does not correlate to the clinical severity. The wide variation of HPV loads among different HPV types and among squamous intraepithelial lesions and CC makes the viral load test unrealistic in differentiating different severities of cervical neoplasia.

Plasma proteomic pattern as biomarkers for ovarian cancer.

Early detection of ovarian cancer remains a challenge. Pathologic changes within an organ might be reflected in proteomic patterns in serum or plasma. The objective of this study was to identify new plasma biomarkers in ovarian cancer patients using mass spectrometry (MS) protein profiling and artificial intelligence. The study included 35 women with ovarian cancer and 30 age-matched disease-free controls. For plasma protein signature analysis, the protein chip array surface-enhanced laser desorption/ionization (SELDI) analysis was performed. The strong anion exchange (SAX) and weak cation exchange (WCX) chips were used for analysis. After a training analysis by SAX and WCX protein chips, learning algorithm and clustering analysis was performed to reach a discriminate pattern of protein signature. SELDI mass spectroscopy was highly reproducible in detecting ovarian tumor-specific protein profiles. Four specific protein peaks were identified in plasma of women with ovarian cancer, but not in controls, with relative molecular masses of 6190.48, 5147.06, 11522.6, and 11537.7 d. Two peaks, with Mr 5295.5 and 8780.48 d, were present in plasma of control but not in women with ovarian cancer. A sensitivity of 90-96.3% and specificity of 100% for this studied cases and controls were reached. This study clearly demonstrates that the combined technology of SELDI-MS and artificial intelligence is effective in distinguishing protein expression between normal and ovary cancer plasma. The identified gained and lost protein peaks in plasma may provide as candidate proteins to be used for the detection or monitoring ovarian cancer.

Identifying the combination of genetic factors that determine susceptibility to cervical cancer.

Cervical cancer is common among women all over the world. Although infection with high-risk types of human papillomavirus (HPV) has been identified as the primary cause of cervical cancer, only some of those infected go on to develop cervical cancer. Obviously, the progression from HPV infection to cancer involves other environmental and host factors. Recent population-based twin and family studies have demonstrated the importance of the hereditary component of cervical cancer, associated with genetic susceptibility. Consequently, single-nucleotide polymorphism (SNP) markers and microsatellites should be considered genetic factors for determining what combinations of genetic factors are involved in precancerous changes to cervical cancer. This study employs a Bayesian network and four different decision tree algorithms, and compares the performance of these learning algorithms. The results of this study raise the possibility of investigations that could identify combinations of genetic factors, such as SNPs and microsatellites, that influence the risk associated with common complex multifactorial diseases, such as cervical cancer.

A research-based tumor tissue bank of gynecologic oncology: characteristics of nucleic acids extracted from normal and tumor tissues from different sites.

This article describes a gynecology and pathology-oriented tumor tissue bank that is approaching the research requirements of modern molecular oncology and compared characteristics of nucleic acids extracted from preserved tissues. Through August 2000, 8869 specimens, including fresh neoplastic tissues and normal counterparts, body fluids (ascites, tumor content, and blood), and cervical scrapings, were procured from 1853 patients. DNA and RNA were extracted from a random sampling of normal (n = 50) and tumor (n = 53) tissues from the uterine cervix (n = 47), endometrium (n = 24), and ovary (n = 32). As expected, tumor tissues conferred a higher yield of DNA (1.56 +/- 1.24 versus 0.94 +/- 0.72 microg/mg tissue, P = 0.001) and RNA (5.04 +/- 6.21 versus 2.12 +/- 1.76 microg/ml, P < 0.001) than normal tissues. However, the RNA message abundance, as measured by RNA yield/DNA yield, was not different between tumor and normal tissues. With a similar content of DNA in the endometrium, uterine cervix, and ovary, RNA yield was higher in the endometrium than the others (P = 0.013). In tumors from these three sites, similar yields of DNA and RNA were noted. Overall the yield of DNA remained unchanged from specimens preserved for as long as 7 years, although at this length of storage, RNA yield became lower and variable. This study provides the basic characteristics of nucleic acids derived from normal and tumor tissues and ensures future research utility of these frozen specimens.