Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING: Merck & Co, Inc.

A mentored cooperative group pilot study: atrophic vaginitis.

OBJECTIVES: To review nursing research initiatives from two cooperative groups and outline a pilot study performed by a junior nurse researcher mentored by cooperative group nurse researchers and institutional physicians. DATA SOURCES: PubMed, Cochrane Library, Scopus, World Wide Web. CONCLUSION: Nursing research can be initiated and led by nurses in the cooperative group setting. The team approach model of research includes several disciplines to examine multiple facets of the same problem, or of multiple problems that a cancer patient may face. This new model will enable a greater number of nurse researchers to investigate symptom management, survivorship, and quality-of-life issues. IMPLICATIONS FOR NURSING PRACTICE: Nurse researchers should be included in every cooperative group study to investigate nurse-sensitive outcomes and issues related to symptom management, survivorship, and quality of life.

Analytical performance of Cervista HPV 16/18 genotyping test for cervical cytology samples.

BACKGROUND: Human papillomavirus (HPV) types 16 and 18 are the 2 most frequent types associated with cervical cancer. Identifying their presence or absence in cervical samples may assist in triaging women for subsequent management. The Cervista HPV 16/18 genotyping test specifically detects the presence of HPV 16 and 18 in ThinPrep cervical specimens. OBJECTIVES: The objective was to establish the analytical performance of the CERVISTA HPV 16/18 genotyping test. STUDY DESIGN: These studies were performed in support of a regulatory submission to the US Food and Drug Administration. Here we report the analytical sensitivity (limit of detection), accuracy compared to consensus L1 gene PCR/bi-directional sequencing, precision, reproducibility, and cross-reactivity (specificity) of the genotyping test. RESULTS: Analytical sensitivity for detection of HPV 16 and 18 ranged between 625 and 1250 copies/reaction for both types. When compared to PCR/sequencing for women with atypical squamous cells of undetermined significance cytology, the positive percent agreement was 94.1% (95% confidence interval [CI], 89.8-96.7) and the negative percent agreement was 85.7% (95% CI, 82.4-88.4). The test demonstrated high within-laboratory and inter-operator precision. Reproducibility within sites and between 3 testing sites resulted in 100% agreement with expected results (150 positive, 90 negative results). The genotyping test did not exhibit cross-reactivity to DNA from common low-risk HPV types and other microorganisms found in the human female reproductive tract. CONCLUSIONS: These analytical performance data support the use of CERVISTA HPV 16/18 genotyping test for the detection and differentiation of HPV 16 and 18 in ThinPrep cervical cytology specimens.

Vaginal agglutination: chronic graft-versus-host disease mimics lichen planus.

BACKGROUND: Graft-versus-host (GVH) disease is a common problem in transplant patients, whereas vulvovaginal gingival syndrome is an uncommon and severe variant of lichen planus characterized by erosions of characteristic mucosal surfaces, with frequent vaginal involvement, resulting in scarring or stricture formation. Both conditions have the potential to present with similar clinical pictures. CASE: We report the history, evaluation, and treatment of a woman who had recently undergone stem cell transplant for acute lymphoblastic leukemia who presented with vaginal agglutination. A clinical diagnosis of erosive lichen planus versus chronic GVH disease was considered. CONCLUSIONS: Lichen planus and GVH disease are both inflammatory processes, which can present with a range of clinical conditions. Each may result in the development of irritative symptoms and erosive lesions on mucosal surfaces. Although lichen planus is a well-defined dermatosis, GVH disease is an iatrogenic process. We report the case history of a patient with erosive vulvovaginal lesions with scarring, likely caused by GVH disease, which mimicked erosive vulvovaginal lichen planus. Although the clinical presentation and treatment of these 2 entities are similar, this case demonstrates the subtle diagnostic difference between the 2 diseases.

Correlation of Pap smear, cervical biopsy, and clinical follow-up with an HPV typing microarray system.

A human papillomavirus (HPV) microarray system allows the determination of HPV type in clinical samples. The purpose of this study was to determine the presence of HPV in liquid-based Pap smears with the MyGene MyHPV Chip Kit HPV genotyping microarray test (MyGene Assay), and to correlate this with the cytology and biopsy diagnoses, clinical follow-up, HPV Hybrid Capture data, and HPV sequence analyses. Four hundred and two Pap smears (93 ThinPrep, 309 SurePath) were available for study. Correlation of HPV DNA detection by the MyGene Assay with the Pap smear diagnosis showed a detection rate of 19/97 (19%) for normal Pap smears, 181/242 (74%) for atypical squamous cells of undetermined significance (ASCUS), and 61/63 (97%) for squamous intraepithelial lesions (SILs). Biopsy data on 248 women were available. HPV was noted by the MyGene Assay in the Pap smear in 98/100 (98%) of the cases, for which the corresponding biopsy had been diagnosed as SIL, compared with 103/148 (69%) of the cases for which the biopsy had been negative for SIL. Clinical follow-ups were available for 200 women with ASCUS Pap smears. A significant increase was observed in the rate of biopsy-proven SILs in women with ASCUS Pap smears that were HPV-positive (63/66=95%) as compared with those that were HPV-negative (96/134=71%, P<0.05). The MyGene Assay and Hybrid Capture system gave equivalent results for all the categories studied, except for the presence of multiple infections, as determined by viral sequence analysis. Specifically, the Hybrid Capture system overestimated the presence of dual infection (low-risk and high-risk positive) by 48% and missed many cases of multiple infections, especially when 2 or more high-risk types were present. It is concluded that the MyGene Assay allows for the routine typing of HPV in liquid-based Pap smears, and that the presence of HPV DNA in ASCUS Pap smears is strongly correlated with a biopsy-proven SIL.

Lipodermatosclerosis as a form of vascular compromise-associated radiation recall dermatitis: case report and a review of literature.

Lipodermatosclerosis (LDS) is a prototypic ischemic dermopathy that is most commonly associated with venous insufficiency. There have been no prior reports describing LDS as a form of radiation recall dermatitis (RRD). We present a case of a 47-year-old female affected by squamous cell carcinoma of the anus who underwent irradiation and subsequent chemotherapy with 5-fluorouracil and cisplatin. She then developed tender, erythematous, indurated plaques on skin of the buttocks, corresponding closely to one of the previous radiotherapy fields. As histopathological studies were compatible with LDS and the skin eruption coincided with drug intake 3 months after radiotherapy, the diagnosis of RRD with LDS features was rendered. This is the first case providing evidence of the causative role of 5-fluorouracil and cisplatin in potentially inducing RRD.

Histologic, infectious, and molecular correlates of idiopathic spontaneous abortion and perinatal mortality.

The purpose of this study was to analyze the placental and neonatal tissues in fatal cases for a wide variety of infectious agents and cytokine expression. Placentas and corresponding neonatal tissues in 21 consecutive cases of idiopathic spontaneous abortion or perinatal death, before or within 2 days of birth, were tested for an infectious agent. The controls included 10 consecutive cases of fetal and placental tissues from therapeutic abortions, 5 placentas from unremarkable childbirths, and 11 placentas from cases of spontaneous abortion or perinatal death of known cause (ruptured uterus, placenta abruption, prolapsed cord). An intrauterine infection was noted in 16 of 21 (76%) of the placentas associated with neonatal mortality; in each case, the same infectious agent was found in the neonatal tissues, primarily the spleen. The most common infectious agent was enterovirus/coxsackie virus (10 cases); the histologic findings in the placenta were nonspecific. There was strong expression of TNF-alpha in the placenta and spleen of each of the cases of intrauterine infection and in none of the 26 controls. It is concluded that in utero infection and the associated cytokine up-regulation are responsible for many cases of unexplained fetal and neonatal loss.

Histologic correlates of viral and bacterial infection of the placenta associated with severe morbidity and mortality in the newborn.

The purpose of this study was to correlate the histologic features of the placenta with the in situ detection of viral or bacterial nucleic acids in cases of severe morbidity and mortality in the neonatal period. The criteria for the cases were either fetal or neonatal death (11 cases with autopsy material available in 8 cases) or idiopathic severe respiratory distress or central nervous system-related symptoms at birth (49 cases). Controls included 11 placentas from births with no morbidity and 6 placentas that were associated with severe neonatal morbidity of known etiology (trisomy, ruptured uterus, prolapsed cord). The 77 placental tissues were analyzed with a consensus bacterial probe and for a wide variety of viral infections. An infectious cause was found in 46/60 (76%) of cases; these were distributed as follows: enterovirus, 23 cases (22 were coxsackie virus); bacterial (consensus probe), 15 cases; cytomegalovirus (CMV), 4 cases; herpes simplex virus (HSV), 2 cases; parvovirus, 2 cases. The infectious agents localized primarily to Hofbauer cells and trophoblasts. In each of the 8 cases for which autopsy material was available, the same infectious agent that was detected in the placenta was also detected in the autopsy material (spleen, heart, central nervous system, or lungs). No infectious agent was detected in any of the 17 controls. Viral inclusions (only evident for DNA viruses) and stem vessel vasculitis were the 2 histologic findings that were associated with infectious disease in the placenta (P = 0.025). These data show that infection of the villi is highly associated with neonatal morbidity and mortality and that the histologic findings are, in most cases, nonspecific for infection.

Human papillomavirus infection in adolescents: a rational approach.

Human papillomavirus (HPV) infection has variable clinical manifestations, from transient subclinical disease to serious cervical cancer precursors. An understanding of the natural history of this common sexually transmitted infection is necessary to allow diagnosis of clinically significant disease and judicious application of treatment modalities, especially in young adolescents. This article reviews new recommendations for initiation of screening, revisions in cytology terminology, and evidence-based guidelines for management of lower genital tract disease, including the application of HPV testing.

The antimicrobial defense mechanism of the female urethra: a reassessment.

PURPOSE: This review of the literature and study of the cytology of the urethra were done to define the potential role of the female urethra as a staging site for urinary tract infection and examine the evidence for a urethral defense mechanism. MATERIALS AND METHODS: We re-analyzed data on the quantitative microbiology of the female urethra published 3 decades ago, reviewed the literature on the initiation of ascending urinary tract infections, the cytology and anatomy of the urethra, and performed studies of the morphology of urethral cells in boys and girls, men, menstruating and menopausal women, and women with acute cystitis. We also considered clues about the urethral microenvironment provided by gonococcal cervicitis and urethritis. RESULTS: We found strong statistical evidence that the female urethra has a powerful antimicrobial defense mechanism, which appears to differ in women with and without recurrent urinary tract infections. We corroborated the findings of previous investigators that the female urethra is lined by cells identical to those of the vagina that respond similarly to estrogens. We found immature basal and parabasal cells in children, and a modest inflammatory response to urinary tract infection. CONCLUSIONS: The female urethra may provide a favorable environment for colonization by uropathogens but it is protected by a powerful defense mechanism. This mechanism may be explained by the shedding of uropathogens bound to exfoliating urethral cells, trapping of bacteria by mucus secreted by the paraurethral glands, intermittent washout by urine, local production of Ig, cytokines and defensins and mobilization of leukocytes.