Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: Population based cohort study

Abstract Objective To compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result. Design Population based cohort study using data from a nationwide pathology register. Setting The Netherlands, 1994 to 2006. Population 38 956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment. Intervention Routine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months. Main outcome measure Incidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up. Results 20 cervical cancers were diagnosed during 56 956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25 020 697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100 000 woman years and 6.4 (6.1 to 6.8) per 100 000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia. Conclusions An excess risk

To vaccinate or not to vaccinate? Perspectives on HPV vaccination among girls, boys, and parents in the Netherlands: A Q-methodological study

Background: Despite the introduction of Human papillomavirus (HPV) vaccination in national immunization programs (NIPs), vaccination rates in most countries remain relatively low. An understanding of the reasons underlying decisions about whether to vaccinate is essential in order to promote wider spread of HPV vaccination. This is particularly important in relation to policies seeking to address shortfalls in current HPV campaigns. The aim of this study was to explore prevailing perspectives concerning HPV vaccination among girls, boys, and parents, and so to identify potential determinants of HPV vaccination decisions in these groups. Method: Perspectives were explored using Q-methodology. Forty-seven girls, 39 boys, and 107 parents in the Netherlands were asked to rank a comprehensive set of 35 statements, assembled based on the health belief model (HBM), according to their agreement with them. By-person factor analysis was used to identify common patterns in these rankings, which were interpreted as perspectives on HPV vaccination. These perspectives were further interpreted and described using data collected with interviews and open-ended questions. Results: The analysis revealed four perspectives: "prevention is better than cure," "fear of unknown side effects," "lack of information and awareness," and "my body, my choice." The first two perspectives and corresponding determinants of HPV vaccination decisions were coherent and distinct; the third and fourth perspectives were more ambiguous and, to some extent, incoherent, involving doubt and lack of awareness and information (perspective 3), and overconfidence (perspective 4). Conclusions: Given the aim of publically funded vaccination programs to minimize the spread of HPV infection and HPV-related disease and the concerns about current uptake levels, our results indicate that focus should be placed on increasing awareness and knowledge, in particular among those in a modifiable phase

Intraperitoneal photodynamic therapy in the rat: Comparison of toxicity profiles for photofrin and mTHPC

Toxicity studies for intraperitoneal photodynamic therapy (IPPDT) were performed in Wag/RijA rats, using specially designed light delivery blocks for proper light distribution and light dosimetry. A recently developed photosensitizer mesotetrahydroxyphenylchlorin (mTHPC), excited at 652‐nm wavelength, was compared with Photofrin (630 nm). Toxicity profiles for various sensitizer doses, light fluences and time intervals were investigated. A light fluence of 15 J ‐ cm−2 delivered to the entire peritoneum 24 hr after 5 mg Photofrin per kg i.v. induced reversible impairment of intestinal, liver and kidney function. A dose of 0.2 mg mTHPC per kg i.v. followed by 6 J · cm−2 at 72 hr appeared to be equitoxic to the intestines; however, functional tests revealed little effect for this mTHPC‐mediated IPPDT regime on liver or kidney. Histology demonstrated focal irreversible damage to the kidneys for both photosensitizers, not reflected in functional impairment. Light doses of 25 to 30 J. cm−2 at 24 hr after Photofrin or 8–12 J · cm−2, 72 hr after mTHPC caused lethal toxicity in the first 2 weeks due to intestinal damage. Higher light doses caused a shock syndrome and rhabdomyolysis resulting in death within 20 hr for both photosensitizers. In conclusion, maximum tolerable schedules for whole‐abdomen IPPDT were defined for Photofrin and mTHPC. Both photosensitizers cause similar toxicity profiles depending on drug dose, light fluence and time interval

Intraperitoneal Photodynamic Therapy: Comparison of Red and Green Light Distribution and Toxicity

The aim of this study was to compare red (652 nm) and green (514 nm) light for photodynamic therapy (PDT) of the peritoneal cavity with emphasis on light distribution and toxicity. Red-light PDT was limited by intestinal toxicity and it was hypothesized that less penetrating green light would allow higher light doses to be used in the peritoneal cavity. Female non-tumor-bearing rats were photo-sensitized with mTHPC (meta-tetrahydroxyphenylchlorin, Foscan®) intravenously or intraperitoneally and the peritoneum was illuminated using a minimally invasive technique. For both red and green light, the time of illumination was varied to give the required dose. Light fluence rate was measured in situ at multiple sites within the abdominal cavity. The toxicity experiments were carried out with a total of 160 J incident red or 640 J incident green light and a drug dose of 0.15 mg/kg Foscan®. For red light a mean fluence rate of 55.2 ± 38.5 mW cm -2 was measured, with a peak fluence rate of 128 mW cm-2 on the intestines. For green light the mean and peak fluence rates were 8.2 ± 9.0 (i.e. including zero fluence rate measurements) and 28 mW cm-2 respectively. Intestines were most vulnerable to red light illumination. The intravenous injection route resulted in increased toxicity for red light, but for green light there were no major differences between intravenous and intraperitoneal routes. The 4 h interval between drug and illumination resulted in very little toxicity for both wavelengths. We conclude that for intraperitoneal PDT green light allows higher light doses than red light, but the light distribution over the peritoneum is much less favorable and may not be suitable for whole peritoneal illumination using a minimal-access technique

HPV16 and increased risk of recurrence after treatment for CIN

Objective.: Addition of high-risk human papillomavirus (hrHPV) testing to post-treatment monitoring policies of women treated for high-grade cervical intraepithelial neoplasia (CIN) may improve the effectiveness of detecting recurrent/residual disease. Recent studies have shown that HPV type 16 confers an increased risk of high-grade CIN and cervical cancer. This study aimed to find out whether the post-treatment CIN3 rate is increased in HPV16-positive women treated for CIN3. Methods.: We included 229 hrHPV-positive women treated for CIN3. HPV typing was performed by GP5+/6+-PCR followed by reverse line blotting on a cervical scrape taken before treatment. HPV typing data were related to the occurrence of post-treatment CIN3 within a median follow-up time of 20.1 months (range 3-85.4 months) following treatment. Results.: Twenty nine of the 151 (19%) HPV16-positive women versus 6 of the 78 (8%) women with other hrHPV types had recurrent/residual CIN3. Post-treatment CIN3 rate was significantly increased in women with HPV16 compared to those harboring other hrHPV types (p = 0.03). None of the other hrHPV types were associated with higher post-treatment CIN3 rates. Conclusion.: Women treated for HPV16 containing CIN3 should be monitored more intensively because of their increased risk of post-treatment CIN3. Thus, the HPV genotype should be considered in post-treatment monitoring policies

Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: Strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA

In this study, we investigated telomerase activity and human telomerase reverse transcriptase (hTERT) mRNA expression in relation to high-risk human papillomavirus (HPV) DNA presence in the spectrum of cervical premalignant lesions. Reconstruction experiments revealed that telomerase activity determined by the telomeric repeat amplification protocol assay and hTERT mRNA by reverse transcriptase-PCR could be detected in down to 100 and 1 SiHa cervical cancer cells, respectively. Telomeric repeat amplification protocol analysis on cervical tissue specimens revealed that none of the histomorphologically normal cervical samples (n = 8) and cervical intraepithelial neoplasia (CIN) grade I (n = 10) and grade II (n = 8) lesions had detectable telomerase activity. However, telomerase activity was shown in 40% of CIN grade III lesions (n = 15) and 96% of squamous cell carcinomas (n = 24). Despite the fact that hTERT mRNA was found at much higher frequencies, semiquantitative reverse transcriptase-PCR revealed that elevated hTERT mRNA levels were strongly correlated with detectable telomerase activity. Furthermore, telomerase activity and elevated hTERT mRNA levels were only detected in cases that contained high-risk HPV DNA. In contrast, low or undetectable hTERT mRNA levels were demonstrated in both high-risk HPV positive and negative cases. These data indicate that telomerase activity detectable with the assay used and concomitant elevated levels of hTERT mRNA reflect a rather late step in the CIN to squamous cell carcinoma sequence, which follows infection with high-risk HPV

Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. II. Systemic but not local IgA responses correlate with clearance of HPV-16

To investigate whether there is an association between local or systemic IgG and IgA responses against human papillomavirus (HPV) type 16 virus-like particles (VLP) containing L1 and L2 and the possible influence of these responses on clearance of HPV-16 and its associated lesions, cervical mucus samples from 125 patients and plasma samples from 100 patients, all participating in a non-intervention cohort study of women with abnormal cytology, were analysed. The results show that local IgG and IgA HPV-16 VLP-specific antibodies do not correlate with virus clearance. However, systemic IgG responses were more frequently detected in patients with a persistent infection (11/24) compared with patients with cleared HPV-16 infections (3/28, P = 0.006). Furthermore, the ultimate development of high-grade lesions was associated with systemic VLP-specific IgG reactivity (P = 0.026). By contrast, systemic IgA responses were correlated with virus clearance (7/28 clearance compared with 1/24 persistence patients, P = 0.06). This correlation was statistically significant when only those clearance patients who tested HPV-16 DNA-positive at more than one visit were included in the analysis (5/11 compared with 1/24, P = 0.007). As these systemic IgA responses were not accompanied by local IgA responses, the systemic IgA responses in HPV-16 clearance patients are suggested to be a by-product of a successful cellular immune response induced at the local lymph nodes, mediated by cytokines

Transcription profiling by array of human vulvar epithelial neoplasia

In order to understand the molecular mechanism behind Vulvar Intraepithelial Neoplasia (VIN), we have analyzed the gene expression profile of VIN lesions in comparison to controls. Experiment Overall Design: Nine VIN and 10 control samples were collected. RNA of each sample was isolated and analyzed using Affymetrix Human U133plus2 GeneChips

Transcription profiling by array of human vulvar epithelial neoplasia

In order to understand the molecular mechanism behind Vulvar Intraepithelial Neoplasia (VIN), we have analyzed the gene expression profile of VIN lesions in comparison to controls. Experiment Overall Design: Nine VIN and 10 control samples were collected. RNA of each sample was isolated and analyzed using Affymetrix Human U133plus2 GeneChips