Johannes E. Bock

Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study

Abstract Objectives: To investigate the role of human papillomavirus (HPV) in the development of cervical neoplasia in women with no previous cervical cytological abnormalities; whether the presence of virus DNA predicts development of squamous intraepithelial lesion; and whether the risk of incident squamous intraepithelial lesions differs with repeated detection of the same HPV type versus repeated detection of different types. Design: Population based prospective cohort study. Setting: General population in Copenhagen, Denmark. Participants: 10 758 women aged 20-29 years followed up for development of cervical cytological abnormalities; 370 incident cases were detected (40 with atypical squamous cells of undetermined significance, 165 with low grade squamous intraepithelial lesions, 165 with high grade squamous intraepithelial lesions). Main outcome measures: Results of cervical smear tests and cervical swabs at enrolment and at the second examination about two years later. Results: Compared with women who were negative for human papillomavirus at enrolment, those with positive results had a significantly increased risk at follow up of having atypical cells (odds ratio 3.2, 95% confidence interval 1.3 to 7.9), low grade lesions (7.5, 4.8 to 11.7), or high grade lesions (25.8,15.3 to 43.6). Similarly, women who were positive for HPV at the second examination had a strongly increased risk of low (34.3,17.6 to 67.0) and high grade lesions (60.7, 25.5 to 144.0). For high grade lesions the risk was strongly increased if the same virus type was present at both examinations (813.0, 168.2 to 3229.2). Conclusions: Infection with human papillomavirus precedes the development of low and high grade squamous intraepithelial lesions. For high grade lesions the risk is greatest in women positive for the same type of HPV on repeated testing.

Human papillomavirus—the most significant risk determinant of cervical intraepithelial neoplasia

Sexual behavior has been consistently identified as a major risk factor for cervical cancer. Population‐based studies have demonstrated that risk related to sexual activity is mediated by human papillomavirus (HPV) infection. We conducted a case‐control study of 199 cases with low‐grade squamous intraepithelial lesions or high‐grade squamous intraepithelial lesions as defined by cytology and 1000 control women selected from an ongoing prospective cohort study in Copenhagen, Denmark. Furthermore, 131 women with equivocal smears (atypical squamous cells of undetermined significance) were examined as a separate borderline case group. At enrollment, all women had a personal interview and a gynecological examination including cervical swabs for HPV testing and a Pap smear. HPV testing was performed using a combination of general primer 5/6‐mediated and type‐specific polymerase‐chain‐reaction‐based methods. Cervical HPV infection was by far the most significant risk factor for cervical squamous intraepithelial lesions. The relationship with HPV was observed for all grades, while strength of association was greater for more severe lesions. The importance of the previously identified epidemiological risk factors for cervical neoplasia was also demonstrated. However, most of the effect of these factors could be explained by taking HPV infection into account, except for schooling and smoking. Non‐use of barrier contraceptives and smoking were the only significant risk factors in HPV‐positive women. In HPV‐negative women, a residual effect existed for different measures of sexual activity, and use of oral contraceptives and smoking constituted significant risk determinants. Overall, 66% of cases could be attributed to HPV; however, if the results were restricted to histologically confirmed high‐grade lesions, the proportion of cases that could be attributed to HPV infection increased to 80%.

Ultrasound-guided fetal intravenous transfusion for severe rhesus haemolytic disease.

Intrauterine, intraperitoneal transfusion is associated with a poor survival rate in fetuses with hydrops and low gestational age. A method of direct fetal intravenous transfusion was used in two fetuses. One fetus with severe rhesus haemolytic disease was given transfusions in the 29th and 30th weeks of gestation, using an ultrasound-guided needle through the hepatic part of the umbilical vein without fetoscopy. In another fetus, an experimental cannulation of the umbilical vein succeeded in the 23rd week of gestation. Ultrasound-guided fetal intravenous transfusion avoids the use of fetoscopy, which has limitations, and may improve the prognosis for rhesus-sensitised fetuses.

High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival

YKL-40 (human cartilage glycoprotein-39) is a member of family 18 glycosyl hydrolases. YKL-40 is a growth factor and is secreted by cancer cells. High serum levels of YKL-40 in patients with colorectal cancer and recurrent metastatic breast cancer have been associated with a poor prognosis. We evaluated the prognostic value of plasma YKL-40 in patients with primary ovarian cancer (OC). YKL-40 was determined by ELISA in plasma obtained preoperatively from 47 women with stage III OC and in plasma from 79 healthy females. The results showed that plasma YKL-40 was elevated compared to healthy females in 57% of the OC patients and was highest in the patients who died during the follow-up compared to the patients still alive (186 vs. 78 micro g/l, p=0.002). Patients with high plasma YKL-40 (>130 micro g/l) had significantly (p=0.0003) shorter survival than patients with normal plasma YKL-40. Multivariate Cox regression analysis showed that plasma YKL-40 (RH=3.95; 95% CI, 1.52-10.27; p=0.005) and radicality after primary surgery (RH=4.03; 95% CI, 1.81-8.97; p=0.001) were independent prognostic factors of survival, whereas age, histological type of tumour and serum CA125 had no independent prognostic value. In conclusion, plasma levels of YKL-40 proved of prognostic value in stage III OC patients.

Sexual Function and Somatopsychic Reactions in Vulvectomy-Operated Women and their Partners

Sexual function and somatopsychic reactions were examined in 25 women following vulvectomy and in 15 of their partners. More than half of the women had both sexual dysfunction and psychological problems. Their partners had no sexual dysfunction but almost half had psychological problems. An important reason for this seems to be insufficient information and advice both pre‐ and postope‐ratively and failure to recognize a developing stricture of the introitus vaginae. Frequent control and advice to both partners both pre‐ and postoperatively is desirable. Less extensive surgical procedures in selected cases should be considered.

Different risk factor patterns for high-grade and low-grade intraepithelial lesions on the cervix among HPV-positive and HPV-negative young women

Risk factors for cervical intraepithelial neoplasia have most often been studied in high‐grade lesions. Furthermore, in a high proportion of the studies, human papillomavirus (HPV), the most significant risk determinant of cervical neoplasia, was not taken into account when evaluating other risk factors. To compare risk factors for ASCUS (atypical cells of undetermined significance), LSIL (low‐grade squamous intraepithelial lesion) and HSIL (high‐grade squamous intraepithelial lesion), we conducted a case‐control study among 20 to 29 year‐old women participating in a prospective cohort study in Copenhagen. It included 131 women with ASCUS, 120 women with LSIL, 79 women with HSIL and 1,000 randomly chosen, cytologically normal, control women. All participants had a personal interview and a gynecological examination including a Pap smear and cervical swabs for HPV DNA detection using general primer‐mediated polymerase chain reaction. The most significant risk determinant of all 3 disease categories was the presence of genital HPV DNA. The risk factor pattern was nearly identical for ASCUS and LSIL, but differed significantly from that for HSIL. Stratified analysis by HPV‐status showed that, apart from, respectively, smoking and parity among HPV‐positive women, and smoking and number of sex partners among HPV‐negative women, no additional risk factors were observed for ASCUS and LSIL. In contrast, among HPV‐negative women with HSIL, long‐term use of oral contraceptives was the most important risk factor. However, our result should be taken with great caution as it is based on very small numbers, and as it is unknown whether the HPV‐negative lesions constitute a true entity. Among HPV‐positive women, the risk of HSIL was associated with e.g., years of sex life without barrier contraceptive use, early age at first genital warts and smoking. Whether the risk factors that are applicable only to HSIL represent factors related to progression remains unknown. Int. J. Cancer 76:613–619, 1998.© 1998 Wiley‐Liss, Inc.

Case control study of risk factors for cervical neoplasia in denmark ii. role of sexual activity reproductive factors and venereal infections

Sexual, reproductive and venereal risk factors for cervical neoplasia were investigated in a population-based case-control study of 586 women with histologically verified, cervical squamous-cell carcinoma in situ, and 59 women with invasive squamous-cell cervical cancer, diagnosed from 1985 to 1986 in Copenhagen. Cases were identified from the computerized Danish Cancer Registry. An age-stratified control group (n=614) was drawn at random from the female population in the study area by means of the Danish Central Population Register. A structured questionnaire was mailed to cases as well as controls. Increasing number of sexual partners exerted a significant effect on the risk both for carcinoma in situ, and invasive cancer, independently of age at first intercourse and other potential confounders. Conversely, the association with early age at first intercourse became statistically insignificant after allowance for other risk factors, although an increasing risk was still observed with decreasing age at sexual debut. Early age at first episode with genital warts was a significant risk factor for carcinoma in situ, perhaps indicating a possible increased susceptibility of the cervix epithelium during adolescence. A history of genital warts was a good predictor of risk for carcinoma in situ, whereas a history of previous gonorrhea was associated with an increased risk for invasive carcinoma. Women with multiple births had a significantly increased adjusted risk, especially for carcinoma in situ, although some association was also observed with invasive cervical cancer. The study supports the hypothesis of cervical neoplasia being a sexually transmitted disease, and that carcinoma in situ and invasive cervical carcinoma, to a high degree, have similar patterns of risk factors.

Sexual function and somatopsychic reactions after local excision of vulvar intra-epithelial neoplasia

Eighteen patients, under the age of 60 years, who have been treated with local excision of the vulva, participated in the study in which sexual function and somatopsychic reactions were evaluated by personal interviews. Furthermore both objective and subjective cosmetic results were registered. After this type of operation, fewer than one‐third of the patients had postoperative sexual and somatopsychic problems, whereas more than half of the patients undergoing vulvectomy did report such problems. Fourteen out of 18 patients were satisfied with the cosmetic result and in 12 of the patients no disfiguration was found. This study shows that local excision of intra‐epithelial neoplasia of the vulva is far less sexually traumatic than is vulvectomy.

History of genital warts in 10,838 women 20 to 29 years of age from the general population : risk factors and association with Papanicolaou smear history

Background and Objectives: The most important risk factor for cervical neoplasia is genital infection with certain types of human papillomavirus (HPV). Genital warts (GW) are an easily recognizable condition caused by HPV. Although only a fraction of HPV infections are clinical, a history of ever having had GW could serve as a marker for exposure to HPV. Goals: To study the risk factors for ever having had GW. The association of GW with abnormal Papanicolaou (Pap) smear and relation to cervical neoplasia is also discussed. Study Design: A case‐control study among 10,838 women aged 20 to 29 years and reporting at least one lifetime sexual partner. The women were participants in a prospective cohort study on the relationship between HPV and cervical neoplasia in Copenhagen, Denmark. Data were obtained by means of personal interviews using structured questionnaires. Results: In all, 1,820 women (17%) reported ever having had GW. The most important risk factor was the number of lifetime of sexual partners (adjusted odds ratio 5.2; 95% confidence interval: 3.4–8.0) for at least 40 partners vs. 1 to 2 partners). The number of regular partners, sexually active years, a history of chlamydial infection, and smoking were also associated with the risk of ever having had GW. Women who had had GW were 1.9 times more likely than other women to report an abnormal Pap smear. Conclusions: The study confirms the sexual transmission of the infection. There is also good concordance between risk factors for ever having had GW and cervical neoplasia. A close relationship between having had GW and an abnormal Pap smear was observed.

Determinants for non-use of contraception at first intercourse; a study of 10,841 young Danish women from the general population☆

Based on interview data from 10841 Danish women aged 20 to 29 years, determinants for non-use of contraception at first intercourse (NU) were studied. One-fourth of the women (n = 2704) reported NU, whereas condoms and oral contraceptives were used by, respectively, 59% and 15%. NU decreased with the birth year of the first male partner (OR = 3.6; 95% CI: 2.8-4.8 for <or=1954 vs. 1968-1974) mainly in favor of condom use. Other determinants were the birth cohort of the woman (OR = 1.4; 95% CI: 1.0-1.9 for 1961-1962 vs. 1970-1972) and the calendar year of the first intercourse (OR = 1.4; 95% CI: 1.2-1.7 for 1985-1986 vs. 1987-1992), both initially in favor of oral contraception and later in favor of condom use, whereas young age at first intercourse was associated with a high prevalence of NU (OR = 1.8; 95% CI: 1.4-2.1 for <or=14 years vs. >or=17 years) at the expense of both oral contraception and condom use. Finally, NU was found to predict high-risk sexual behavior in terms of subsequent multiple sex partners, non-use of condoms, and induced abortion.