Implications of a two-stage clonal expansion model to indoor radon risk assessment.

Spreadsheet macro programs for calculations of exact hazard and probability of having contracted cancer were used to study the implications of the lung cancer model of Moolgavkar et al. Excess lifetime risk ELR and loss of life expectancy LLE were calculated from the annual values of hazard and probability, using published life tables. The influence of various factors on ELR and LLE was studied, as well as the lifetime risk projection in epidemiological studies. At indoor concentrations, ELR and LLE are coarsely proportional to lifetime exposure. The main factors determining the proportionality coefficient are 1. Smoking status, 2. General life expectancy, 3. Exposure schedule, and 4. Sex. For constant domestic exposure, the sex is less important, because the longer life of women is compensated by the lower hazard. ELR and LLE for a population with 30% smokers and life expectancies of 72.1 y and 79.5 y for men and women, respectively, are 56 per million per WLM and 860 y per million per WLM, respectively. For an exposure schedule with one high radon period, the mean age during the period becomes important, and the age-specific values for men and women differ from each other. Furthermore, the model predicts that case-control epidemiological studies overestimate the lifetime risk by an amount which may arise to several tens of percent.

Indoor radon exposure and risk of lung cancer: a nested case-control study in Finland.

BACKGROUND: Inhaled radon has been shown to cause lung cancer among underground miners exposed to very high radon concentrations, but the results regarding the effects of residential radon have been conflicting. PURPOSE: Our aim was to assess the effect of indoor radon exposure on the risk of lung cancer. METHODS: To investigate this effect, a nested case-control study was conducted in Finland. The subjects of the study were the 1973 lung cancer case patients (excluding patients with cancers of the pleura) diagnosed from January 1, 1986, until March 31, 1992, within a cohort of Finns residing in the same one-family house from January 1, 1967, or earlier, until the end of 1985 and 2885 control subjects identified from the same cohort and matched by age and sex. In September 1992, a letter was sent to all study subjects or proxy respondents explaining the purpose and methods of the study. After giving informed consent, the study participants were asked to fill out a questionnaire on smoking habits, occupational exposures, and other determinants of lung cancer risk and radon exposure. The odds ratio (OR) of lung cancer was estimated from matched and unmatched logistic regression analyses relative to indoor radon concentration assessed by use of a 12-month measurement with a passive alpha track detector. RESULTS. Five hundred seventeen case-control pairs were used in the matched analysis, and 1055 case subjects and 1544 control subjects were used in the unmatched analysis. The OR of lung cancer for indoor radon exposure obtained from matched analysis was 1.01 (95% confidence interval [CI] = 0.94-1.08) per 2.7 pCi/L (100 Bq m-3) after adjustment for the cigarette smoking status, intensity, duration, and age at commencement of smoking by subjects. For indoor radon concentrations 1.4-2.6, 2.7-5.3, 5.4-10.7, and 10.8-34.5 pCi/L (50-99, 100-199, 200-399, and 400-1277 Bq m-3, respectively), the matched ORs were 1.03 (95% CI = 0.84-1.26), 1.00 (95% CI = 0.78-1.29), 0.91 (95% CI = 0.61-1.35), and 1.15 (95% CI = 0.69-1.93), respectively, relative to the concentration below 1.4 pCi/L (0-49 Bq m-3). The unmatched analysis yielded similar results with somewhat smaller CIs. In the analyses stratified by age, sex, smoking status, or histologic type of lung cancer, no statistically significant indications of increased risk of lung cancer related to indoor radon concentration were observed for any of the subgroups. CONCLUSIONS: Our results do not indicate increased risk of lung cancer from indoor radon exposure. IMPLICATION: Indoor radon exposure does not appear to be an important cause of lung cancer.

Decreased numbers of lymphocyte beta 2-adrenoceptors in pregnant women receiving beta 2-adrenergic agonist therapy.

Intravenous infusion of buphenine hydrochloride was administered on 4 successive days to 8 pregnant women with imminent preterm labor. Serial blood samples taken before and throughout the study were assayed for lymphocyte beta 2-adrenoceptor density and cyclic adenosine-3',5'-monophosphate (cAMP). The lymphocyte beta 2-adrenoceptor density declined significantly (p less than 0.01) during the treatment. The plasma cAMP concentration was highest 4 h after commencement of infusion and decreased thereafter. Despite the decrease in lymphocyte beta 2-adrenoceptor density, the clinical response remained good and the parturients did not go into labor until several days after infusion was started.

Prevalence, incidence, and estimated life-time risk of cervical human papillomavirus infections in a nonselected Finnish female population.

The authors derived prevalence and incidence figures for cervical human papillomavirus (HPV) infections in an unselected Finnish population of women aged 22. This paper is an epidemiologic study utilizing the mass-screening program that has been conducted in Finland for cervical cancer since the early 1960s. The authors estimated the lifetime risk of cervical HPV infections based on the figures in this program and on those derived from a random sample of 2,084 (out of 28,861) routine Papanicolaou (Pap) smears examined in their laboratory. The mass-screening program was performed between 1985-1986 focusing on a total cohort of 22-year-old women (born in 1963) in Kuopio province. In 1985, 2,013 women were invited of which 1,289 attended. One year later, 1,768 women of those 2,013 were reinvited, and the number of women screened at the second round was 1,069. The routine cervicovaginal Pap smears were taken, including a cell sample from the vagina, exocervix, and endocervix. All smears were screened for the HPV-induced cytopathic changes by the same cytopathologist. The prevalence of HPV infection among the 22-year-old women was about 3% at the beginning of the follow-up and about 7% one year later. The crude annual incidence was 7.0%. According to the estimates for the life-time risk, half of the sexually active women would experience at least one HPV infection within 10 years. Up to 79% of the Finnish females would contract at least one HPV infection between ages 20 and 79 years. This indicates that factors, which are poorly understood at the moment, exist that regulate the development of an invasive carcinoma from a CIS lesion.

Lymphocyte beta-2-adrenoceptors and plasma catecholamines in fetal hypoxia.

Conclusive evidence has been furnished that the beta 2-adrenoceptor density in circulating lymphocytes is related to that of beta 2-adrenoceptors in tissues from the same subjects. This study was designed to evaluate the effect of fetal hypoxia on lymphocyte beta 2-adrenoceptor density. The material consisted of 8 hypoxic newborns, 4 delivered by vacuum extraction and 4 by Caesarean section, after approximately 10 h parturition. The control group consisted of 8 vaginally delivered newborns without hypoxia. Umbilical plasma adrenaline and noradrenaline were significantly elevated in the hypoxic newborns. Their lymphocyte beta 2-adrenoceptor density was lower (p less than 0.01) than that in the controls. A plausible explanation for this finding might be downregulation of beta 2-adrenoceptors because of elevated plasma catecholamine level.

Lymphocyte beta 2-adrenoceptor density during menstrual cycle and pregnancy, in delivery and puerperium.

Lymphocyte beta 2-adrenoceptor density was determined in 11 women during the normal menstrual cycle and 15 women during normal pregnancy. No significant difference in lymphocyte beta 2-adrenoceptor density was established in this follow-up study during the menstrual cycle or pregnancy. Lower lymphocyte beta 2-adrenoceptor density was established just after delivery and in puerperium compared with that during pregnancy. It is likely that the high catecholamine concentration during parturition together with the duration of labour and delivery caused down-regulation of the beta 2-adrenoceptors. In puerperium the irregular day-rhythm and the stress of caring for the newborn may also have an effect.

Effect of freezing and ultrasonication on the density of human lymphocyte beta 2-adrenoceptors.

In this study 21 pregnant volunteers were divided into three equal groups; blood samples were taken from each, and after isolation of the lymphocytes the cell suspensions were divided into two equal samples. The density of beta 2-adrenoceptor in intact lymphocytes was compared with the receptor density for lymphocytes stored 7 days or 19 days at -70 degrees C and with cells disrupted by ultrasonication. Storage by lymphocytes at -70 degrees C for 7 days to 19 days decreased the beta 2-adrenoceptor density by 20% and 37%, respectively; ultrasonication decreased the density by 65%.

Prospective follow-up of cervical HPV infections: life table analysis of histopathological, cytological and colposcopic data.

A total of 532 women with established cervical HPV infection have been prospectively followed (without treatment) since 1981 for a mean of 45 (SD 21) months. The patients were examined by colposcopy, PAP smears and/or punch biopsy every 6 months. The life-table method was applied to analyze the clinical course (i.e. regression and progression) of the HPV lesions, stratified by their colposcopic pattern, PAP smear findings and grade of CIN. During the follow-up, 107 (41.8%) of 256 patients with HPV-NCIN lesion in the first punch biopsy, experienced spontaneous regression. The corresponding proportions for HPV-CIN I, HPV-CIN II and HPV-CIN III lesions were 31.1%, 34.2%, and 20.7%, respectively. In the overall comparison between these four groups, the heterogeneity in the probability of regression was statistically significant (p = 0.0005). Clinical progression was also associated significantly with the histological grade of the lesions in the first biopsy. Progression rate was only 5.8% for HPV-NCIN lesions, as compared to 12.3% for HPV-CIN I, 20% for HPV-CIN II, and 55.2% for HPV-CIN III. The probability of progression varied significantly between the four groups (p less than 0.00001). Cumulative proportion of regression was 46% for patients with PAP smear class I, 84% with class II, and 82% for those with class III, cells, i.e. PAP smear was not of value in predicting the regression. However, PAP smears predicted clinical progression (p = 0.006 overall).(ABSTRACT TRUNCATED AT 250 WORDS)

Cryotherapy and CO2-laser vaporization in the treatment of cervical and vaginal human papillomavirus (HPV) infections.

A series of 119 women with Human papillomavirus (HPV) infections of the uterine cervix and/or vagina were included in the present study, where the efficacy of cryotherapy and CO2-laser vaporization was assessed after a mean follow-up of 14 months (SD 6 months) after treatment, as related to the natural history of the disease. Routine Papanicolaou (PAP) smears with HPV-induced changes were the basis for patient recruitment. Patients with cervical HPV lesions (HPV-NCIN, HPV-CIN I or II) were randomly allocated into laser (55 women) and cryotherapy (42 women) groups. Women with combined lesions (HPV-CIN & HPV-VAIN) were treated by laser (22 patients). The cure rate after laser vaporization was practically identical to that of cryotherapy, 64% and 54%, respectively (difference not statistically significant). The success rate was significantly lower (40%) for the combined lesions (HPV-CIN & HPV-VAIN) (p less than 0.05). The residual disease encountered in patients after the first treatment with cryotherapy and laser was classified as HPV-NCIN in 78.9% and 37.0%, respectively. The number of patients is still too small to draw reliable conclusions on the effects of these therapy modes, as related to HPV type of lesion (HPV 6, 11, 16, 18, 31 and 33). The cure rates for both cryotherapy and laser in our treatment groups were significantly higher than the spontaneous regression rate (p less than 0.001), suggesting that treatment by either cryotherapy or CO2-laser vaporization significantly changes the natural history of genital HPV infections. More patients and longer follow-up are still needed, however, to fully establish the efficacy of the current treatment modalities in gynecological HPV infections.

Factors associated with progression of cervical human papillomavirus (HPV) infections into carcinoma in situ during a long-term prospective follow-up.

In the course of a prospective study of 508 women with papillomavirus (HPV) lesions of the uterine cervix, 66 lesions that progressed into carcinoma in situ (CIS) were identified and treated by conization during a mean follow-up period of 35 months. The lesions were investigated with light microscopy and with in-situ DNA hybridization using 35S-labelled probes for HPV 6, 11, 16, 18, 31 and 33. After radical cone treatment, 11 of the 66 women (16.7%) have presented with a recurrent HPV infection. The recurrence rate increased with the duration of the follow-up period from less than 10% at the mean follow-up of 25 months to 16.7% at the most recent follow-up at 35 months. Most of these 66 HPV lesions (89%) presented with concomitant CIN in the first punch biopsy, but it is noteworthy that the other 11% presented without concomitant CIN. HPV DNA of at least one of the six types examined was found in 73% of the first biopsies and it is noteworthy that the so-called 'low-risk' types, HPV 6 and 11, were found as frequently as the 'high-risk' types, HPV 16 and 18 (18% and 17%, respectively). This would suggest a similarity in the biological behaviour of these two HPV groups. Although the concept of the 'high-risk' and 'low-risk' HPV types may remain at least partially valid, it is imperative to realize that infection by HPV 6 and 11 by no means excludes the possibility for clinical progression into CIS and eventually to an invasive carcinoma.

Cervical smears in assessment of the natural history of human papillomavirus infections in prospectively followed women.

The value of cervical (Papanicolaou) smears in monitoring the natural history of cervical human papillomavirus (HPV) infections was assessed in a series of 513 women prospectively followed since 1981. On each clinic visit, the patients were subjected to colposcopy accompanied by cervical smears and/or punch biopsies. The latter were analyzed by light microscopy for concomitant cervical intraepithelial neoplasia (CIN) and by transmission electron microscopy (TEM) for HPV particles as well as for HPV structural proteins. The stromal immunocompetent cell (ICC) infiltrates were phenotypically characterized using monoclonal antibodies for T-cell subsets, NK and K cells and Langerhans cells. HPV DNA typing was accomplished by Southern blot, spot and in situ hybridization using probes for HPV 6, 11, 16, 18 and 31. Lesions showing only changes consistent with HPV infection (HPV-NCIN) were associated with less severe atypia in cervical smears than were lesions with coexistent CIN (HPV-CIN). Normal smears were observed, however, in 24.7% of the cases with HPV-NCIN lesions, in 11.5% of cases with HPV-CIN I lesions but only exceptionally in cases with HPV-CIN II and III lesions (2.2% and 3.3%). The percentages of the different ICC phenotypes did not correlate with the atypia in cervical smears, but there was a shift towards the lower values of the T-helper/T-suppressor (OKT4+/OKT8+) cell ratio in parallel with increasing atypia. The possibility of latent HPV infection was suggested by the detection of viral particles, HPV antigens and HPV DNA in lesions shedding normal cells in the smears. The high-risk HPV types 16 and 18 were associated with the highest frequency of severely atypical cells; in the majority of cases, the low-risk types HPV 6 and 11 presented with less severe atypia. The first cervical smear seems to be of value as a predictor of the natural history of HPV lesions, as indicated by the fact that regression was inversely and progression directly related to initial cellular atypia. The present results confirm the intimate association between HPV infections and CIN. Although the biologic potential of the HPV infections seems to be dependent on multiple factors, routine cervical smears, because of their potential value in monitoring the natural history of this infection, should constitute an important means in the prospective follow-up of these patients.

Plasma renin activity and cAMP in termination of pregnancy induced by sulprostone.

Plasma renin activity (PRA), plasma concentrations of cyclic adenosine-3',5'-monophosphate (cAMP) and the serum levels of oestradiol, progesterone, chorionic gonadotrophin, potassium, sodium and calcium were estimated in connection with termination of pregnancy induced in 23 women by sulprostone, a derivative of prostaglandin E2. A rapid decrease in PRA was observed during and after infusion of 1000 micrograms or 1500 micrograms sulprostone. PRA returned to the initial values at 24 h after drug administration. The lowest levels of PRA were 36% and 51% of the initial values (P less than 0.001) in the two drug concentration groups. No significant changes were observed in the control group. The value for plasma cAMP did not correspond completely to the changes in PRA. Serum concentrations of oestradiol, progesterone and chorionic gonadotrophin showed a gradual decrease during drug administration. The changes in serum potassium, sodium and calcium were minimal. The decrease in PRA associated with sulprostone is very surprising. Our finding elucidates in part the still rather poorly known mechanisms and function of renin-angiotensin system in pregnancy.

Evolution of human papillomavirus infections in the uterine cervix during a long-term prospective follow-up.

A series of 513 women presented with cervical human papillomavirus (HPV) infections (with or without cervical intraepithelial neoplasia; CIN) have been prospectively followed up since 1981 (mean 25.6 months), at 6-month intervals, by colposcopy with PAP smears and/or punch biopsies. The latter were analyzed by light microscopy, as well as immunohistochemically for HPV structural proteins. HPV DNA typing was accomplished by Southern blot, spot, and in situ hybridization techniques using the DNA probes for HPV 6, 11, 16, 18 and 31. Of the 513 lesions, 24.8% regressed, 59.8% persisted, and 14.1% progressed, 11.9% having been coned due to progression to carcinoma in situ (CIS). So far, 1.1% of lesions have recurred after such a treatment. The natural history was significantly associated with the grade of CIN (HPV-NCIN versus HPV-CIN, p less than 0.01). The progression rate was highest (33.3%) and regression lowest (5.6%) in HPV 16 lesions. All the recurrent lesions disclosed HPV 16 DNA, this type being found most frequently in the severest lesions (CIN III). Depending on the hybridization technique used, changes in HPV type were found in 11-17% of the lesions during the follow-up. Noteworthy is the discovery of all the HPV types also in biopsies with no signs of HPV infection on light microscopy, suggesting a latent HPV infection in these 'regressor' lesions. The results confirm that cervical HPV infections show a natural history comparable to that of classical CIN. Although the high-risk character of HPV 16 (and HPV 18) was clearly established, the inherent potential for progression (25.6%) of the HPV 6/11 lesions should not be neglected in therapeutic considerations.

Human papillomavirus (HPV) infections involved in the neoplastic process of the uterine cervix as established by prospective follow-up of 513 women for two years.

A total of 513 women with cervical HPV infections have been followed-up since 1981 (mean 25.6 months) to establish the biological potential of HPV in cervical carcinogenesis. On each attendance, the patients were subjected to colposcopy accompanied by Papanicolaou (PAP) smears and/or punch biopsies. The latter were analysed for HPV particles on TEM, for the cytopathic changes of HPV, as well as for HPV structural proteins. The local immunocompetent cell (ICC) infiltrates are enumerated using ANAE-technique to define B-, MPS- and T cells, and monoclonal antibodies for T cell subsets, NK and K cells and Langerhans cells. HPV DNA typing was accomplished by Southern blot and spot hybridization using the DNA probes for HPV 6, 11, 16 and 18. Antibody titres for HSV were measured, and Chlamydia trachomatis isolations completed in cervical swabs. No correlation with the clinical course, e.g. regression (RE), persistence (PE), progression (PR) or recurrence (RC) of the HPV lesions could be established for the following factors; expression of HPV antigens, presence of HPV particles on TEM, Chlamydia in cervical swabs, the levels of HSV antibodies, and the levels of the ICCs. The OKT4+/OKT8+ cell ratio, however, was inversely correlated with PR, being most markedly reduced in recurrent lesions. Of the 513 lesions, 24.8% regressed, 59.8% remained persistent, and 14.1% progressed, 11.9% having been coned due to progression into CIS. So far, 1.1% of lesions have recurred after such a treatment. The progression rate was highest (45.5%) in HPV 16 lesions, followed by that (27.3%) in HPV 18 lesions, as contrasted to 0% and 13.3% for HPV 6 and 11, respectively. The results clearly confirm that cervical HPV infections are capable of progressing into CIS and thus show a natural history equivalent to that of classical CIN. The inherent potential of HPV 16 and HPV 18 lesions for clinical progression was clearly established, supporting the concept on HPV 16 and HPV 18 as the high risk HPV types in cervical carcinogenesis.

Coexistent chlamydial infections related to natural history of human papillomavirus lesions in uterine cervix.

To assess the role of Chlamydia trachomatis in the development of cervical intraepithelial neoplasia (CIN) and to evaluate possible synergism between chlamydiae and human papillomavirus (HPV) in this process, 418 women who had been prospectively followed up for cervical HPV infections at our clinic since 1981 were tested for chlamydiae. At each visit the patients were examined by colposcopy, and other investigations, such as Papanicolaou (Pap) smears, punch biopsies, urethral, and cervical swabs, were undertaken as indicated. In biopsy specimens the cytopathic changes of HPV, concomitant CIN, and the local immunocompetent cell infiltrates were analysed. The latter were measured and further identified using an alpha naphthyl acetate esterase (ANAE) technique to define B cells, macrophages, and T cells and using monoclonal antibodies to define T cell subsets, NK (natural killer cells), and Langerhans cells. Chlamydial isolation (4.1% in the cervix, and 3.6% in the urethra) did not positively correlate with the degree of cytological atypia in PAP smears or with the degree of CIN lesions associated with HPV. Chlamydial cervicitis did not affect the ANAE definable cell composition of the immunocompetent cell infiltrates in HPV lesions, or that of the immunocompetent cell subsets, including the ratios of T helper to T suppressor cells and the numbers of NK cells. Chlamydial infection did not alter the natural history of HPV lesions, of which 30% regressed, 53% persisted, and 17% progressed during follow up. The present results do not provide evidence to substantiate the hypothesis that chlamydiae and HPV might act synergistically in cervical carcinogenesis, or the view that C trachomatis may be a major aetiological agent of CIN lesions. Chlamydiae and HPV are covariables of sexual behaviour, and their concomitant appearance in sexually promiscuous women is best explained by this fact. As we do not have more direct evidence for the oncogenic potential of C trachomatis (as we have of HPV), it seems reasonable to consider that this agent is not a major cause of CIN, but rather a sexually transmitted agent commonly found in women with CIN because of their promiscuous sexual behaviour.

Determination of cyclic 3'-5'-adenosine monophosphate in plasma by RIA methods in the presence of EDTA.

Calcium ions definitively increase the ability of cyclic 3',5'-adenosine monophosphate (cAMP) to bind to its antibody. In contrast, ethylenedinitrolotetra-acetic acid as its disodium salt (EDTA) shows a dose-dependent inhibition of the binding of cAMP to its antibody. The less sensitive protein binding methods are not affected by EDTA. This is inconvenient, because the EDTA-plasmas can be stored frozen without breakdown of cAMP, but are unsuitable for sensitive radioimmunoassays. The aim of this investigation was to determine how calcium ions and EDTA affect the binding of cAMP to its antibody. Based on these results, we describe an alternative procedure for commercial RIA methods for the determination of cAMP in EDTA-plasma. The almost complete inhibition of the hapten-antibody reaction by EDTA can be abolished by adding an equivalent concentration of calcium ions to the reaction medium together with trichloroacetic acid. Thus a simple and rapid procedure was found for the storage of plasma and for the determination of plasma cAMP.

Natural killer (NK) cells with HNK-1 phenotype in the cervical biopsies of women followed-up for human papillomavirus (HPV) lesions.

Local immunocompetent cell infiltrates in 263 cervical punch biopsies of women followed-up since 1981 (16 +/- 14 months, M +/- SD) for an established Human papillomavirus (HPV) lesion with or without concomitant cervical intra-epithelial neoplasia (CIN) were analysed for presence of human natural killer (NK) cells, defined by the monoclonal antibody HNK-1 (Leu-7) using the avidin-biotin peroxidase complex (ABC) technique. HNK-1+ cells remained at a constant low level (1.8 to 3.0% of the cells) in the different types of HPV lesions (flat, inverted, or papillomatous condylomas), their percentages (range 1.3 to 2.5% of cells) remaining similarly unaffected by the severity of associated CIN. As shown to be the case with human NK cell function in the peripheral blood, the percentages of local HNK-1+ cells did not evidence any age-dependence. Furthermore, the intensity of the infiltrate did not correlate with the relative levels of HNK-1+ cells in the biopsies. Slightly (but not significantly) higher levels (2.5%) of HNK-1+ cells were found in the first biopsies of the HPV lesions found to regress during the follow-up period (28.8% of cases), when compared with those (1.7% and 1.8%, respectively) in persisting lesions (52.1% of cases) or progressing lesions (19.1% of lesions). The results are discussed in terms of the proposed immune surveillance function of human NK cells in malignant growths, and the conclusion is drawn that the present study does not provide any firm evidence to suggest that local NK cell function would contribute significantly to the clinical behavior of the cervical HPV lesions.

Human papillomavirus (HPV) DNA sequences demonstrated by in situ DNA hybridization in serial paraffin-embedded cervical biopsies.

An in situ DNA hybridization technique was used to identify various types of Human papillomavirus (HPV) in paraffin sections of serial punch biopsies taken from 64 patients having colposcopy because of abnormal smears. There women were in fact 64 consecutive patients out of 505 attending our clinic (at 6-month intervals) since 1981 for HPV infections. HPV 6 DNA sequences were found in 20%, HPV 11 in 17%, HPV 16 in 8% and HPV 18 in 5% of the 64 biopsies analysed with this method so far. More than 60% of HPV 6-positive lesions belong to HPV-NCIN (HPV lesion without concomitant CIN) or HPV-CIN I categories, as contrasted with HPV 16-positive lesions, 80% of which belong to HPV-CIN II and III categories. None of the HPV 16- or HPV 18-infected lesions regressed, as contrasted with 23% and 45% in those infected with HPV 6 and HPV 11, respectively (P less than 0.01). The rate of progression (38.4% and 45.5%, respectively) was markedly lower in HPV 6- and HPV 11 lesions as compared with that (80%) of HPV 16 lesions. The present results while supporting the concept on HPV 16 and HPV 18 as the high risk HPV types in cervical carcinogenesis also emphasize the applicability of the in situ DNA hybridization as a powerful tool in analysis of the specific HPV DNA sequences in routinely progressed biopsies of these lesions.

Electron microscopy in assessment of the biological behavior of human papillomavirus infections in the uterine cervix.

To asses the natural history of human papillomavirus (HPV) infections in uterine cervix, currently implicated in etiology of cervical cancer, a prospective follow-up study has been conducted for 418 women at our clinic since 1981. The present communication summarized the current follow-up data of these patients, with special emphasis on detection of the virus in cervical punch biopsies, as correlated with other characteristics pertinent to the clinical behavior of cervical HPV infections. On each attendance, the patients are subjected to colposcopy accompanied either by Papanicolaou (PAP) smears or punch biopsies. The latter are analyzed for the cytopathic changes of HPV, for concomitant cervical intraepithelial neoplasia (CIN), for HPV structural proteins with IP-PAP technique as well as on transmission electron microscopy (TEM) for the presence of HPV particles. The local immunocompetent cell (ICC) infiltrates are analyzed using ANAE technique to define B cells, MPS cells and T cells and monoclonal antibodies (McAb) for T cell subsets, NK (natural killer) cells and Langerhans cells. HPV particles were disclosed with equal frequency (approx. 65%) in all three types of HPV lesions. Surprisingly, HPV particles were present in 70% of the biopsies derived from the regressed lesions (e. g. in those without histological evidence of HPV lesions), suggesting a possibility of a latent HPV infection. Presence of viral particles did not bear any direct correlations with the expression of HPV antigens, intensity or cellular composition of the ICC infiltrate, defined by ANAE or using McAb. Presence of HPV particles was not a major prognostic determinant, whereas the clinical course was most significantly influenced by the grade of HPV-associated CIN, to which regression was inversely and progression directly related. The results clearly confirm that cervical HPV infections are capable of progressing into carcinoma in situ and thus present with a natural history equivalent to that of classical CIN.

Natural history of cervical human papillomavirus (HPV) infections based on prospective follow-up.

To assess the natural history of human papillomavirus (HPV) lesions in the uterine cervix, a prospective follow-up of untreated lesions has been conducted since late 1981. The present report summarizes the data on 343 women with cervical HPV lesions currently followed-up for a mean of 18.7 (SD 15.2) months by colposcopy and PAP smears (group B) or by additional punch biopsy (group A). Initially these two groups were classified on the first PAP smears, presenting with HPV-induced cytopathic changes, and either with (group A) or without (group B) concomitant changes suggestive of cervical intraepithelial neoplasia (CIN). The clinical course of the HPV lesions could not be predicted adequately from the findings of the first PAP smears, as evidenced by the higher progression rate (15.4%) in the 214 women initially classified in group B, compared with 11.6% in the 129 women classified in group A. Furthermore, the number progressing to carcinoma in situ requiring conization was equal (seven patients) in the two groups. This necessitated a more flexible approach to follow-up, permitting transfer of patients between groups, which resulted in a final allocation of 261 women to group A, and 82 to group B. To date, 25% of the total of 343 HPV lesions have regressed, 61% have persisted, and 14% have progressed. Of the latter, a total of 14 (4.1%) have been coned due to progression to carcinoma in situ. The rate of regression seems to be inversely related, and progression directly related, to the degree of HPV-associated CIN.(ABSTRACT TRUNCATED AT 250 WORDS)