Frank Bergman

Type-Specific Persistence of Human Papillomavirus DNA before the Development of Invasive Cervical Cancer

BACKGROUND Infection with the human papillomavirus (HPV) has been established as a cause of cervical cancer, but the association between a positive test for HPV DNA and the risk of the subsequent development of invasive cervical cancer is unknown. METHODS In a study of women who participated in a population-based screening program for cancer of the cervix in Sweden from 1969 to 1995, we compared the proportion of normal cervical smears (Pap smears) that were positive for HPV DNA among 118 women in whom invasive cervical cancer developed an average of 5.6 years later (range, 0.5 month to 26.2 years) with the proportion of HPV DNA-positive smears from 118 women who remained healthy during a similar length of follow-up (controls). The control women were matched for age to the women with cancer, and they had had two normal Pap smears obtained at time points that were similar to the times of the baseline smear and the diagnosis of cancer confirmed by biopsy in the women with cancer. RESULTS At baseline, 35 of the women with cancer (30 percent) and 3 of the control women (3 percent) were positive for HPV DNA (odds ratio, 16.4; 95 percent confidence interval, 4.4 to 75.1). At the time of diagnosis, 80 of the 104 women with cancer for whom tissue samples were available (77 percent) and 4 of the 104 matched control women (4 percent) were positive for HPV DNA. The HPV DNA type was the same in the base-line smear and the biopsy specimen in all of the women with cancer in whom HPV DNA was detected at base line. None of the control women had the same type of HPV in both smears. CONCLUSIONS A single positive finding of HPV DNA in a Pap smear confers an increased risk of future invasive cervical cancer that is positive for the same type of virus as identified earlier.

Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection

Smoking, nutrition, parity and oral contraceptive use have been reported as major environmental risk factors for cervical cancer. After the discovery of the very strong link between human papillomavirus (HPV) infection and cervical cancer, it is unclear whether the association of these environmental factors with cervical cancer reflect secondary associations attributable to confounding by HPV, if they are independent risk factors or whether they may act as cofactors to HPV infection in cervical carcinogenesis. To investigate this issue, we performed a population-based case–control study in the Västerbotten county of Northern Sweden of 137 women with high-grade cervical intra-epithelial neoplasia (CIN 2–3) and 253 healthy age-matched women. The women answered a 94-item questionnaire on diet, smoking, oral contraceptive use and sexual history and donated specimens for diagnosis of present HPV infection (nested polymerase chain reaction on cervical brush samples) and for past or present HPV infections (HPV seropositivity). The previously described protective effects of dietary micronutrients were not detected. Pregnancy appeared to be a risk factor in the multivariate analysis (P< 0.0001). Prolonged oral contraceptive use and sexual history were associated with CIN 2–3 in univariate analysis, but these associations lost significance after taking HPV into account. Smoking was associated with CIN 2–3 (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.7–4.0), the effect was dose-dependent (P = 0.002) and the smoking-associated risk was not affected by adjusting for HPV, neither when adjusting for HPV DNA (OR 2.5, CI 1.3–4.9) nor when adjusting for HPV seropositivity (OR 3.0, CI 1.9–4.7). In conclusion, after taking HPV into account, smoking appeared to be the most significant environmental risk factor for cervical neoplasia.

A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma

Persistent human papillomavirus (HPV) infection is an established cause of cervical cancer, but the role of other sexually transmitted agents, most notably Chlamydia trachomatis, has not been well defined. The women participating in the population‐based cervical cancer screening program in Västerbotten county of Northern Sweden were followed up for up to 26 years to identify 118 women who developed cervical cancer after having had a normal Pap smear (on average 5.6 years later; range 0.5 months–26 years). As controls, we selected another 118 women who were matched by birth cohort, time‐point of sampling of the baseline normal smear and who had a normal smear at the time when the corresponding case was diagnosed with cancer. The Pap smears and cervical cancer biopsies were analyzed by PCR for C. trachomatis DNA and for HPV DNA. At baseline, C. trachomatis DNA was present in 8% of cases but not among any one of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6–∞).The presence of C. trachomatis and of HPV were not interrelated. Whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short lag time before cancer diagnosis. Whereas most women who were HPV DNA‐positive in the prediagnostic smear were also positive for the same virus in the cervical cancer biopsy, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the subsequent cervical cancer. In conclusion, a prior cervical C. trachomatis infection was associated with an increased risk for development of invasive cervical cancer.

Genetic alterations in cervical carcinomas: Frequent low-level amplifications of oncogenes are associated with human papillomavirus infection

The development of cervical carcinoma is closely associated with HPV infection. However, other genetic alterations also play an important role. In this study, we analyzed copy number alterations of several oncogene loci in a panel of 84 cervical tumors. Sixty‐five (77%) tumors were HPV DNA‐positive, and most were infected with type 16 or type 18 or both. The oncogenes studied include PIK3CA at 3q26.3, TERT at 5p15.33, C‐MYC at 8q24, CCND1 at 11q13.3, ERBB2 at 17q21.2 and locus region 20q13.2. Amplification of 1 or more genes was detected in 55 (65%) cases using interphase FISH. PIK3CA was amplified in 43% of tumors, followed by TERT (33%), 20q13.2 (30%), ERBB2 (29%), C‐MYC (25%) and CCND1 (12%). Most tumors showed low‐level amplification with 3–7 copies of these genes, and complex changes involving 3 or more genes occur more frequently in tumors at advanced stages. Increased protein expression of c‐erbB2 and c‐myc was observed in tumors with the corresponding gene amplification. Oncogene alterations were found more often in HPV‐infected cases, particularly for C‐MYC and TERT. These findings indicate that HPV‐associated cervical carcinomas bear frequent alterations of these genes, which may have critical biologic impact on the development and progression of carcinoma of the uterine cervix.

A prospective study on the risk of cervical intra-epithelial neoplasia among healthy subjects with serum antibodies to HPV compared with HPV DNA in cervical smears

To estimate the risk of developing cervical intra‐epithelial neoplasia (CIN) among women exposed to human papillomavirus (HPV) type 16, we performed a prospective study in a population‐based cohort of more than 15,000 women followed for 34.9 months. Seventy‐four women developed CIN during follow‐up and were matched for age, time of sampling and area of residence with 148 women who remained CIN‐free during follow‐up. The blood samples taken at enrollment were tested for serum antibodies to HPV types 16, 18 and 33 capsids. Cervical smears or biopsies were analyzed for the presence of HPV DNA by nested PCR using HPV general primers and by HPV 16‐ and 18‐type‐specific PCR. HPV serology and HPV‐PCR were in good agreement, particularly when the blood sample and the Pap smear were taken less than 6 months apart. HPV DNA was found in 88% of cases and 4% of controls, whereas HPV 16 DNA was present in 44% of cases and in 1 of 142 controls. HPV‐16‐seropositive women had a 3‐fold increased risk of developing CIN. The risk was highest among women younger than 35 years of age, of whom an estimated 3.4% of HPV‐16‐seropositive and 0.5% of seronegative women developed CIN. Since the risk associated with HPV‐16 seropositivity (a measure of past or present infection) was 35‐fold lower than that of HPV DNA (present infection), most infections appear to be eliminated before CIN develops. In conclusion, HPV 16 infection does confer an excess risk of CIN development, and HPV DNA detection has a high predictive value for the presence of high‐grade CIN.

Fine-needle aspiration biopsy in diagnosis, and classification of ovarian carcinoma

The authors assess the value of fine‐needle aspiration biopsy for determining malignancy and the type of ovarian carcinoma. Smears of fine‐needle biopsy specimens from 80 cases of palpable ovarian tumors were examined for malignancy. The cases were followed‐up to a definite histologic diagnosis or a final clinical diagnosis. The diagnostic accuracy of the method was 93–95%. The possibility of classifying ovarian carcinoma with fine‐needle aspiration biopsy specimens was estimated in 52 cases of ovarian carcinoma. Subsequent operation and histologic examination showed good agreement between the cytologic and the histologic diagnoses.

Tumors of the minor salivary glands: A report of 46 cases

This paper records the frequency and the types of all 46 verified tumors of the minor salivary glands seen during a 8‐year period at the University departments of Pathology and Oral Histopathology, Umeå, Sweden. The series consisted of 39 benign mixed tumors, 1 oxyphil adenoma, 2 malignant mixed tumors, 3 mucoepidermoid carcinomas and 1 adenoid cystic carcinoma. This series was compared with other series regarding classification and pathologic anatomy. Attention has been called especially to differences in the reported incidences of malignant tumors: in the present series the incidence was unusually low. It is proposed that the nature of the hospitals where most of the published materials were collected could explain the divergencies between different series, which thus seem to represent biased samples. This implies that the widely accepted belief that an unusually high percentage of malignant tumors is found in the minor salivary glands must be seriously questioned.

An analysis of data on human hepatic bile. Relationship between main bile components, serum cholesterol and serum triglycerides

Hepatic bile samples were taken from the common duct during interval operations for gallstone disease, performed under standardized conditions. Prior to operation serum cholesterol and triglycerides levels were determined. The concentrations of Cholesterol (Chol), phospholipids (Lip P) and of the three major bile acids (BA) were determined in ninety-seven samples. The data were subjected to statistical analysis. A highly significant rank correlation was found between the Chol- and the Lip P molar fractions. The rank correlation between the Chol molar fraction and the BA/Lip P ratio was highly significantly negative. Reasons are given why the observed intraindividual differences are interpreted as reflecting interindividual changes. The conclusion is that just as in the animal model, a rise of Chol in human hepatic bile is accompanied by a decrease of the BA/Lip P ratio. A significant correlation was found between chenodeoxycholic acid (CDCA), and the ratio between the two other main bile acids (CA/DCA). High lithogenicity was associated with low CDCA- and high DCA values. In a mathematical representation valid in the sense of a rank correlation, the bile/serum Chol ratio rose with increasing DCA values combined with increasing absolute differences between the other acids. Serum triglycerides were negatively correlated with the BA molar fraction and with the absolute concentration of BA. As a result there was an association between serum triglycerides and lithogenicity.

A comparative study of the acute inhalation toxicity of smoke from TiO2-hexachloroethane and Zn-hexachloroethane pyrotechnic mixtures

Rats were exposed to white smoke generated from mixtures of titanium dioxide-hexachloroethane (TiO2-HC) and zinc-hexachloroethane (Zn-HC), respectively, in an inhalation chamber operated in the static mode. The dose was varied by varying the amount of smoke mixture and/or the exposure time. The acute inhalation toxicity of TiO2-HC smoke was much lower than the Zn-HC smoke. Thus, the animals survived exposure to TiO2-HC smoke, even at relatively high smoke concentrations. This smoke was irritating to the animals and minor, acute inflammatory changes were seen in lung tissue. In contrast, Zn-HC smoke was very toxic and caused lethal injuries to the experimental animals, even at relatively low concentrations. Pulmonary injuries were extensive and death was due to blood congestion with pulmonary oedema. Since the TiO2-HC and Zn-HC mixtures form TiCl4 and ZnCl2, respectively, a separate study was performed in which rats were exposed to TiCl4 gas or ZnCl2 aerosol. No animals died from exposure to TiCl4 at concentrations between 370 and 2900 mg/m3 for 10 min. The LC50 of ZnCl2 was found to be around 2000 mg/m3 during a 10-min exposure period. The difference between the two types of smoke is explained by the difference in toxicity between TiCl4 and ZnCl2.

Wound healing with Ordinary Adhesive tape: A Clinical and Experimental Study

A report is given of the good clinical experience the authors have had of the treatment of wounds with ordinary adhesive tape. These experiences are compared with the results of experiments on animals concerned with the healing time of wounds and histological and bacteriological conditions.