| 1. |
- Andersson, Sonia
(författare)
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The role of human papillomavirus in adenocarcinoma of the uterine cervix
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cervical carcinoma is the third most common malignant disease in women worldwide. The absolute frequency of adenocarcinoma of cervix uteri has increased during the last decade and accounts for about 15-20% of invasive cervical cancers. Human papillomavirus (HPV) is considered the most important factor in the development of cervical squamous cell carcinomas. HPV DNA has been identified in about 95% of cervical carcinomas. Adenocarcinomas of the cervix are also linked to HPV but the correlation is probably less pronounced. The aim of this study was to analyse cervical adenocarcinomas with regard to the presence of HPV, the frequency of a specific mutation of the E6 gene of HPV 16 and the presence of p53 polymorphism, all of which may influence the risk of acquiring this carcinoma. Moreover, we intended to describe the symptoms and methods of detection of this tumour. Material and methods: For the identification and typing of HPV, 173 cervical adenocarcinomas were analysed with Polymerase Chain Reaction (PCR), Single-Strand Conformation Polymorphism (SSCP) and/or DNA sequencing. In HPV16 positive cervical adenocarcinomas (28 cases), the E6 gene was analysed using the PCR-SSCP method for identification of the specific mutation (L83V). The results were correlated to those of 103 HPV 16 positive precancerous cervical lesions and 31 HPV 16 positive invasive cervical squamous cell carcinomas. For the analysis of p53 polymorphism, a PCR and SSCP based technique was used on 111 specimens and 188 controls (cell samples from women with normal cytology). Results: HPV was present in 68% of 173 adenocarcinomas. There was a significant correlation between the presence of HPV and age, illustrated by the fact that adenocarcinomas in younger women were more often HPV-positive than those in older women (p<0,001). The most common types of HPV were 18, 16 and 45. The HPV16 E6 variant L83V was present in 54% of the invasive adenocarcinomas. However, the predominance of the HPV16 variant observed earlier in squamous cell carcinomas was not seen in adenocarcinomas. Homozygosity for arginine in codon 72 of the p53 gene was present in 71% of the adenocarcinomas but only in 47% of the samples from healthy female controls (p<0,001). These results support the hypothesis that women with homozygosity for arginine in the p53 gene codon 72 may have an increased risk of developing adenocarcinoma of the cervix. Our data demonstrate that 70% of the cervical adenocarcinomas were detected due to manifested symptoms (mainly vaginal bleeding) and 92% of the women tested with a Pap smear had normal results within three years before the cancer was detected. Conclusion: HPV was identified in 68% of the cervical adenocarcinomas, and was predominant in younger women. Hence, the prevalence of HPV in women with cervical adenocarcinomas is age-related. The most frequently occurring type of HPV was 18. Women with homozygosity for arginine of the p53 gene may have an increased risk of developing cervical adenocarcinoma. Since there has been an increase in the incidence of adenocarcinoma of cervix uteri among younger women, and Pap smear screening is inadequate for its detection, there is a need for other screening techniques. Repetitive HPV testing and analysis of p53 may help identify women at risk.
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| 2. |
- Druvefors, Emma, 1985-
(författare)
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Fertility in Inflammatory Bowel Disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammatory bowel diseases (IBD) often present in adolescence or early adulthood and is thus frequently diagnosed in men and women in their reproductive age. Previous population-based studies of fertility in patients with IBD are scarce.From the Swedish National Patient Register (NPR) all patients diagnosed with IBD of fertile age between 1964–2014 were identified. Statistics Sweden identified a matched reference cohort (ratio 1:5) from the general population matched for sex, age and place of birth. Children born were identified through the Medical Birth Register and the Swedish Multigeneration Register. For subgroup analyses information about medication was collected through Medical Drug Register and information about socioeconomic status from Longitudinal Integrated Database for Health Insurance and Labour Market Studies. From the SWedish Inflammatory Bowel disease quality REGister (SWIBREG) a cohort of women with UC who underwent colectomy 2000–2020 was identified. Demographic data from SWIBREG and information from a study specific questionnaire regarding reproductive history and voluntary childlessness were analysed.From the NPR 27,331 women and 29,104 men with IBD were identified, corresponding to 272,793 matched individuals.The fertility rate in women with IBD was 1.52 (standard deviation [SD] 1.22) births per 1000 person-years, compared with 1.62 (SD 1.28) (p <0.001) in the matched reference cohort. Fertility was negatively affected mainly in women with Crohn's disease (CD) and IBD-unclassified (IBD-U) and to a lesser extent in ulcerative colitis (UC). Disease activity, bowel resections and, in the case of CD, also perianal disease further adversely affected fertility. For women with UC and IBD-U, but not for women with CD, fertility improved throughout the study period. Contraceptive use was higher in female IBD patients, both before and after the diagnosis.In total 2,989 women underwent colectomy during the study period. Reconstruction with ileal pouch anal anastomosis (IPAA) and ileorectal anastomosis (IRA) was used to about the same extent in UC and IBD-U, although this was rare in CD. Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (HR 0.65, CI 0.61–0.69), with least impact for operations that left the rectum intact (HR 0.79, CI 0.70–0.90). When the comparison was made within the group of patients undergoing colectomy, fertility in female patients remained nearly unaffected after IRA in all subtypes of IBD, but was impaired after IPAA, especially in UC (HR 0.67 CI 0.50–0.88), and after completion proctectomy in all subtypes of IBD (CD 0.61 CI 0.38–0.96), UC HR 0.65, CI 0.49–0.85 and IBD-U0.68, 0.55–0.85).The survey regarding reproductive behavior after colectomy was completed by 214 (73%) out of 294 eligible women identified in SWIBREG. The desire to have children was negatively affected by disease onset in 59% of the women, colectomy in 44% and by reconstruction in 37%. Altogether, 39% women with UC estimated that they chose to have fewer children in the end because of the disease, but only 10% expressed that the disease made them completely restrain from having children. On the contrary 37% of the women reported that they had experienced difficulties to conceive and 19% expressed that they could not conceive at all. Of the women undergoing reconstruction post colectomy, 37% reported that the choice of reconstruction method was influenced by their desire to have children. Difficulty conceiving was more commonly reported after reconstruction with IPAA (odds ratio [OR] 5.54) than IRA (OR 2.57).Men with IBD also had lower fertility rate compared with the matched reference population, although the impact on parity was limited; 1.28 (SD 1.27) versus 1.35 (SD 1.31) (p < 0.001). Fertility in men was nevertheless impaired in all IBD subtypes. The disease severity measured as order of hospital admissions (UC and IBD-U), intensity of medical treatment (CD), and bowel surgery (IBD-U) were further associated with impaired fertility in men. In the 3,771 men undergoing colectomy during the study period, fertility was only marginally (HR 0.89, CI 0.85–0.94) impaired, regardless of reconstruction.In conclusion, women with IBD have only slightly reduced fertility rates compared with the matched reference population with some exceptions. In non-surgically treated patients, the impact was most pronounced in female patients with CD. Women post colectomy have a particularly marked impact on fertility independent of IBD subtype. Bowel reconstruction with IPAA and proctectomy had a pronounced negative impact on fertility, while fertility was not further affected after IRA. More than half of the women with UC post colectomy reported that developing UC has affected their desire to have children, but difficulty to conceiving is also commonly reported. The impact of IBD in men was only minor.
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| 3. |
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| 4. |
- Lindquist, David
(författare)
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Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.
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| 5. |
- Lindström, Annika, 1953-
(författare)
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Prognostic factors for squamous cell cervical cancer : tumor markers, hormones, smoking, and S-phase fraction
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cervical cancer is the second most common malignancy in women worldwide and one of the leading causes of cancer mortality globally. In patients with invasive cervical cancer prognostic factors are of value for the choice of treatment, monitoring of treatment and follow-up. The most important clinical prognostic factors are stage, tumor volume, parametrial infiltration, vascular invasion, lymph node metastases, and distant metastases. An improved estimation of the prognosis of cervical cancer is desirable, especially in early cancer stages.The aim of this research was to study possible associations between tumor markers, female sex steroids, smoking, S-phase fraction (SPF), and prognosis in invasive squamous cell cervical cancer (SCC). The study comprised 190 patients with SCC, stages IB-IV, admitted to the Department of Gynecologic Oncology at Norrland University Hospital in Umeå between September 1984 and October1990. Ten year mortality was estimated.In study I, of a total of 103 patients, it was found that increased tumor growth, measured by the DNA SPF, was associated with elevated serum progesterone and smoking in the premenopasual patients and with aneuploidy in the whole group.In study II, comprising 128 patients, survival length related to hormone levels and SPF was evaluated in women who died of cervical cancer. In both pre- and postmenopausal women, who died of cervical cancer, SPF at or above 12% was correlated with reduced survival. There was significant positive correlation between a low serum estradiol/progesterone ratio and short survival in those premenopausal women who died of cancer (p=0.02).In study III, ten-year follow-up results in 128 women were compared with the expression of ten relevant tumor markers, assessed by immunohistochemistry. The overall ten-year survival rate in patients with low COX-2 and high CD4+ expression was 76%, versus 53% in the remaining women. The survival rate with absent p53 and high COX-2 expression in the tumors was 42%, versus 71%, while the corresponding figure for the combination of high COX-2 intensity and expression of c-myc was 27%, versus 62%. None of the single markers correlated significantly with outcome in the final Cox regression analyses, while five combinations did.Study IV addressed possible associations between selected tumor markers and cofactors in SCC. Ten tumor markers were examined in 128 patients. Smoking habits and previous oral contraceptive use were recorded. Serum estradiol and progesterone levels were evaluated in 80 women. Highly significant associations were found between strong c-myc staining and increased progesterone, low EGFR staining and high serum estradiol, and absence of p53 staining and smoking. There was an association between absence of p53 and high serum progesterone.In study V, LRIG1 expression was studied in 128 patients and was compared with expression of nine other tumor markers, smoking history, hormone levels, and prognosis. LRIG1 appears to be a significant prognostic predictor in early stage SCC, independent of the other tumor markers that were studied. Diminished expression in advanced cancer stages and the inverse correlation to serum progesterone and smoking indicate that LRIG1 is a tumor suppressor in squamous cell cervical cancer.Conclusion: The results of these studies support a role of progesterone as a promoter of cervical cancer and indicate that smoking is associated with tumor progression. A combination of tumor markers might be of help in prognostic prediction. LRIG1 acts as a tumor suppressor. These findings might contribute towards greater understanding of prognostic prediction of squamous cell cervical cancer.
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