LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking.

The aim is to evaluate LRIG1 as a prognosis predictor and correlations to cofactors in squamous cell cervical cancer. LRIG1 expression was studied in 128 cervical carcinomas and was compared with expression of nine other tumor markers. Smoking history was registered and pretreatment serum estradiol and progesterone levels were evaluated in 79 women. At clinical stage IB, 58% of the tumors showed LRIG1 expression, but there was a decline by increasing stage (33% in stage IV). Ninety percent of women with stage IB cancer and LRIG1 positivity survived, as compared to 64% without expression (P = 0.02). LRIG1 expression did not predict prognosis in advanced stages, but in stage IIA there was a marked relative difference, with 75% survival in tumors expressing LRIG1, as compared to 43% in those without. No correlation was found between LRIG1 and the other nine tumor markers studied. A high serum progesterone and smoking correlated to absent LRIG1 expression. We conclude that LRIG1 appears to be a significant prognosis predictor in early-stage cervical cancer, independent of the other tumor markers that were studied. Diminished expression in advanced stages and the inverse correlation to serum progesterone and smoking indicates that LRIG1 is a tumor suppressor in cervix.

Matrix metalloproteinases-2 and -9 in cervical cancer: different roles in tumor progression.

The incidence of uterine cervical cancer has increased slightly in Western countries, with an increase in relatively young women. Overexpression of matrix metalloproteinases (MMPs)-2 and -9 has turned out as a prognostic factor in many cancers. We compared the expression of the proteins MMP-2 and MMP-9 in cervical primary tumors with clinical outcome and risk factors of cervical cancer. One hundred sixty-one patients with cervical cancer treated in Umeå University Hospital or Sahlgrenska University Hospital, Sweden, between 1991 and 1995 were included in the study. Paraffin-embedded tissue samples obtained prior to treatment were examined immunohistochemically by specific antibodies for MMP-2 and MMP-9. Forty-two percent of the tumors were intensively positive for MMP-2 and 31% for MMP-9. Nineteen percent of the samples were intensively positive for both proteinases and 47% negative or weak for both. Overexpression of MMP-2 seemed to predict unfavorable survival under Kaplan-Meier analysis and in the multivariate analysis. Early sexual activity and low parity seemed to correlate to overexpression of MMP-2. MMP-9 was not associated with survival or sexual behavior. Intensive MMP-9 was noted in grade 1 tumors. We conclude that MMP-2 and MMP-9 have different roles in uterine cervical cancer. MMP-2 could be associated with aggressive behavior, but MMP-9 expression diminishes in high-grade tumors.

The clinicopathologic significance of laminin-5 gamma2 chain expression in cervical squamous carcinoma and adenocarcinoma.

Carcinoma of the uterine cervix is one of the most prevalent malignancies among women in developing countries and the third most common type worldwide. Squamous cell carcinoma predominates in the cervix uteri, while adenocarcinoma and adenosquamous carcinomas represent about 10-15% of all cervical cancers. Many studies have confirmed that the human papillomavirus (HPV) is the most important etiologic factor in the development of cervical cancer. The aim of our study was to investigate the expression of the laminin-5 gamma2 chain in primary malignancies of the cervix uteri and to focus on the clinicopathologic significance of the expression of the laminin-5 gamma2 chain in cervical squamous carcinoma and adenocarcinoma with respect to age and survival of the patients. The study consisted of a total of 89 cases of invasive cervical cancer (54 squamous carcinomas and 35 adenocarcinomas). The laminin-5 gamma2 chain was found in 80% of all the squamous carcinoma and in 66% of cervical adenocarcinoma. There was no correlation of the high expression of laminin-5 with survival. The univariate analysis in squamous cell carcinoma showed that factors such as the stage of the disease and positive lymph nodes had an impact on the survival of the patients, whereas in the multivariate analysis, only age at diagnosis was an independent prognostic factor. However, in cases with cervical adenocarcinoma, only the stage of the disease was an independent prognostic factor. There was no difference between HPV-positive and HPV-negative tumors concerning the high expression of laminin-5 gamma2 chain. Our results indicate that the majority of the primary cervical tumors, especially squamous cell carcinoma, showed expression of laminin-5 gamma2 chain immunoreactivity. Independent prognostic values for the survival of the patients were age and stage of the disease.

Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level.

The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression in trophoblast has been implied as one of the mechanisms of fetal tolerance. However, the expression of membranal FasL by trophoblast has failed to explain this role of FasL. Two objections can be raised: (1) there have been contradictions considering which trophoblast cells, syncytiotrophoblast (ST) or cytotrophoblast, express FasL; (2) in vivo and in vitro studies have shown that the membranal form of FasL evokes inflammatory response and thus may promote fetal rejection. Using different assays and the FasL-specific antibody G247-4 we demonstrate beyond doubt that in vivo, (1) FasL is produced by and stored in the first trimester human ST only and (2) the human ST lacks surface membranal FasL. Instead, FasL, loaded in microvesicles, is stored in cytoplasmic granules. These results complement the recent in vitro studies of the microvesicular form of FasL secretion by cultured trophoblast cells, and suggest that placental FasL is synthesized by villous ST, stored in microvesicular form and secreted as exosomes. Secretion of the exosome-associated form of FasL may be one mechanism by which the placenta promotes a state of immune privilege. Additionally, FasL expression in Hofbauer cells is also demonstrated.

Correlations between serum progesterone and smoking, and the growth fraction of cervical squamous cell carcinoma.

BACKGROUND: Possible correlations between growth fraction of squamous cervical carcinomas and serum progesterone (se-P) concentrations, smoking habits and DNA ploidy were studied. MATERIALS AND METHODS: The DNA S-phase fraction (SPF), measured by flow cytometry was used as a marker of tumour growth in 103 cases of squamous cervical cancer stage IB-IV. DNA-ploidy (peridiploidy vs. aneuploidy), Se-P, se-Estradiol, smoking habits, parity, menopausal status, clinical stage and histopathological grading were compared to SPF < 14% vs. SPF > or = 14%. RESULTS: Aneuploidy, (odds ratio (OR) 10.0), se-P > or = 2.6 nmol/l (OR 7.5) and smoking (OR 3.0) were significantly associated with SPF > or = 14%, after adjustments for all factors included in the study. The association with se-P and smoking was attributed to an increased risk for the premenopausal women in the study. DISCUSSION: In this study an increased tumour growth was associated with increased leves of se-P, smoking and aneuploidy in women with invasive squamous cervical carcinoma. This study seems to experimentally confirm epidemiological studies, where smoking and long-term use of oral contraceptives have been linked to cervical neoplasms.

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.

Iohexol clearance for renal function measurement in gynaecologic cancer patients.

PURPOSE: To determine a valid and practical routine for glomerular filtration rate measurement in gynaecologic cancer patients. MATERIAL AND METHODS: The established method, endogenous creatinine clearance, was compared to 51Cr-EDTA clearance and contrast medium clearance in 68 women with various gynaecologic carcinomas. Contrast medium clearance was determined in association with conventional urography (iohexal 300 mg I/ml, 40 ml) for evaluation of urinary tract involvement by the tumour. Automated X-ray fluorescence analysis equipment was used for the plasma analysis of iohexol and clearance calculations. Endogenous creatinine clearance and 51Cr-EDTA clearance were determined according to standard routine procedures. Simultaneous determinations of contrast medium clearance and 51Cr-EDTA clearance (n = 33), contrast medium clearance and endogenous creatinine clearance (n = 50), as well as 51Cr-EDTA clearance and endogenous creatinine clearance (n = 30) were compared. RESULTS AND CONCLUSION: The mean differences were -2.8 (SD 6.6), -1.8 (SD 22.3), and 2.7 (SD 18.3) ml/min/1.73 m2, respectively. It is concluded that contrast medium clearance is as adequate as 51Cr-EDTA clearance for glomerular filtration rate measurement. We suggest that contrast medium clearance should replace endogenous creatinine clearance, especially in patients referred for urography.

Doxorubicin-melphalan with and without cisplatin in advanced ovarian cancer--ten-year survival results from a prospective randomized study by the Swedish Cooperative Ovarian Cancer Study Group.

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m2 + melphalan (M) 0.4 mg/kg was compared with A + M + cisplatin (C) 50 mg/m2 given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs. 50%, p < 0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p < 0.006) and in median survival time (26 months vs. 19 months, p = 0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage. Objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.

Association between orosomucoid types and cancer.

Orosomucoid (ORM) is a polymorphic acute-phase reactant with immunosuppressive properties. Previous investigations have suggested that ORM and other acute-phase reactants may act as blocking factors protecting tumor cells against immunological attack, thereby contributing to the 'immune escape' of the tumor. ORM types were studied by isoelectric focusing and immunoprinting in patients with carcinoma of the breast, lung, ovary and endometrium and in population controls. In accordance with a previous study, the frequencies of the ORM1*2 allele and the ORM1 2 phenotype were found to be significantly increased in patients with different types of carcinomas. The results suggest that the ORM1 2 variant may influence the progression of cancer by being more immunosuppressive than the ORM1 1 variant. The relative risk for carcinoma in patients with the ORM1 2 type was 1.56 (95% confidence interval:1.16-2.09).

Experiences of the male partner in cervical and endometrial cancer--a prospective interview study.

This article focuses on social, psychological and sexual experiences of 47 men before their partner was treated for cervical or endometrial cancer and 1 year later. As a complement to the interviews the men completed a symptom check-list. Before initiation of treatment, a great majority of the men were in psychological crisis. The number of psychological symptoms decreased from the first to the last interview. Symptoms with psychosomatic character increased, however, considerably. In the endometrial group, several had intrapsychic problems, while interpersonal problems were more common in the cervical group. Both groups found it difficult to know how to behave and how to communicate with their partner, friends and acquaintances. A majority had nobody to whom they could speak honestly, and most did not obtain basic information about their partner's disease. The experiences of intercourse were much more negative after completed treatment and a majority described impaired sexual desire. Provided that the woman herself desires it, the coping and rehabilitation of the woman, the man and the couple would improve if the male were integrated in the care program from the moment the diagnosis of cancer is made.

Sex steroid hormones and receptors in relation to S-phase fraction and ploidy level in endometrial carcinoma.

Although endogenous hormones exert an effect on the proliferation of endometria adenocarcinoma, there also seems to be an autonomous proliferation of the malignant cells. Simultaneous measurement of endocrine and cell proliferation related variables in endometrial adenocarcinoma specimens are expected to increase the understanding of factors responsible for progression or regression of this form of cancer. Sixty patients with endometrial adenocarcinoma were examined. The following parameters were analysed: endogenous plasma concentration of oestradiol, oestrone, progesterone, androstenedione and testosterone; S-phase fraction (SPF) and ploidy level, by flow cytometry; oestrogen and progesterone receptors, by immunohistochemistry. The oestrogen receptor positive tumours had a lower S-phase fraction that receptor negative tumours (p < 0.05), but SPF was still under the mean for the whole group. ER positive tumours were all diploid, while progesterone receptors were found also in aneuploid tumours. The presence of PR did not relate to lower SPF, but in an earlier study increased progesterone concentration was found to relate to lower SPF, and the antiproliferative effect of progesterone was also seen in more malignant tumours.

Serum antibody responses against human papillomavirus in relation to tumor characteristics, response to treatment, and survival in carcinoma of the uterine cervix.

To investigate whether the serum antibody responses to human papillomavirus (HPV) in cervical carcinoma were related to the clinical and histopathological features of the tumors and how the antibody responses were affected by treatment, pretreatment serum samples from 66 patients with carcinoma of the cervix were studied for the presence of IgA or IgG responses against six defined HPV epitopes. Posttreatment serum samples were drawn from the same patients 2-24 months after initiation of treatment. There was no significant correlation between pretreatment level of any of the investigated antibodies and clinical stage or differentiation of tumor. For the IgA responses to the epitopes 245:16 and 245:18 in the E2 protein there was a significant correlation between an increased pretreatment antibody level and a shortened survival. A high pretreatment value of IgA against 245:16 was also associated with the absence of any complete response after therapy. The antibody levels declined dramatically after therapy for most of the antigens studied. However, this decline was seen both among the 53 patients with complete remission and among the 13 patients with remaining or progressive disease. Thus, the investigated serological responses were not useful as tumor markers, since patients with progressive, late-stage disease may fail to mount an antibody response to these proteins. However, pretreatment levels of the serological responses to the HPV epitopes 245:16 and 245:18 were associated with prognosis in cervical cancer.

Synergistic interaction between ORM1 and C3 types in disease associations.

In previous studies of orosomucoid (ORM) types and disease the ORM1 1 type has been found to be associated with sarcoidosis and other immunogenetic diseases, and the ORM 1 2 type with different types of carcinomas. We report significant associations between ORM1 and C3 types in sarcoidosis and breast cancer, but not in healthy individuals. The ORM1 1 and C3S variants in combination increased the risk of sarcoidosis, and the ORM1 2 and C3F variants together gave an increased risk of breast cancer. A probable mechanism may be that the ORM1 and C3 molecules modify the immune response by interacting with the lymphoid cell surface.

Antibodies against linear and conformational epitopes of human papillomavirus type 16 that independently associate with incident cervical cancer.

In a seroepidemiological study of incident cervical cancer, 94 cases and 188 population-based controls were used to evaluate the disease-association of IgG and IgA antibody responses against 6 human papillomavirus (HPV) type-16 antigens. Nine of the tested antibody responses were positively associated with cervical cancer, with odds ratios (ORs) ranging from 2.5 to 15.0. The antibody responses most strongly associated with cervical cancer were IgA against E6:10, an epitope derived from the carboxyterminal part of the HPV16 E6 [OR = 15.0, confidence intervals (CI) = 5.9-48.6], IgG against HPV16 virus-like particles (OR = 9.5, CI = 3.9-28.0) and IgG against the E1:19 epitope in the middle part of the E1 protein of HPV16 (OR = 7.7, C1 = 3.9-16.5). When the 3 serological assays that showed the strongest association with cervical cancer were combined, positivity for 2 assays was found among 52% of cases at an OR of 29.9. We conclude that antibody responses to several linear and conformational HPV epitopes are independently associated with cervical cancer and that combined analysis of several HPV antibody responses can result in better predictive values for HPV-associated cancer.

Steroid-hormone production and receptors in relation to ki-67, p53, s-phase fraction and ploidy in epithelial ovarian-tumors.

In this investigation, the in vitro production of progesterone and estradiol in ovarian tissues was studied for the first time in relation to the immunohistochemical expression of steroid hormone receptors, Ki-67, p53, DNA ploidy and S-phase fraction. Ovarian tissue from 44 women was examined. Steroid receptors were found more frequently in normal than in tumor ovaries. A substantial focal staining heterogeneity was demonstrated. Mucinous tumors were always progesterone receptor negative. Furthermore, the Ki-67 index was negatively correlated to the progesterone production of the tumor ovaries. Among the malignant tumors, all the high producers of progesterone expressing PR were low proliferating, diploid and p53-negative.

Progesterone and estradiol stimulate release of epidermal growth factor/transforming growth factor alpha by ovarian tumours in vitro.

Previous studies have demonstrated locally increased steroid production and release of EGF/TGF-alpha in ovarian carcinomas. The influence of added steroid hormones on EGF-like activity in ovarian tumours in vitro was investigated. Using radioreceptor assay, EGF-like activity was measured in media from incubations of postmenopausal ovaries, benign and malignant epithelial ovarian tumours from 27 patients. The 3-hour incubations were performed with and without addition of progesterone, testosterone or estradiol. Addition of progesterone and estradiol significantly increased the release of EGF/TGF-a from benign tumour tissue but did not stimulate release from control ovaries. A stimulating effect was also noted for malignant tumour tissue but the increase was not significant. Addition of EGF or IGF-1 did not affect the release of steroid hormones from ovarian tumours. A positive correlation between progesterone and EGF-like activity was found in incubation media of peritoneal fluid cells from cancer patients.

EGF/TGF-alpha and progesterone in urine of ovarian cancer patients.

EGF/TGF-alpha and progesterone were measured in the urine of 74 ovarian carcinoma patients, 21 postmenopausal women with non-gynecological disseminated cancer, 20 premenopausal and 20 postmenopausal controls. Radically operated women excreted significantly less EGF/TGF-alpha into urine than women with residual tumour mass. The patients who died from ovarian carcinoma had significantly higher concentrations of growth factor in urine than patients who were alive and disease-free at follow-up. The highest urinary concentrations were found in the premenopausal control group and among women with non-ovarian malignancies. A significant correlation between concentrations of progesterone and EGF/TGF-alpha in urine was noted.

Peritoneal fluid and HCG influence on steroid production from ovarian tumor tissue, in vitro.

Steroids are produced by malignant and benign epithelial ovarian tumor tissue in vitro, but the regulation is unknown. The effect of peritoneal fluid and beta-HCG on steroid production was analysed. Tissue from 17 malignant or benign epithelial ovarian tumors and 6 normal postmenopausal ovaries were incubated. In 11 cases tissue was incubated with and without addition of the patient's own peritoneal fluid (Part I). Tissue from 22 ovaries was incubated with and without HCG (100 IU/ml medium), (Part II). Furthermore, the release from tumorous and control ovaries of beta-HCG, progesterone, androstenedione and estradiol measured using radioimmunoassay (Part III). Peritoneal fluid stimulated the release of progesterone from both malignant and benign tissue and androstenedione or estradiol stimulated release from benign tissue (Part I). There was no stimulatory effect of HCG on steroid release from malignant tissue. HCG stimulated release of estradiol in benign tissue (Part II). All malignant tumors and 4 out of 6 benign tumors released beta-HCG (Part III). There seems to exist factors in peritoneal fluid which are able to stimulate steroid production from ovarian tumors.

A population-based seroepidemiological study of cervical cancer.

The epidemiology of cervical cancer indicates the presence of a sexually transmitted risk factor, attributable at least in part to infection with human papillomavirus (HPV) type 16 or 18. We performed a seroepidemiological study of HPV and cervical cancer in the counties of Västerbotten and Norrbotten in Northern Sweden, a low-risk area for cervical cancer. Sera from 94 cases of incident cervical cancer were matched against 188 age- and sex-matched controls derived from a population-based blood bank. IgG and IgA antibodies were measured against a panel of 12 antigens derived from HPV types 6, 11, 16, or 18, as well as against Herpes simplex virus type 1 and 2, Chlamydia trachomatis, cytomegalovirus, Epstein-Barr virus, and bovine papillomavirus. Significantly increased relative risks (RRs) were found for IgG to HPV 16- or 18-derived antigens from the L1 (RR = 3.1), E2 (RRs = 2.8 and 9.2), and E7 (RRs = 3.8 and 2.7) open reading frames and for IgA to HPV 16-derived antigens from the E2 (RR = 3.3) and E6 (RR = 2.7) open reading frames. The highest RR (9.2, confidence intervals 4.4-19.4) was associated with IgG to an HPV 18 E2 antigen. Antibodies against cytomegalovirus, Herpes simplex virus type 2, Epstein-Barr virus, or bovine papillomavirus were, on their own, not significantly associated with cervical cancer, but seropositivity against multiple infections was associated with a successively increased relative risk. An increased risk was also found for IgG to Chlamydia trachomatis (RR = 1.7, confidence interval = 1.0-2.7). The results indicate that several HPV antibodies are strongly associated with cervical cancer, providing further seroepidemiological support for an etiological role of HPV in cervical cancer.

Release of epidermal growth-factor transforming growth-factor-alpha by ovarian-tumors in-vitro.

EGF-like activity was measured in media from 3-hour incubations of ovarian tissue from 27 patients with normal postmenopausal ovaries, malignant or benign epithelial tumours. EGF-like activity in the medium was measured using a radioreceptor assay. Malignant tumour tissue released significantly more EGF/TGF-alpha than benign tissues and aneuploid carcinomas more than diploid carcinomas. In spite of varying amounts of tumour cells there was a strong correlation in EGF/TCF-alpha release from the different tissue samples of each patient suggesting paracrine rather than autocrine regulation. The level of EGF-like activity may be a feature of the patient rather than of the tumour cells.